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MEDICAL SCIENCES (2268 journals)            First | 1 2 3 4 5 6 7 8 | Last

Showing 201 - 400 of 3562 Journals sorted alphabetically
Audiology - Communication Research     Open Access   (Followers: 10)
Auris Nasus Larynx     Full-text available via subscription  
Australasian Journal of Ultrasound in Medicine (AJUM)     Hybrid Journal  
Australian Coeliac     Full-text available via subscription   (Followers: 1)
Australian Family Physician     Full-text available via subscription   (Followers: 3)
Australian Journal of Medical Science     Full-text available via subscription   (Followers: 2)
Autopsy and Case Reports     Open Access  
Avicenna     Open Access   (Followers: 3)
Avicenna Journal of Clinical Medicine     Open Access  
Avicenna Journal of Medicine     Open Access   (Followers: 1)
Bangabandhu Sheikh Mujib Medical University Journal     Open Access   (Followers: 1)
Bangladesh Journal of Anatomy     Open Access   (Followers: 2)
Bangladesh Journal of Bioethics     Open Access  
Bangladesh Journal of Medical Biochemistry     Open Access   (Followers: 4)
Bangladesh Journal of Medical Education     Open Access   (Followers: 2)
Bangladesh Journal of Medical Microbiology     Open Access   (Followers: 4)
Bangladesh Journal of Medical Physics     Open Access   (Followers: 1)
Bangladesh Journal of Medical Science     Open Access  
Bangladesh Journal of Medicine     Open Access   (Followers: 1)
Bangladesh Journal of Physiology and Pharmacology     Open Access  
Bangladesh Journal of Scientific Research     Open Access   (Followers: 1)
Bangladesh Medical Journal     Open Access  
Bangladesh Medical Journal Khulna     Open Access  
Basal Ganglia     Hybrid Journal  
Basic Sciences of Medicine     Open Access   (Followers: 2)
Batı Karadeniz Tıp Dergisi / Medical Journal of Western Black Sea     Open Access  
Baylor University Medical Center Proceedings     Hybrid Journal  
BBA Clinical     Open Access  
BC Medical Journal     Free  
Benha Medical Journal     Open Access  
Beni-Suef University Journal of Basic and Applied Sciences     Open Access   (Followers: 4)
Bijblijven     Hybrid Journal  
Bijzijn     Hybrid Journal   (Followers: 1)
Bijzijn XL     Hybrid Journal  
Bio-Algorithms and Med-Systems     Hybrid Journal   (Followers: 2)
BioDiscovery     Open Access   (Followers: 2)
Bioelectromagnetics     Hybrid Journal   (Followers: 2)
Bioelectronic Medicine     Open Access   (Followers: 1)
Bioengineering & Translational Medicine     Open Access  
Bioethics     Hybrid Journal   (Followers: 17)
Bioethics Research Notes     Full-text available via subscription   (Followers: 14)
Biologics in Therapy     Open Access  
Biology of Sex Differences     Open Access   (Followers: 2)
Biomarker Research     Open Access   (Followers: 3)
Biomarkers in Medicine     Hybrid Journal   (Followers: 2)
BioMed Research International     Open Access   (Followers: 4)
Biomédica     Open Access  
Biomedical & Life Sciences Collection     Full-text available via subscription   (Followers: 3)
Biomedical and Biotechnology Research Journal     Open Access   (Followers: 1)
Biomedical Engineering     Hybrid Journal   (Followers: 17)
Biomedical Engineering and Computational Biology     Open Access   (Followers: 13)
Biomedical Engineering Letters     Hybrid Journal   (Followers: 6)
Biomedical Engineering Research     Open Access   (Followers: 7)
Biomedical Informatics Insights     Open Access   (Followers: 8)
Biomedical Journal     Open Access   (Followers: 3)
Biomedical Materials     Hybrid Journal   (Followers: 7)
Biomedical Microdevices     Hybrid Journal   (Followers: 8)
Biomedical Optics Express     Open Access   (Followers: 6)
Biomedical Photonics     Open Access  
Biomedical Reports     Full-text available via subscription  
Biomedical Research Reports     Full-text available via subscription   (Followers: 2)
Biomedical Safety & Standards     Full-text available via subscription   (Followers: 8)
Biomedical Science and Engineering     Open Access   (Followers: 7)
BioMedicine     Open Access  
Biomedicine Hub     Open Access  
Biomedicines     Open Access   (Followers: 1)
Biomedika     Open Access  
Biomolecular and Health Science Journal     Open Access   (Followers: 1)
Biophysics Reports     Open Access  
BioPsychoSocial Medicine     Open Access   (Followers: 8)
Biosalud     Open Access   (Followers: 1)
Biostatistics & Epidemiology     Hybrid Journal   (Followers: 1)
Birat Journal of Health Sciences     Open Access  
BIRDEM Medical Journal     Open Access   (Followers: 1)
Birth Defects Research     Hybrid Journal  
Birth Defects Research Part A : Clinical and Molecular Teratology     Hybrid Journal   (Followers: 3)
Birth Defects Research Part C : Embryo Today : Reviews     Hybrid Journal  
BJR|Open     Open Access   (Followers: 1)
BJS Open     Open Access   (Followers: 1)
Black Sea Journal of Health Science     Open Access  
BLDE University Journal of Health Sciences     Open Access  
Blickpunkt Medizin     Hybrid Journal  
BMC Biomedical Engineering     Open Access  
BMC Medical Ethics     Open Access   (Followers: 21)
BMC Medical Research Methodology     Open Access   (Followers: 9)
BMC Medicine     Open Access   (Followers: 13)
BMC Obesity     Open Access   (Followers: 8)
BMC Proceedings     Full-text available via subscription   (Followers: 1)
BMC Research Notes     Open Access   (Followers: 4)
BMC Sports Science, Medicine and Rehabilitation     Open Access   (Followers: 34)
BMH Medical Journal     Open Access   (Followers: 2)
BMI Journal : Bariátrica & Metabólica Iberoamericana     Open Access  
BMJ     Hybrid Journal   (Followers: 1751)
BMJ Case Reports     Hybrid Journal   (Followers: 26)
BMJ Evidence-Based Medicine     Hybrid Journal   (Followers: 3)
BMJ Global Health     Open Access   (Followers: 3)
BMJ Innovations     Hybrid Journal   (Followers: 6)
BMJ Leader     Hybrid Journal  
BMJ Open     Open Access   (Followers: 42)
BMJ Open Quality     Open Access   (Followers: 19)
BMJ Open Science     Open Access   (Followers: 1)
BMJ Sexual & Reproductive Health     Hybrid Journal   (Followers: 2)
BMJ Surgery, Interventions, & Health Technologies     Open Access  
Bodine Journal     Open Access  
Boletín del Consejo Académico de Ética en Medicina     Open Access  
Boletín del ECEMC     Open Access  
Boletin Médico de Postgrado     Open Access  
Boletín Médico del Hospital Infantil de México     Open Access  
Bone     Hybrid Journal   (Followers: 18)
Bone and Tissue Regeneration Insights     Open Access   (Followers: 2)
Bone Marrow Research     Open Access   (Followers: 2)
Bone Reports     Open Access  
Bosnian Journal of Basic Medical Sciences     Open Access  
Bozok Tıp Dergisi / Bozok Medical Journal     Open Access  
Brachytherapy     Full-text available via subscription   (Followers: 6)
Brain and Development     Full-text available via subscription   (Followers: 5)
Brain Connectivity     Hybrid Journal   (Followers: 5)
Brain Impairment     Full-text available via subscription   (Followers: 2)
Brazilian Journal of Medical and Biological Research     Open Access  
Brazilian Journal of Medicine and Human Health     Open Access  
Brazilian Journal of Pain (BrJP)     Open Access  
Brazilian Journal of Physical Therapy     Open Access   (Followers: 1)
Breastfeeding Review     Full-text available via subscription   (Followers: 18)
British Journal of Biomedical Science     Full-text available via subscription   (Followers: 7)
British Journal of General Practice     Full-text available via subscription   (Followers: 38)
British Journal of Hospital Medicine     Full-text available via subscription   (Followers: 16)
British Medical Bulletin     Hybrid Journal   (Followers: 6)
Buddhachinaraj Medical Journal     Open Access  
Bulletin Amades     Open Access  
Bulletin de la Société de pathologie exotique     Hybrid Journal   (Followers: 1)
Bulletin of Legal Medicine     Open Access  
Bulletin of Medical Sciences     Open Access  
Bulletin of the History of Medicine     Full-text available via subscription   (Followers: 18)
Bulletin of the Menninger Clinic     Full-text available via subscription  
Bulletin of The Royal College of Surgeons of England     Free  
Bulletin of the Scientific Centre for Expert Evaluation of Medicinal Products     Open Access  
Bundesgesundheitsblatt - Gesundheitsforschung - Gesundheitsschutz     Hybrid Journal   (Followers: 6)
Burapha Journal of Medicine     Open Access  
Burns     Hybrid Journal   (Followers: 10)
Cadernos de Naturologia e Terapias Complementares     Open Access   (Followers: 1)
Calcified Tissue International     Hybrid Journal   (Followers: 2)
Canadian Bulletin of Medical History     Hybrid Journal  
Canadian Family Physician     Partially Free   (Followers: 13)
Canadian Journal of Pain     Open Access   (Followers: 2)
Canadian Journal of Rural Medicine     Full-text available via subscription   (Followers: 1)
Canadian Medical Association Journal     Open Access   (Followers: 17)
Canadian Medical Education Journal     Open Access   (Followers: 10)
Canadian Prosthetics & Orthotics Journal     Open Access  
Cannabis and Cannabinoid Research     Hybrid Journal   (Followers: 1)
Cardiac Electrophysiology Clinics     Full-text available via subscription   (Followers: 1)
Care Management Journals     Hybrid Journal   (Followers: 5)
Case Reports     Open Access  
Case Reports in Acute Medicine     Open Access  
Case Reports in Clinical Medicine     Open Access   (Followers: 1)
Case Reports in Clinical Nutrition     Open Access   (Followers: 1)
Case Reports in Medicine     Open Access   (Followers: 2)
Case Reports in Transplantation     Open Access  
Case Reports in Vascular Medicine     Open Access  
Case Reports in Women's Health     Open Access   (Followers: 4)
Case Study and Case Report     Open Access   (Followers: 5)
CBU International Conference Proceedings     Open Access   (Followers: 3)
Cell & Bioscience     Open Access   (Followers: 6)
Cell Adhesion & Migration     Open Access   (Followers: 9)
Cell and Molecular Response to Stress     Full-text available via subscription   (Followers: 2)
Cell and Tissue Transplantation and Therapy     Open Access   (Followers: 2)
Cell Cycle     Full-text available via subscription   (Followers: 6)
Cell Death and Differentiation     Hybrid Journal   (Followers: 7)
Cell Death Discovery     Open Access   (Followers: 1)
Cell Health and Cytoskeleton     Open Access   (Followers: 1)
Cell Medicine     Open Access   (Followers: 6)
Cell Research     Hybrid Journal   (Followers: 8)
Cell Transplantation     Open Access   (Followers: 4)
CEN Case Reports     Hybrid Journal  
Central African Journal of Medicine     Full-text available via subscription  
Ceylon Journal of Medical Science     Open Access  
Ceylon Medical Journal     Open Access  
Chattagram Maa-O-Shishu Hospital Medical College Journal     Open Access  
Chiang Mai Medical Journal     Open Access  
ChiangRai Medical Journal     Open Access  
Chimerism     Full-text available via subscription  
Chinese Journal of Integrative Medicine     Hybrid Journal   (Followers: 3)
Chinese Journal of Natural Medicines     Full-text available via subscription   (Followers: 1)
Chinese Medical Journal     Open Access   (Followers: 10)
Chinese Medical Record English Edition     Hybrid Journal  
Chinese Medical Sciences Journal     Full-text available via subscription   (Followers: 2)
Chinese Medicine     Open Access   (Followers: 2)
Chinese Medicine     Open Access   (Followers: 4)
Chisholm Health Ethics Bulletin     Full-text available via subscription   (Followers: 1)
CHRISMED Journal of Health and Research     Open Access   (Followers: 2)
Christian Journal for Global Health     Open Access  
Chronic Diseases and Translational Medicine     Open Access  
Chronic Illness     Hybrid Journal   (Followers: 6)
Chronic Wound Care Management and Research     Open Access   (Followers: 4)
Chronobiology International     Hybrid Journal   (Followers: 3)
ChronoPhysiology and Therapy     Open Access  
Chulalongkorn Medical Bulletin     Open Access  
Chulalongkorn Medical Journal     Open Access  
Ciencia e Innovación en Salud     Open Access  
Ciencia e Investigación Medico Estudiantil Latinoamericana     Open Access  
Ciencias Clínicas     Open Access  

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Bone Reports
Journal Prestige (SJR): 0.354
Citation Impact (citeScore): 1
Number of Followers: 0  

  This is an Open Access Journal Open Access journal
ISSN (Online) 2352-1872
Published by Elsevier Homepage  [3147 journals]
  • Treadmill running and targeted tibial loading differentially improve bone
           mass in mice

    • Abstract: Publication date: June 2019Source: Bone Reports, Volume 10Author(s): Alycia G. Berman, Madicyn J. Hinton, Joseph M. WallaceAbstractTreadmill running and tibial loading are two common modalities used to assess the role of mechanical stimulation on the skeleton preclinically. The primary advantage of treadmill running is its physiological relevance. However, the applied load is complex and multiaxial, with observed results influenced by cardiovascular and musculoskeletal effects. In contrast, with tibial loading, a direct uniaxial load is applied to a single bone, providing the advantage of greater control but with less physiological relevance. Despite the importance and wide-spread use of both modalities, direct comparisons are lacking. In this study, we compared effects of targeted tibial loading, treadmill running, and their combination on cancellous and cortical architecture in a murine model. We show that tibial loading and treadmill running differentially improve bone mass, with tibial loading resulting in thicker trabeculae and increased cortical mass, and exercise resulting in greater number of trabeculae and no cortical mass-based effects. Combination of the modalities resulted in an additive response. These data suggest that tibial loading and exercise may improve mass differentially.
       
  • Bruton's tyrosine kinase (Btk) inhibitor tirabrutinib suppresses
           osteoclastic bone resorption

    • Abstract: Publication date: June 2019Source: Bone Reports, Volume 10Author(s): Yuko Ariza, Masayuki Murata, Yoshiko Ueda, Toshio YoshizawaAbstractOsteoclasts are responsible for bone erosion in osteoporosis and rheumatoid arthritis (RA). Both Btk and Tec kinases have essential functions in osteoclast differentiation. Tirabrutinib is a highly potent and dual oral Btk/Tec inhibitor with an IC50 in the nmol/L range and significantly inhibits the M-CSF and RANKL-driven osteoclast differentiation. It was hypothesized that the in vitro activity of tirabrutinib could be demonstrated in mice bone resorption model. The RANKL model studies show that tirabrutinib significantly suppressed bone loss with the inhibition of serum TRAPCP5b and urinary CTX-1. Bone Mineral Density (BMD) loss in tirabrutinib-treated mice was 55% (P 
       
  • Targeted sequencing of DCSTAMP in familial Paget's disease of
           bone

    • Abstract: Publication date: June 2019Source: Bone Reports, Volume 10Author(s): M.A. Sultana, N.J. Pavlos, Lynley Ward, J.P. Walsh, S.L. ReaAbstractPaget's disease of bone (PDB) has a strong genetic component. Variants in SQSTM1 are found in up to 40% of patients with a family history of the disease, where a pattern of autosomal dominance with incomplete penetrance is apparent. By contrast, SQSTM1 variants are only found in up to 10% of patients with sporadic disease. It has been hypothesised that the remaining genetic susceptibility to PDB, particularly in familial cases, could be explained by rare genetic variants in loci previously identified by Genome Wide Association Studies. It is likely that polygenic factors are involved in many individuals. In this study we utilised whole exome sequencing to investigate predisposing genetic factors in an unsolved PDB kindred and identified a c.1189C > T p.L397F variant in DC-STAMP, also known as TM7SF4, that co-segregated with disease. DCSTAMP was identified as a gene of interest in PDB following Genome Wide Association Studies and has been previously shown to play critical roles in osteoclast fusion. The variant we identified has also been reported in association with PDB in a French-Canadian cohort however the significance of this variant was inconclusive. Targeted screening of DCSTAMP in our familial cohort of PDB patients revealed an additional 8 variants; however we did not find a significant association between any of these, including p.L397F, with PDB. Osteoclastogenesis assays from the affected proband and his unaffected brother demonstrated an increase in osteoclast number and nucleation, consistent with the pagetic phenotype. In converse to other established Paget's associated genetic variations such as SQSTM1, TNFRSF11A and OPTN, expression of the mutant DC-STAMP protein attenuated the activation of transcription factors NFκB and AP-1 when exogenously expressed. We found that the p.L397F variant did not influence the subcellular localization of the protein. Based on these findings we conclude that genetic variation in DCSTAMP is not a significant predisposing factor in our specific cohort of PDB patients and the p.L397F variant is unlikely to be a contributing factor in PDB pathogenesis.
       
  • Insulin Receptor deletion in S100a4-lineage cells accelerates age-related
           bone loss

    • Abstract: Publication date: June 2019Source: Bone Reports, Volume 10Author(s): Valentina Studentsova, Emma Knapp, Alayna E. LoiselleAbstractType I and Type II Diabetes dramatically impair skeletal health. Altered Insulin Receptor (IR) signaling is a common feature of both diseases, and insulin has potent bone anabolic functions. Several previous studies have demonstrated that loss of IR in bone cells results in disrupted bone homeostasis during early post-natal growth. Here we have deleted IR in S100a4-lineage cells (IRcKOS100a4) and assessed the effects on bone homeostasis in both young (15 weeks) and older adult (48 weeks) mice. S100a4-Cre has previously been shown to target the perichondrium during bone development, and here we show that S100a4 is expressed by adult trabecular and cortical bone cells, and that S100a4-Cre effectively targets adult bone, resulting in efficient deletion of IRβ. Deletion of IRβ in S100a4-lineage cells does not affect initial bone acquisition or homeostasis with no changes in cortical, trabecular or mechanical properties at 15-weeks of age, relative to wild type (WT) littermates. However, by 48-weeks of age, IRcKOS100a4 mice display substantial declines in trabecular bone volume, bone volume fraction and torsional rigidity, relative to age-matched WT controls. This work establishes the utility of using S100a4-cre to target bone and demonstrates that IRβ in S100a4-lineage cells is required for maintenance of bone homeostasis in adult mice.
       
  • Regulation of cytoskeleton and adhesion signaling in osteoclasts by
           tetraspanin CD82

    • Abstract: Publication date: June 2019Source: Bone Reports, Volume 10Author(s): Alexis Bergsma, Sourik S. Ganguly, Mollie E. Wiegand, Daniel Dick, Bart O. Williams, Cindy K. MirantiAbstractWe used a myeloid-specific Cre to conditionally delete CD82 in mouse osteoclasts and their precursors. In contrast to global loss of CD82 (gKO), conditional loss of CD82 (cKO) in osteoclasts does not affect cortical bone, osteoblasts, or adipocytes. CD82 loss results in greater trabecular volume and trabecular number but reduced trabecular space in 6-month old male mice. Though this trend is present in females it did not reach significance; whereas there was an increase in osteoclast numbers and eroded surface area only in female cKO mice. In vitro, there is an increase in osteoclast fusion and defects in actin assembly in both gKO and cKO mice, irrespective of sex. This is accompanied by altered osteoclast morphology and decreased release of CTX in vitro. Integrin αvβ3 expression is reduced, while integrin β1 is increased. Signaling to Src, Syk, and Vav are also compromised. We further discovered that expression of Clec2 and its ligand, Podoplanin, molecules that also signal to Syk and Vav, are increased in differentiated osteoclasts. Loss of CD82 reduces their expression. Thus, CD82 is required for correct assembly of the cytoskeleton and to limit osteoclast fusion, both needed for normal osteoclast function.
       
  • Rapid onset of hypercalcemia from high-grade lymphoma in the setting of
           HIV-related immune reconstitution inflammatory syndrome

    • Abstract: Publication date: June 2019Source: Bone Reports, Volume 10Author(s): Stephanie J. Kim, Michael J. Peluso, Yongmei Wang, Daniel Bikle, Dolores Shoback, Sarah KimAbstractHypercalcemia in HIV patients has been previously reported, but 1,25-(OH)2 vitamin D-mediated hypercalcemia, due to increased activity of extrarenal 1-alpha hydroxylase, is rarely described with HIV-related infections or malignancies. We describe a case of 1,25-(OH)2 vitamin D-mediated hypercalcemia in a patient presenting with progressive cognitive decline and weakness. Initial evaluation revealed a new diagnosis of HIV, for which he was started on antiretroviral therapy (ART). He was also noted to have mild asymptomatic hypocalcemia, likely from his acute illness and malnutrition, which was not further investigated at the time. While the patient's mental status initially improved with ART, he became progressively delirious and was found to be hypercalcemic approximately 4 weeks after the initiation of ART. Possible etiologies for hypercalcemia were vigorously evaluated, including granulomatous disease, infection, and malignancy, in the setting of suspected immune reconstitution inflammatory syndrome (IRIS), due to recent initiation of ART. Infectious workup was unrevealing, but computed tomography (CT) of the chest, abdomen, and pelvis revealed new extensive diffuse lymphadenopathy and hepatomegaly, not present on admission studies. Cytology and flow cytometry of a liver biopsy specimen revealed CD10 positive high-grade B-cell lymphoma. Chemotherapy was not pursued due to poor performance status. Over the next week, spontaneous tumor lysis developed, and the patient expired. Postmortem, his 1,25-(OH)2 vitamin D level returned as markedly elevated. Immunohistochemical staining of his liver biopsy tissue showed strong expression of CYP27B1.1,25-(OH)2 vitamin D-mediated hypercalcemia is uncommon in a patient with newly diagnosed HIV and, in this case, was likely due to IRIS unmasking an underlying high-grade lymphoma and restoration of immune function (including T-cells and cytokine production). This case emphasizes the importance of including aggressive lymphomas, capable of progressing over days to weeks, in the evaluation of hypercalcemia in HIV patients at risk for developing IRIS and the rapid dynamic changes in mineral homeostasis that can occur with such an aggressive tumor in an immunocompromised host.
       
  • Brown tumor diagnosed three years after parathyroidectomy in a patient
           with nail-patella syndrome: A case report

    • Abstract: Publication date: June 2019Source: Bone Reports, Volume 10Author(s): Naoya Toriu, Toshiharu Ueno, Hiroki Mizuno, Akinari Sekine, Noriko Hayami, Rikako Hiramatsu, Keiichi Sumida, Masayuki Yamanouchi, Eiko Hasegawa, Tatsuya Suwabe, Junichi Hoshino, Naoki Sawa, Kenmei Takaichi, Takeshi Fujii, Tomoka Hasegawa, Norio Amizuka, Motoko Yanagita, Yoshifumi UbaraAbstractWe report a 48-year-old Japanese man with a brown tumor of the right distal tibia. At the age of 25 years, hemodialysis was initiated due to nail-patella syndrome. Severe secondary hyperparathyroidism and osteoporosis progressed over time, so parathyroidectomy was performed at age 45. Spontaneous fracture of the right distal tibia occurred suddenly at age 48. Imaging studies revealed a bone tumor-like lesion and surgery was performed. The resected specimen was a brown mass consisting of multinucleated giant cells on a fibrous tissue background, and these findings were consistent with a diagnosis of brown tumor. Immunohistochemistry revealed that multinucleated giant cells near areas of bone matrix were positive for tartrate-resistant acid phosphatase and cathepsin K, but the majority of the giant cells in the lesion were negative for these markers. Even after parathyroidectomy, brown tumor should be considered in the differential diagnosis of bone tumor-like lesions in patients on long-term dialysis. This case suggests that osteoclast activation may not contribute to development of brown tumors, although these lesions are generally considered to arise from subperiosteal bone resorption related to osteoclast overactivity in patients with hyperparathyroidism.
       
  • Longitudinal changes in bone mineral density, bone mineral content and
           bone area at the lumbar spine and hip in postmenopausal women, and the
           influence of abdominal aortic calcification

    • Abstract: Publication date: June 2019Source: Bone Reports, Volume 10Author(s): Sarah M. Bristow, Greg D. Gamble, Anne M. Horne, Ian R. ReidAbstractLongitudinal studies often report that spine bone mineral density (BMD), measured by DXA, is stable in older adults, which has been attributed to osteophyte development and the presence of aortic calcification. A decline in projected spine area as a result of loss of intervertebral disc height might also contribute to higher BMD. We utilised data from 297 postmenopausal women (mean 73 years) who had DXA measurements of the lumbar spine, total hip and femoral neck 5 years apart, and abdominal aortic calcification scoring from vertebral morphometry. BMD declined by −4.4% at the total hip and −3.9% at the femoral neck (p 
       
  • Activation of cancer-related and mitogen-activated protein kinase
           signaling pathways in human mature osteoblasts isolated from patients with
           type 2 diabetes

    • Abstract: Publication date: June 2019Source: Bone Reports, Volume 10Author(s): Tomoyuki Kuroiwa, Megumi Matsumoto, Ryuji Kato, Akimoto Nimura, Toshitaka Yoshii, Atsushi Okawa, Koji FujitaAbstractDiabetes mellitus is a disease of glucose metabolism, and it adversely affects bone metabolism and increases the risk of cancer development. Previously, we reported a method for the direct isolation of human mature osteoblasts and indicated that osteoblasts were associated with type 2 diabetes mellitus-related signaling pathways. In addition, a recent report suggested that osteoblasts are involved in glucose metabolism. Thus, we sought to examine the effects of diabetes on osteoblast signaling in vivo. We recruited eight patients with type 2 diabetes and eight non-diabetic individuals. We isolated human mature osteoblasts from the resected femoral heads during orthopaedic surgery and extracted their RNA. We compared the gene expression between the two groups by RNA microarray and pathway analyses. Microarray analysis showed significant differences in 885 of 19,463 genes between the two groups (p 
       
  • Short-term intermittent PTH 1–34 administration and bone marrow blood
           vessel ossification in Mature and Middle-Aged C57BL/6 mice

    • Abstract: Publication date: June 2019Source: Bone Reports, Volume 10Author(s): Seungyong Lee, Rhonda D. PrisbyAbstractIntermittent parathyroid hormone (PTH) administration augments bone and progressive bone marrow blood vessel (BMBV) ossification occurs with advancing age. Since intermittent PTH administration augments bone, it may also serve to increase BMBV ossification. We assessed the influence of 5- and 10-days of intermittent PTH 1–34 administration on trabecular and cortical bone and BMBV ossification in mature (6–8 mon; n = 30) and middle-aged (10–12 mon; n = 30) male and female C57BL/6 mice. Mice were divided accordingly: control (CON) and 5-days (5dPTH) and 10-days (10dPTH) of PTH. Mice were given PBS (50 μl) or PTH 1–34 (43 μg/kg/d) for 5- and 10-consecutive days. Trabecular bone microarchitecture (i.e., BV/TV [%], Tb.Th [μm], Tb.N [/mm], and Tb.Sp [μm]) was assessed in the distal femoral metaphysis and cortical bone parameters (i.e., Ct.Th [μm] and CSMI [mm4]) at the femoral mid-shaft. BMBV ossification (i.e., ossified vessel volume [OsVV, %] and ossified vessel thickness [OsV.Th, μm]) was assessed in the medullary cavity of the femoral shaft. All parameters were determined by μCT. At this sample size, no gender-related differences were observed so female and male data were pooled. There were no main effects nor interactions for trabecular microarchitecture and Ct.Th. However, CSMI was larger (p 
       
  • Bone structure is largely unchanged in growing male CD-1 mice fed lower
           levels of vitamin D and calcium than in the AIN-93G diet

    • Abstract: Publication date: June 2019Source: Bone Reports, Volume 10Author(s): C. Brent Wakefield, Jenalyn L. Yumol, Sandra M. Sacco, Philip J. Sullivan, Elena M. Comelli, Wendy E. WardAbstractBackgroundCalcium (Ca) and vitamin D (vit D) in the AIN-93G diet may be higher than required for healthy bone development, and mask the potential benefit of a dietary intervention.ObjectiveThe objective was to determine if lower levels of Ca and vit D than is present in the AIN-93G diet supports bone development in growing male CD-1 mice.MethodsWeanling male CD-1 mice were randomized to modified AIN-93G diets containing either 100 (Trial 1) or 400 (Trial 2) IU vit D/kg diet within one of two or three Ca levels (0.35, 0.30, or 0.25% Ca diet in Trial 1 or 0.35% or 0.25% in Trial 2) or the AIN-93G diet (1000 IU/kg vit D and 0.5% Ca) from weaning to 4 months of age (n = 13–15/group). At 2 and 4 months of age, BMD and structural properties of the tibia were analyzed in vivo. Structure of lumbar vertebra 4 (L4) and mandible, and femur strength were assessed ex vivo at age 4 months.ResultsThere were no differences in tibia, L4, and mandible structure between the AIN-93G diet and the 0.35% Ca groups at either vit D level. A few structure outcomes were compromised with the 0.25 and/or 0.3% Ca diets but there were no differences in femur biomechanical strength compared to AIN-93G group in either Trial.ConclusionAt 400 or 100 IU vit D/kg diet, Ca can be lowered to 0.35% without detriment to BMD or bone structure while bone strength is not altered at lower Ca (0.25%) compared to CD-1 mice fed AIN-93G diet. Because of genetic variation in CD-1 mice among different breeding facilities, results in CD-1 mice from other facilities may differ from the present study.
       
  • Ectopic expression of Klotho in fibroblast growth factor 23
           (FGF23)-producing tumors that cause tumor-induced rickets/osteomalacia
           (TIO)

    • Abstract: Publication date: June 2019Source: Bone Reports, Volume 10Author(s): Yuka Kinoshita, Yuichi Takashi, Nobuaki Ito, Shiro Ikegawa, Hiroyuki Mano, Tetsuo Ushiku, Masashi Fukayama, Masaomi Nangaku, Seiji FukumotoAbstractTumor-induced rickets/osteomalacia (TIO) is a rare paraneoplastic syndrome caused by tumors that ectopically express fibroblast growth factor 23 (FGF23). FGF23 is a bone-derived hormone that regulates serum phosphate concentrations. Patients with TIO develop hypophosphatemic rickets/osteomalacia due to FGF23 excess and suffer from symptoms such as leg deformities, bone pain, skeletal muscle myopathy, and multiple fractures/pseudofractures. Usually, successful surgical removal of the causative tumors normalizes serum FGF23 and phosphate concentrations in patients with TIO. Most FGF23-producing tumors associated with TIO are histologically called phosphaturic mesenchymal tumor, mixed connective tissue variant (PMTMCT). The precise mechanism by which these tumors ectopically overproduce FGF23 outside of bone is yet to be clarified. Therefore, we performed an RNA sequencing analysis of a PMTMCT that was found in the left parotid gland of a patient with TIO. Among the upregulated genes, we focused on Klotho, the protein product of which is a single pass transmembrane protein that works along with an FGF receptor 1c as a receptor complex for FGF23. Subsequent histological analysis confirmed the ectopic expression of Klotho in other PMTMCTs. From these results, we assume that the ectopic expression of Klotho in PTMMCTs enables a positive feedback loop in FGF23 production via the activation of FGF receptor 1c and exacerbates disease manifestations in TIO.
       
  • The long-term impact of very preterm birth on adult bone mineral density

    • Abstract: Publication date: June 2019Source: Bone Reports, Volume 10Author(s): Li Feng Xie, Nathalie Alos, Anik Cloutier, Chanel Béland, Josée Dubois, Anne Monique Nuyt, Thuy Mai LuuAbstractIntroductionPreterm infants are at increased risk of osteopenia of prematurity due to insufficient bone mineral accretion. Data on long term effects of prematurity on bone health are conflicting. This study aimed to compare bone mineral density (BMD) in young adults born very preterm and full-term controls and to examine factors associated with long-term bone health.MethodsThis observational cross-sectional study enrolled 101 young adults (18–29 years) born
       
  • Impact of frequent apheresis blood donation on bone density: A
           prospective, longitudinal, randomized, controlled trial

    • Abstract: Publication date: June 2019Source: Bone Reports, Volume 10Author(s): Walter Bialkowski, Robert D. Blank, Cheng Zheng, Jerome L. Gottschall, Paula E. PapanekAbstractBackgroundBlood for transfusion is lifesaving and essential to many elements of modern medical practice. The global blood supply relies on volunteer blood donors. Apheresis is increasingly used to collect blood and requires anticoagulant to prevent extracorporeal coagulation. Citrate, the standard apheresis anticoagulant, chelates ionized calcium with consequent perturbations of serum calcium, parathyroid hormone, vitamin D, and markers of bone remodeling in donors. Cross-sectional studies of bone mineral density (BMD) among apheresis donors exhibit conflicting results.MethodsThe longitudinal, randomized, controlled ALTRUYST trial (NCT02655055) was undertaken to determine whether BMD declined following high frequency apheresis blood donation over 1 year. The study was powered at 80% to detect the primary outcome of a 3% decline in BMD. Subjects new to apheresis agreed to make ≥20 apheresis donations in a one-year period and were randomized to treatment (high frequency apheresis) or control (no apheresis). Dual-energy x-ray absorptiometry was performed before and after participation. Two-sided t-test and multivariable logistic regression were used to assess outcomes.FindingsMean lumbar spine BMD did not change during the study among control donors (−0.002 g/cm2, 95%CI [−0.020, 0.016], p = 0.78), or among donors in the apheresis arm (mean change = 0.007 g/cm2, 95%CI [−0.005, 0.018], p = 0.24). Mean total hip BMD did not change for control donors (mean change = 0.002 g/cm2, 95%CI [−0.006, 0.009], p = 0.63) or apheresis donors (−0.004 g/cm2, 95%CI [−0.10, 0.002], p = 0.16). Tests for differences in proportions of donors with change in BMD exceeding the least significant change at the lumbar spine in either a positive [8 apheresis (31%), 4 control (27%), p = 0.78] or negative direction [4 apheresis (15%), 5 control (33%)] were statistically non-significant (p = 0.18). Proportional increases [0 apheresis (0%), 1 control (7%), p = 0.18] and decreases [3 apheresis (12%), 1 control (14%)] were also not significantly different at the total hip (p = 0.61).InterpretationALTRUYST is the first longitudinal trial to demonstrate that apheresis blood collection guidelines in the United States adequately protect the skeletal health of male volunteer blood donors.FundingMarquette University and the BloodCenter Research Foundation.
       
  • Relaxin 2 carried by magnetically directed liposomes accelerates rat
           midpalatal suture expansion and subsequent new bone formation

    • Abstract: Publication date: June 2019Source: Bone Reports, Volume 10Author(s): Hiroyuki Kamimoto, Yukiho Kobayashi, Keiji MoriyamaAbstractRelaxin (RLN) is an insulin-like peptide hormone that enables softening and lengthening of the pubic symphysis and uterine cervix. Here, we analyzed the effects of RLN2 on the expansion of rat midpalatal suture (MPS) using a magnetically directed liposome-based drug delivery system. Thirty-six male rats were divided into three groups: control (MPS was not expanded), lipo (expanded for 1 week with vehicle liposomes encapsulating ferric oxide and Cy5.5), and RLN-lipo (expanded for 1 week with the liposomes coated with RLN2). Rats were sacrificed after 1 week of expansion or after 2 weeks of retention. To accumulate RLN2-liposomes, a magnetic sheet was fixed to the palatal mucosa of the MPS. In vivo imaging showed magnetically controlled accumulation of liposomes in the MPS for 72 h. Immunohistochemistry revealed RLN2 expression in the MPS after expansion and relaxin receptor (RXFP) 2 expression at the osteogenic front (OF) in the RLN-lipo group; all groups expressed RXFP1 in the MPS. MPS expansion and bone formation were significantly accelerated at the OF in RLN-lipo group compared with the other groups. In the RLN-lipo group, significantly accelerated serrate bone deposition and elevated periostin (POSTN), iNOS, and MMP-1 levels were observed in the MPS. Sclerostin (SOST) expression was significantly reduced in newly formed bone in the RLN-lipo group. Our data revealed that RLN2 enhanced suture expansion via MMP-1 and iNOS secretion in the sutural fibroblasts and new bone formation via POSTN expression in osteoblasts at the OF. These properties may be useful for developing a new less-invasive orthopedic treatment aiming at sutural modification of cranio- and maxillofacial deformity patients.
       
  • PI3K activation increases SDF-1 production and number of osteoclast
           precursors, and enhances SDF-1-mediated osteoclast precursor migration

    • Abstract: Publication date: Available online 22 March 2019Source: Bone ReportsAuthor(s): Naga Suresh Adapala, Sierra Root, Joseph Lorenzo, Hector Aguila, Archana SanjayAbstractOur previous studies showed that in a mouse model in which PI3K-AKT activation was increased (YF mice), osteoclast numbers and levels of SDF-1, a chemokine, were augmented. The purpose of this study was to delineate the role of PI3K activation in regulating SDF-1 production and examine whether SDF-1 can stimulate differentiation and/or migration of osteoclast precursors. Using flow cytometric analysis, we demonstrated that compared to wild type mice, bone marrow of YF mice had increased numbers of CXCL12 abundant reticular (CAR) cells, that are a major cell type responsible for producing SDF-1. At the molecular level, transcription factor specificity protein 1 (Sp1) induced an increased transcription of SDF-1 that was dependent on PI3K/AKT activation. YF mice also contained an increased number of osteoclast precursors, in which expression of CXCR4, a major receptor for SDF-1, was increased. SDF-1 did not induce differentiation of osteoclast precursors into mature osteoclasts; compared to cells derived from WT mice, cells obtained from YF mice were more responsive to SDF-1. In conclusion, we demonstrate that PI3K activation resulted in increased SDF-1, increased the number of osteoclast precursors, and enhanced osteoclast precursor migration in response to SDF-1.
       
  • Calcium isotope ratios in blood and urine: A new biomarker for the
           diagnosis of osteoporosis

    • Abstract: Publication date: Available online 16 March 2019Source: Bone ReportsAuthor(s): A. Eisenhauer, M. Müller, A. Heuser, A. Kolevica, C.-C. Glüer, M. Both, C. Laue, U.v. Hehn, S. Kloth, R. Shroff, J. SchrezenmeirAbstractWe assessed the potential of Calcium (Ca) isotope fractionation measurements in blood (δ44/42CaBlood) and urine (δ44/42CaUrine) as a new biomarker for the diagnosis of osteoporosis. One hundred post-menopausal women aged 50 to 75 years underwent dual-energy X-ray absorptiometry (DXA), the gold standard for determination of bone mineral density. After exclusion of women with kidney failure and vitamin D deficiency (
       
  • Ptychographic X-ray CT characterization of the osteocyte
           lacuno-canalicular network in a male rat's glucocorticoid induced
           osteoporosis model

    • Abstract: Publication date: December 2018Source: Bone Reports, Volume 9Author(s): Antonia Ciani, Hechmi Toumi, Stéphane Pallu, Esther H.R. Tsai, Ana Diaz, Manuel Guizar-Sicairos, Mirko Holler, Eric Lespessailles, Cameron M. KewishAbstractPtychographic X-ray computed tomography (PXCT) is a quantitative imaging modality that non-destructively maps the 3D electron density inside an object with tens of nanometers spatial resolution. This method provides unique access to the morphology and structure of the osteocyte lacuno-canalicular network (LCN) and nanoscale density of the tissue in the vicinity of an osteocyte lacuna. Herein, we applied PXCT to characterize the lacunae and LCN in a male Wistar rat model of glucocorticoid-induced osteoporosis (GIO). The ptychographic images revealed significant (p 
       
  • Vitamin D and kidney disease

    • Abstract: Publication date: December 2018Source: Bone Reports, Volume 9Author(s): Lisa Keung, Farzana PerwadAbstractCalcium and phosphorus are essential minerals required for many critical biologic functions including cell signaling, energy metabolism, skeletal growth and integrity. Calcium and phosphate homeostasis are maintained primarily by regulation of epithelial calcium and phosphate cotransport in the kidney and intestine, processes that are tightly regulated by hormones including 1,25 dihydroxyvitamin D (1,25(OH)2D), fibroblast growth factor 23 (FGF23) and parathyroid hormone (PTH). In patients with chronic kidney disease (CKD), as renal function declines, disruption of feedback loops between these hormones have adverse consequences on several organ systems, including the skeleton, heart and vascular system. CKD-associated mineral and bone disorder (CKD-MBD) is defined as a systemic disorder of mineral and bone metabolism due to CKD manifested by abnormalities of calcium, phosphorus, PTH or vitamin D metabolism, abnormalities of bone turnover, mineralization and volume, and ectopic soft tissue calcification. Complications of CKD-MBD include vascular calcification, stroke, skeletal fracture and increased risk of death. Increased FGF23 and PTH concentrations, and 1,25(OH)2D deficiency contribute to the pathogenesis of CKD-MBD. Therefore, treatment of patients with CKD-MBD is focused on restoring the feedback loops to maintain normal calcium and phosphate balance to prevent skeletal and cardiovascular complications.
       
  • Vitamin D deficiency in immigrants

    • Abstract: Publication date: December 2018Source: Bone Reports, Volume 9Author(s): Paul Lips, Renate T. de JonghAbstractVitamin D deficiency and rickets are more common in non-western immigrants and refugees than in the native population. Severe vitamin D deficiency (serum 25-hydroxyvitamin D
       
  • Calcitriol and cancer therapy: A missed opportunity

    • Abstract: Publication date: December 2018Source: Bone Reports, Volume 9Author(s): Donald L. TrumpAbstractThe vitamin D receptor is expressed in most tissues of the body – and the cancers that arise from those tissues. The vitamin D signaling pathway is active in those tissues and cancers. This is at least consistent with the hypothesis that perturbing this signaling may have a favorable effect on the genesis and growth of cancers. Epidemiologic data indicate that vitamin D signaling may be important in the initiation and outcome of a number of types of cancer. Many studies have shown that calcitriol (1,25 dihydroxycholecalciferol) and other vitamin D compounds have antiproliferative, pro-apoptotic, anti-cell migration and antiangiogenic activity in a number of preclinical studies in many different cancer types. Unfortunately, the assessment of the activity of calcitriol or other vitamin D analogues in the treatment of cancer, as single agents or in combination with other anticancer agents has been stymied by the failure to adhere to commonly accepted principles of drug development and clinical trials conduct.
       
  • Prevalence of glucocorticoid induced osteonecrosis in the mouse is not
           affected by treatments that maintain bone vascularity

    • Abstract: Publication date: December 2018Source: Bone Reports, Volume 9Author(s): Nancy E. Lane, Geetha Mohan, Wei Yao, Kie Shidara, Yu-An Evan Lay, Jia Junjing, Alanna Dubrovsky, Donald B. KimmelAbstractObjectiveDetermine if LLP2A-Ale or PTH (1–34) affects the prevalence of glucocorticoid-induced osteonecrosis (ON) in a mouse model.MethodsEight-week-old young adult male BALB/cJ mice were weight-randomized into Control (Con), glucocorticoid (GC)-only, or concurrent treatments with GC and LLP2A-Ale (250 μg/kg or 500 μg/kg, IV, Days 1, 14, 28) or parathyroid hormone hPTH (1–34) (40 μg/kg, 5×/week). Mice were necropsied after 45 days for qualitative evaluation of prevalent ON and quantitative evaluation of vascularity in the distal femoral epiphysis (DFE); and quantitative evaluation of bone mass, microarchitecture, and strength in the distal femoral metaphysis and lumbar vertebral body.ResultsThe prevalence of ON was 14% in the Con group and 36% in the GC-only group (P = 0.07). The prevalence of ON did not differ among GC-only, GC + LLP2A-Ale, and GC + PTH groups. GC-only mice had significantly lower trabecular and cortical bone strength than Con, while GC + LLP2A-Ale (500 μg/kg) and GC + PTH (1–34) groups had significantly greater trabecular bone strength than the GC-only group. GC + LLP2A-Ale (250 μg/kg and 500 μg/kg) and GC + PTH had significantly higher trabecular bone volume than GC-only mice at the vertebrae, distal femoral epiphyses and distal femoral metaphyses. DFE vascularity was lower in GC-only mice than in all other groups.ConclusionNeither LLP2A-Ale nor hPTH (1–34) reduced the prevalence of GC-induced ON, compared to GC-only mice. However, GC-treated mice given LLP2A-Ale or hPTH (1–34) had better bone mass, microarchitecture, and strength in trabecular-rich regions, and higher levels of vascularity than GC-only mice.
       
  • Glucocorticoids affect bone mineral density and bone remodelling in OVX
           sheep: A pilot study

    • Abstract: Publication date: December 2018Source: Bone Reports, Volume 9Author(s): Diana Cabrera, Frances M. Wolber, Keren Dittmer, Chris Rogers, Anne Ridler, Danielle Aberdein, Tim Parkinson, Paul Chambers, Karl Fraser, Nicole C. Roy, Marlena KrugerAbstractThe aim of this study was to validate the combination of ovariectomy and glucocorticoid treatment in sheep as a large animal model for osteoporosis by measuring the concentration of specific biomarkers in the blood of the sheep and measuring bone loss over five months. Aged Merino ewes were randomly allocated into four groups: control, ovariectomy (OVX), and two OVX groups receiving glucocorticoids—one group once-monthly for five months (OVXG), and the other for two months followed by no treatment for three months (OVXG2). Parameters measured were biochemical markers of bone turnover, areal bone mineral density, volumetric bone mineral density, and total and trabecular bone parameters. Ovariectomy increased the concentrations of bone resorption marker C-terminal telopeptides of type 1 collagen (CTx-1) and bone turnover marker serum osteocalcin (OC) concentrations in the OVX group compared to control sheep. The combination of ovariectomy and glucocorticoid treatment increased the concentrations of CTx-1 and decreased serum OC concentrations in the OVXG group compared to OVXG2. Femur and lumbar spine bone density were lower in experimentally treated groups when compared with the control group. Total and trabecular vBMD in the proximal tibia were significantly lower in the treatment groups when compared with the control group. A significant negative correlation between femoral bone density and CTx-1 was found. The results of this study suggest that the combination of OVX and glucocorticoids induces bone loss in a short period of time in sheep.
       
  • High-precision method for cyclic loading of small-animal vertebrae to
           assess bone quality

    • Abstract: Publication date: December 2018Source: Bone Reports, Volume 9Author(s): Megan M. Pendleton, Saghi Sadoughi, Alfred Li, Grace D. O'Connell, Joshua S. Alwood, Tony M. KeavenyAbstractOne potentially important bone quality characteristic is the response of bone to cyclic (repetitive) mechanical loading. In small animals, such as in rats and mice, cyclic loading experiments are particularly challenging to perform in a precise manner due to the small size of the bones and difficult-to-eliminate machine compliance. Addressing this issue, we developed a precise method for ex vivo cyclic compressive loading of isolated mouse vertebral bodies. The method has three key characteristics: 3D-printed support jigs for machining plano-parallel surfaces of the tiny vertebrae; pivotable loading platens to ensure uniform contact and loading of specimen surfaces; and specimen-specific micro-CT-based finite element analysis to measure stiffness to prescribe force levels that produce the same specified level of strain for all test specimens. To demonstrate utility, we measured fatigue life for three groups (n = 5–6 per group) of L5 vertebrae of C57BL/6J male mice, comparing our new method against two methods commonly used in the literature. We found reduced scatter of the mechanical behavior for this new method compared to the literature methods. In particular, for a controlled level of strain, the standard deviation of the measured fatigue life was up to 5-fold lower for the new method (F-ratio = 4.9; p 
       
  • Cathepsin K inhibition preserves compressive load in lumbar vertebrae of
           osteoporotic monkeys

    • Abstract: Publication date: December 2018Source: Bone Reports, Volume 9Author(s): Isabel D. Colón-Bernal, Le T. Duong, Brenda Pennypacker, James Henderson, Kenneth M. Kozloff, Mark M. Banaszak HollAbstractAnti-resorptive drugs treat bone loss by blocking osteoclast activity through a variety of mechanisms of action. Once significant bone loss has occurred, the ability to restore biomechanical function may differ based on the drug chosen. To assess this question, bisphosphonate (alendronate, ALN) and cathepsin K inhibitor (MK-0674, CatKi) were employed in treatment mode to compare the relative changes to cancellous bone microstructure and mechanical properties in ovariectomized (OVX) cynomolgus monkeys. Lumbar vertebrae (LV) bone mineral density (BMD) values taken two years post-surgery prior to drug treatment show a 10–15% decrease (p 
       
  • Skeletal disease in a father and daughter with a novel monoallelic WNT1
           mutation

    • Abstract: Publication date: December 2018Source: Bone Reports, Volume 9Author(s): Kathleen Ang, Elizabeth Sanchez Rangel, Qianying Yuan, Dianqing Wu, Thomas O. Carpenter, Karl InsognaAbstractContextMost heritable causes of low bone mass in children occur due to mutations affecting type 1 collagen. We describe two related patients with low bone mass and fracture without mutations in the type 1 collagen genes.Case descriptionWe describe the index case of a 10-year-old girl with low-impact fractures in childhood and her 59-year-old father with traumatic fractures in adulthood, both with low bone mineral density. They were found to have the same heterozygous missense mutation in the WNT1 gene (p.Gly222Arg), occurring in a highly conserved WNT motif in close proximity to the Frizzled binding site.ConclusionsThe WNT-ligand WNT1, signaling through the canonical WNT-β­catenin pathway, plays a critical role in skeletal development, adult skeletal homeostasis, and bone remodeling. Biallelic mutations have been described and are associated with moderate to severe osteogenesis imperfecta, in some cases with extra-skeletal manifestations. Patients with monoallelic mutations, as in our case, seem to present with low bone mineral density and less severe disease. The phenotypic difference between biallelic and monoallelic mutations highlights that the aberrant protein in monoallelic mutations may exert a dominant negative effect on the wild type protein as heterozygous carriers in families with biallelic disease are usually asymptomatic. With better understanding of disorders associated with WNT1 mutations, therapies targeting this signaling pathway may offer therapeutic benefit.
       
  • Glucocorticoids cause mandibular bone fragility and suppress osteocyte
           perilacunar-canalicular remodeling

    • Abstract: Publication date: December 2018Source: Bone Reports, Volume 9Author(s): A. Sean Alemi, Courtney M. Mazur, Tristan W. Fowler, Jonathon J. Woo, P. Daniel Knott, Tamara AllistonAbstractOsteocytes support dynamic, cell-intrinsic resorption and deposition of bone matrix through a process called perilacunar/canalicular remodeling (PLR). In long bones, PLR depends on MMP13 and is tightly regulated by PTH, sclerostin, TGFβ, and glucocorticoids. However, PLR is regulated differently in the cochlea, suggesting a mechanism that is anatomically distinct. Unlike long bones, the mandible derives from neural crest and exhibits unique susceptibility to medication and radiation induced osteonecrosis. Therefore, we sought to determine if PLR in the mandible is suppressed by glucocorticoids, as it is in long bone. Hemimandibles were collected from mice subcutaneously implanted with prednisolone or vehicle containing pellets for 7, 21, or 55 days (n = 8/group) for radiographic and histological analyses. Within 21 days, micro-computed tomography revealed a glucocorticoid-dependent reduction in bone volume/total volume and trabecular thickness and a significant decrease in bone mineral density after 55 days. Within 7 days, glucocorticoids strongly and persistently repressed osteocytic expression of the key PLR enzyme MMP13 in both trabecular and cortical bone of the mandible. Cathepsin K expression was significantly reduced only after 55 days of glucocorticoid treatment, at which point histological analysis revealed a glucocorticoid-dependent reduction in the lacunocanalicular surface area. In addition to reducing bone mass and suppressing PLR, glucocorticoids also reduced the stiffness of mandibular bone in flexural tests. Thus, osteocyte PLR in the neural crest-derived mandible is susceptible to glucocorticoids, just as it is in the mesodermally-derived femur, highlighting the need to further study PLR as a target of drugs, and radiation in mandibular osteonecrosis.
       
  • FGF2 crosstalk with Wnt signaling in mediating the anabolic action of PTH
           on bone formation

    • Abstract: Publication date: December 2018Source: Bone Reports, Volume 9Author(s): Liping Xiao, Yurong Fei, Marja M. HurleyAbstractThe mechanisms of the anabolic effect of parathyroid hormone (PTH) in bone are not fully defined. The bone anabolic effects of PTH require fibroblast growth factor 2 (FGF2) as well as Wnt signaling and FGF2 modulates Wnt signaling in osteoblasts. In vivo PTH administration differentially modulated Wnt signaling in bones of wild type (WT) and in mice that Fgf2 was knocked out (Fgf2KO). PTH increased Wnt10b mRNA and protein in WT but not in KO mice. Wnt antagonist SOST mRNA and protein was significantly higher in KO group. However, PTH decreased Sost mRNA significantly in WT as well as in Fgf2KO mice, but to a lesser extent in Fgf2KO. Dickhopf 2 (DKK2) is critical for osteoblast mineralization. PTH increased Dkk2 mRNA in WT mice but the response was impaired in Fgf2KO mice. PTH significantly increased Lrp5 mRNA and phosphorylation of Lrp6 in WT but the increase was markedly attenuated in Fgf2KO mice. PTH increased β-catenin expression and Wnt/β-catenin transcriptional activity significantly in WT but not in Fgf2KO mice. These data suggest that the impaired bone anabolic response to PTH in Fgf2KO mice is partially mediated by attenuated Wnt signaling.
       
  • A moderate form of osteogenesis imperfecta caused by compound heterozygous
           LEPRE1 mutations

    • Abstract: Publication date: December 2018Source: Bone Reports, Volume 9Author(s): Adolfredo Santana, Jeanne M. Franzone, Cristina M. McGreal, Richard W. Kruse, Michael B. BoberAbstractOsteogenesis imperfecta (OI) is a genetic disorder causing skeletal fragility, multiple fractures, and other extraskeletal manifestations. Most cases are caused by mutations in COL1A1 or COL1A2. Recent investigations have discovered several other autosomal recessive genes responsible for OI. Among these genes is LEPRE1, which is involved in post-translational modifications of collagen. To date, more than 40 LEPRE1 mutations have been described. One of these mutations is carried by 1.5% of West Africans and 0.4% of African Americans, and is associated with OI Type VIII. We describe the case of a five year old male with a moderate form of OI and compound heterozygous LEPRE1 mutations (c.1080 + 1G > T; c.1646 T > G, p.Met549Arg). He was diagnosed shortly after birth following a skeletal survey demonstrating multiple healing fractures as well as lower extremity deformity suggestive of remote fractures. He was then without a fracture until a calvarial fracture at 18 months of age, a femur fracture at 4 years and seven months and a second femur fracture at 5 years and 4 months. He walked at age 14 months and has been an active boy. Pamidronate infusions began at seven weeks of age and were discontinued at three years of age due to increased bone mineral density and absence of fractures. Type VIII OI typically causes a severe to lethal phenotype presenting at birth with severe osteopenia, congenital fractures and other clinical manifestations. Only a few individuals have survived to childhood. This case description serves to expand the clinical phenotyping of this recessive form of OI into the more moderate spectrum.
       
  • Juvenile onset IIH and CYP24A1 mutations

    • Abstract: Publication date: December 2018Source: Bone Reports, Volume 9Author(s): Karl P. Schlingmann, Walburga Cassar, Martin KonradAbstractThe term Idiopathic infantile hypercalcemia (IIH) was first introduced almost 70 years ago when symptomatic hypercalcemia developed in children after receiving high doses of vitamin D for the prevention of rickets. The underlying pathophysiology remained unknown until recessive mutations in CYP24A1 encoding Vitamin D3-24-hydroxylase were discovered. The defect in vitamin D degradation leads to an accumulation of active 1,25(OH)2D3 with subsequent hypercalcemia. Enhanced renal calcium excretions lead to hypercalciuria and nephrocalcinosis. Meanwhile, the phenotypic spectrum associated with CYP24A1 mutations has significantly broadened. Patients may present at all age groups with symptoms originating from increased serum calcium levels as well as from increased urinary calcium excretions, i.e. kidney stones. Possible long term sequelae comprise chronic renal failure as well as cardiovascular disease. Here, we present a family with two affected siblings with differing clinical presentation as an example for the phenotypic variability of CYP24A1 defects.
       
  • Associations between trabecular bone score and biochemistry in surgically
           vs conservatively treated outpatients with primary hyperparathyroidism: A
           retrospective cohort study

    • Abstract: Publication date: December 2018Source: Bone Reports, Volume 9Author(s): Julius Simoni Leere, Christian Kruse, Maciej Robaczyk, Jesper Karmisholt, Peter VestergaardPurposeTrabecular Bone Score (TBS) is a software-based method for indirect assessment of trabecular bone structure of the spine, based on analysis of pixels in dual energy x-ray absorptiometry (DXA) images. Few studies describe the use of TBS in patients with primary hyperparathyroidism (PHPT). This study aimed at further describing this relationship, investigating possible correlations between biochemistry, body mass index (BMI), fracture incidence and TBS.MethodsCross-sectional study of 195 patients with verified PHPT, surgically (27) or conservatively (168) treated at the Department of Endocrinology, Aalborg University Hospital. TBS was acquired by reanalyzing DXA-images of the included subjects from the outpatient clinic. Biochemical variables were obtained from clinical routine blood samples taken in relation to the DXA-scans. History of fractures and medical history was obtained from radiology reports and medical charts.ResultsPatients with active PHPT had a TBS-score signifying a partly degraded bone structure, whereas surgically treated patients had a normal bone structure as judged by TBS, though the difference in TBS-score was not statistically significant. Use of antiresorptive treatment was negatively associated with BMD but not TBS. No correlations between the biochemical variables and TBS were found. A negative correlation between TBS and BMI in patients with PHPT was present. Patients experiencing a fragility fracture had a significantly lowered TBS, BMD and T-Score.ConclusionBiochemistry does not seem to predict bone status in terms of TBS in patients with PHPT. TBS is negatively correlated to BMI, which is also seen in patients not suffering from PHPT. The lack of a predictive value for antiresorptive treatment for TBS may raise concern. TBS appears to have a predictive value when assessing risk of fracture in patients with PHPT.Mini abstractThis cross-sectional study investigates possible correlations between biochemical variables, body mass index (BMI) and trabecular bone score (TBS) in 195 patients with primary hyperparathyroidism. It finds no correlation between biochemical variables and TBS, but finds a negative correlation between TBS and BMI and a clear association between fracture incidence and low TBS-score.
       
  • Polyethylene particles inserted over calvarium induce cancellous bone loss
           in femur in female mice

    • Abstract: Publication date: December 2018Source: Bone Reports, Volume 9Author(s): Kenneth A. Philbrick, Carmen P. Wong, Arianna M. Kahler-Quesada, Dawn A. Olson, Adam J. Branscum, Russell T. Turner, Urszula T. IwaniecAbstractFocal bone resorption (osteolysis) induced by wear particles contributes to long-term orthopedic joint failure. However, the impact of focal osteolysis on remote skeletal sites has received less attention. The goal of this study was to determine the effects of polyethylene particles placed over calvaria on representative axial and appendicular skeletal sites in female mice. Because recent work has identified housing temperature as an important biological variable in mice, response to particle treatment was measured in animals housed at room (22 °C) and thermoneutral (32 °C) temperature. Osteolysis was evident in skeletal tissue adjacent to particle insertion. In addition, cancellous bone loss was observed in distal femur metaphysis. The bone loss was associated with lower osteoblast-lined perimeter and lower mineralizing perimeter in distal femur, lower osteocalcin gene expression in tibia, and lower serum osteocalcin, suggesting the response was due, at least in part, to reduced bone formation. Mild cold stress induced by sub-thermoneutral housing resulted in cancellous bone loss in distal femur and lumbar vertebra but did not influence skeletal response to particles. In summary, the results indicate that focal inflammation induced by polyethylene particles has the potential to result in systemic bone loss. This is significant because bone loss is a risk factor for fracture.
       
  • Characteristics of bone strength and metabolism in type 2 diabetic model
           Tsumura, Suzuki, Obese Diabetes mice

    • Abstract: Publication date: December 2018Source: Bone Reports, Volume 9Author(s): Hiroaki Tanaka, Takenori Yamashita, Misao Yoneda, Satoshi Takagi, Toshihiro MiuraAbstractObjectiveType 2 diabetes mellitus (T2DM) is a metabolic disease characterized by hyperglycemia, hyperinsulinemia, and complications such as obesity and osteoporosis. The Tsumura, Suzuki, Obese Diabetes (TSOD) mouse is an animal model of spontaneous obese T2DM. However, bone metabolism in TSOD mice is yet to be investigated. The objective of the present study was to investigate the effects of T2DM on bone mass, metabolism, microstructure, and strength in TSOD mice.MethodsWe determined the following parameters in TSOD mice and Tsumura, Suzuki, Non-obesity (TSNO) mice (as controls): serum glucose levels; serum insulin levels; bone mass; bone microstructure; bone metabolic markers; and bone strength. We also performed the oral glucose tolerance test and examined histological sections of the femur. We compared these data between both groups at pre-diabetic (10 weeks) and established (20 weeks) diabetic conditions.ResultsBone strength, such as extrinsic mechanical properties, increased with age in the TSOD mice and intrinsic material properties decreased at both 10 weeks and 20 weeks. Bone resorption marker levels in TSOD mice were significantly higher than those in the control mice at both ages, but there was no significant difference in bone formation markers between the groups. Bone mass in TSOD mice was lower than that in controls at both ages. The trabecular bone volume at the femoral greater trochanter increased with age in the TSOD mice. The femoral mid-diaphysis in TSOD mice was more slender and thicker than that in TSNO mice at both ages.ConclusionsBone mass of the femur was lower in TSOD mice than in TSNO mice because hyperinsulinemia during pre-diabetic and established diabetic conditions enhanced bone resorption due to high bone turnover. In addition, our data suggest that the bone mass of the femur was significantly reduced as a result of chronic hyperglycemia during established diabetic conditions in TSOD mice. We suggest that bone strength in the femur deteriorated due to the reduction of bone mass and because the femoral mid-diaphysis was more slender in TSOD mice.
       
  • Loss of RANKL in osteocytes dramatically increases cancellous bone mass in
           the osteogenesis imperfecta mouse (oim)

    • Abstract: Publication date: December 2018Source: Bone Reports, Volume 9Author(s): Sarah M. Zimmerman, Melissa E. Heard-Lipsmeyer, Milena Dimori, Jeff D. Thostenson, Erin M. Mannen, Charles A. O'Brien, Roy MorelloAbstractOsteogenesis imperfecta (OI) is characterized by osteopenia and bone fragility, and OI patients during growth often exhibit high bone turnover with the net result of low bone mass. Recent evidence shows that osteocytes significantly affect bone remodeling under physiological and pathological conditions through production of osteoclastogenic cytokines. The receptor activator of nuclear factor kappa-B ligand (RANKL) produced by osteocytes for example, is a critical mediator of bone loss caused by ovariectomy, low-calcium diet, unloading and glucocorticoid treatment. Because OI bone has increased density of osteocytes and these cells are embedded in matrix with abnormal type I collagen, we hypothesized that osteocyte-derived RANKL contributes to the OI bone phenotype. In this study, the conditional loss of RANKL in osteocytes in oim/oim mice (oim-RANKL-cKO) resulted in dramatically increased cancellous bone mass in both the femur and lumbar spine compared to oim/oim mice. Bone cortical thickness increased significantly only in spine but ultimate bone strength in the long bone and spine was minimally improved in oim-RANKL-cKO mice compared to oim/oim mice. Furthermore, unlike previous findings, we report that oim/oim mice do not exhibit high bone turnover suggesting that their low bone mass is likely due to defective bone formation and not increased bone resorption. The loss of osteocyte-derived RANKL further diminished parameters of formation in oim-RANKL-cKO. Our results indicate that osteocytes contribute significantly to the low bone mass observed in OI and the effect of loss of RANKL from these cells is similar to its systemic inhibition.
       
  • Bisphosphonate conjugation for bone specific drug targeting

    • Abstract: Publication date: December 2018Source: Bone Reports, Volume 9Author(s): Kristen B. Farrell, Alexander Karpeisky, Douglas H. Thamm, Shawn ZinnenAbstractBones provide essential functions and are sites of unique biochemistry and specialized cells, but can also be sites of disease. The treatment of bone disorders and neoplasia has presented difficulties in the past, and improved delivery of drugs to bone remains an important goal for achieving effective treatments. Drug targeting strategies have improved drug localization to bone by taking advantage of the high mineral concentration unique to the bone hydroxyapatite matrix, as well as tissue-specific cell types. The bisphosphonate molecule class binds specifically to hydroxyapatite and inhibits osteoclast resorption of bone, providing direct treatment for degenerative bone disorders, and as emerging evidence suggests, cancer. These bone-binding molecules also provide the opportunity to deliver other drugs specifically to bone by bisphosphonate conjugation. Bisphosphonate bone-targeted therapies have been successful in treatment of osteoporosis, primary and metastatic neoplasms of the bone, and other bone disorders, as well as refining bone imaging. In this review, we focus upon the use of bisphosphonate conjugates with antineoplastic agents, and overview bisphosphonate based imaging agents, nanoparticles, and other drugs. We also discuss linker design potential and the current state of bisphosphonate conjugate research progress. Ongoing investigations continue to expand the possibilities for bone-targeted therapeutics and for extending their reach into clinical practice.
       
  • Bones in human CYP26B1 deficiency and rats with hypervitaminosis A
           phenocopy Vegfa overexpression

    • Abstract: Publication date: December 2018Source: Bone Reports, Volume 9Author(s): Thomas Lind, Roberta Lugano, Ann-Marie Gustafson, Maria Norgård, Arie van Haeringen, Anna Dimberg, Håkan Melhus, Stephen P. Robertson, Göran AnderssonAbstractAngulated femurs are present prenatally both in CYP26B1 deficient humans with a reduced capacity to degrade retinoic acid (RA, the active metabolite of vitamin A), and mice overexpressing vascular endothelial growth factor a (Vegfa). Since excessive ingestion of vitamin A is known to induce spontaneous fractures and as the Vegfa-induced femur angulation in mice appears to be caused by intrauterine fractures, we analyzed bones from a CYP26B1 deficient human and rats with hypervitaminosis A to further explore Vegfa as a mechanistic link for the effect of vitamin A on bone. We show that bone from a human with CYP26B1 mutations displayed periosteal osteoclasts in piles within deep resorption pits, a pathognomonic sign of hypervitaminosis A. Analysis of the human angulated fetal femur revealed excessive bone formation in the marrow cavity and abundant blood vessels. Normal human endothelial cells showed disturbed cell-cell junctions and increased CYP26B1 and VEGFA expression upon RA exposure. Studies in rats showed increased plasma and tissue Vegfa concentrations and signs of bone marrow microhemorrhage on the first day of excess dietary vitamin A intake. Subsequently hypervitaminosis A rats displayed excess bone formation, fibrosis and an increased number of megakaryocytes in the bone marrow, which are known characteristics of Vegfa overexpression. This study supports the notion that the skeletal phenotype in CYP26B1 deficient human bone is caused by excess RA. Our findings suggest that an initial part of the vitamin A mechanism causing bone alterations is mediated by excess Vegfa and disturbed bone marrow microvessel integrity.
       
  • Expression of pro-apoptotic markers is increased along the osteochondral
           junction in naturally occurring osteochondrosis

    • Abstract: Publication date: December 2018Source: Bone Reports, Volume 9Author(s): Stacy A. Semevolos, Katja F. Duesterdieck-Zellmer, Maureen Larson, Marc A. KinsleyAbstractOsteochondrosis (OC) is a naturally occurring disease of the articular-epiphyseal cartilage and subchondral bone layers, leading to pain and decreased mobility. The objective of this study was to characterize gene and protein expression of apoptotic markers in chondrocytes surrounding cartilage canals and along the osteochondral junction of osteochondrosis (OC)-affected and normal cartilage, using naturally occurring disease in horses. Paraffin-embedded osteochondral samples (6 OC, 8 normal controls) and cDNA from chondrocytes captured with laser capture microdissection (4 OC, 6 normal controls) were obtained from the lateral trochlear ridge of femoropatellar joints in 14 immature horses (1–6 months of age). Equine-specific caspase-3, caspase-8, caspase-10, Fas, Bcl-2, BAG-1, TNFα, cytochrome C, thymosin-β10, and 18S mRNA expression levels were evaluated by two-step real-time quantitative PCR. Percentage of cell death was determined using the TUNEL method. Protein expression of caspase-10, Fas, cytochrome C, and thymosin-β10 was determined following immunohistochemistry. Statistical analysis was performed using the Wilcoxon rank sum test or two-sample t-test (p 
       
  • Metabolomics-based profiles predictive of low bone mass in menopausal
           women

    • Abstract: Publication date: December 2018Source: Bone Reports, Volume 9Author(s): Takeshi Miyamoto, Akiyoshi Hirayama, Yuiko Sato, Tami Koboyashi, Eri Katsuyama, Hiroya Kanagawa, Atsuhiro Fujie, Mayu Morita, Ryuichi Watanabe, Toshimi Tando, Kana Miyamoto, Takashi Tsuji, Atsushi Funayama, Tomoyoshi Soga, Masaru Tomita, Masaya Nakamura, Morio MatsumotoAbstractOsteoporosis is a skeletal disorder characterized by compromised bone strength and increased risk of fracture. Low bone mass and/or pre-existing bone fragility fractures serve as diagnostic criteria in deciding when to start medication for osteoporosis. Although osteoporosis is a metabolic disorder, metabolic markers to predict reduced bone mass are unknown. Here, we show serum metabolomics profiles of women grouped as pre-menopausal with normal bone mineral density (BMD) (normal estrogen and normal BMD; NN), post-menopausal with normal BMD (low estrogen and normal BMD; LN) or post-menopausal with low BMD (low estrogen and low BMD; LL) using comprehensive metabolomics analysis. To do so, we enrolled healthy volunteer and osteoporosis patient female subjects, surveyed them with a questionnaire, measured their BMD, and then undertook a comprehensive metabolomics analysis of sera of the three groups named above. We identified 24 metabolites whose levels differed significantly between NN/LN and NN/LL groups, as well as 18 or 10 metabolites whose levels differed significantly between NN/LN and LN/LL, or LN/LL and NN/LN groups, respectively. Our data shows metabolomics changes represent useful markers to predict estrogen deficiency and/or bone loss.
       
  • Effect of a cathepsin K inhibitor on arthritis and bone mineral density in
           ovariectomized rats with collagen-induced arthritis

    • Abstract: Publication date: December 2018Source: Bone Reports, Volume 9Author(s): Takahiro Yamashita, Hiroshi Hagino, Ikuta Hayashi, Masako Hayashibara, Atsushi Tanida, Keita Nagira, Ryohei Fukui, Hideki NagashimaAbstractObjectivesCathepsin K is expressed by osteoclasts and synovial fibroblasts and degrades key components of bone and cartilage. Inhibition of cathepsin K protease activity may be beneficial for the prevention of bone erosion and cartilage degradation in rheumatoid arthritis (RA). The collagen-induced arthritis (CIA) rat model is well established for studying the pathology and treatment of RA. We investigated the effect of ONO-KK1-300-01, a cathepsin K inhibitor (CKI), on arthritis and bone mineral density (BMD) in rats with CIA.MethodsSeven-month-old female Sprague Dawley rats were divided into 5 groups: rats without CIA (CNT); CIA rats that underwent ovariectomy (OVX) and were treated with CKI; CIA rats that underwent OVX and were treated with vehicle (Veh); CIA rats that underwent sham surgery and were treated with CKI; and CIA rats that underwent sham surgery and were treated with Veh. CKI was orally administered at a dose of 15 mg/kg, thus initiating collagen sensitization, until death at 4 weeks. We evaluated hind paw thickness and the arthritis score every week until death. Radiographs of the resected left foot were obtained with a soft X-ray apparatus. Destruction of bone and cartilage was classified and scored as previously described by Engelhardt et al. BMD was measured by bone densitometry at the halfway point between the distal metaphysis and the diaphysis of the resected right femur. We also performed histomorphometry of the proximal left tibia, histological evaluation of arthritis, and a bone strength test.ResultsCKI administration significantly reduced hind paw thickness and the arthritis score, and prevented a decrease in BMD. The radiographic score was significantly lower in the CKI group than in the Veh group. In the histomorphometric analysis, bone-resorption parameters were significantly lower in the CKI groups than in the Veh groups. CKI significantly inhibited synovial proliferation in the CIA rats. In the bone strength test, the ultimate stress was significantly higher in the CKI groups than in the Veh groups.ConclusionOur findings indicate that cathepsin K inhibitors may inhibit systemic and local bone loss, ameliorate arthritis, and attenuate the decrease of bone strength in an animal model of arthritis.
       
  • Vitamin D and bone and beyond

    • Abstract: Publication date: December 2018Source: Bone Reports, Volume 9Author(s): Daniel D. Bikle, Roger Bouillon
       
  • Cortical bone is an extraneuronal site of norepinephrine uptake in adult
           mice

    • Abstract: Publication date: December 2018Source: Bone Reports, Volume 9Author(s): Yuantee Zhu, Yun Ma, Florent ElefteriouAbstractThe sympathetic nervous system is a major efferent pathway through which the central nervous system controls the function of peripheral organs. Genetic and pharmacologic evidence in mice indicated that stimulation of the β2 adrenergic receptor (β2AR) in osteoblasts promotes bone loss, leading to the paradigm that high sympathetic nervous activity is deleterious to bone mass. However, considerably less data exist to understand the putative impact of endogenous norepinephrine (NE), released by sympathetic nerves, on bone homeostasis. In this study, we investigated the in vivo expression and activity of the norepinephrine transporter (NET), a membrane pump known to actively uptake NE from the extracellular space in presynaptic neurons. Consistent with previously published in vitro data showing NET uptake activity in differentiated osteoblasts, we were able to detect active NET-specific NE uptake in the mouse cortical bone compartment in vivo. This uptake was the highest in young mice and accordingly with an age-related reduction in NET uptake, NE bone content increased whereas Net RNA and protein expression decreased with age. Histologically, NET expression in adult mouse bones was detected in osteocytes via immunofluorescence. Lastly, taking advantage of tissue-specific fluorescent reporter mice, we used CLARITY imaging and light sheet microscopy to visualize the 3D distribution of sympathetic fibers in whole mount preparations of bone tissues. These analyses allowed us to detect tyrosine hydroxylase (TH)-positive sympathetic nerve fibers penetrating the cortical bone, where NET+ osteocytes reside. Together, these in vitro results support the existence of an age-dependent extraneuronal and osteocytic function of NET with potential to buffer the bone catabolic action of endogenous NE released by sympathetic nerves in vivo.
       
 
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