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  This is an Open Access Journal Open Access journal
   ISSN (Online) 2473-4039
   Published by John Wiley and Sons Homepage  [1592 journals]
  • Whole Exome Sequencing Identifies an Intronic Cryptic Splice Site in
           SERPINF1 Causing Osteogenesis Imperfecta Type VI

    • Abstract: The heritable disorder osteogenesis imperfecta (OI) is characterized by bone fragility and low bone mass. OI type VI is an autosomal recessive form of the disorder with moderate to severe bone fragility. OI type VI is caused by mutations in the serpin peptidase inhibitor, clade F, member 1 (SERPINF1), the gene coding for pigment‐epithelium derived factor (PEDF). Here, we report a patient with OI type VI caused by a novel homozygous intronic variant in SERPINF1 identified by whole exome sequencing (WES). The mutation was not identified using a low bone mass gene panel based on next generation sequencing. This variant creates a novel consensus splice donor site (AGGC to AGGT) in intron 4. Analysis of cDNA generated from fibroblasts revealed retention of a 32 bp intronic fragment between exons 4 and 5 in the cDNA, a result of alternative splicing from the novel splice donor site. As a result, the aberrant insertion of this intronic fragment generated a frameshift pathogenic variant and induced nonsense‐mediated decay. Furthermore, gene expression by quantitative PCR showed SERPINF1 expression was dramatically reduced in patient fibroblasts, and PEDF level was also significantly reduced in the patient's plasma. In conclusion, we report a novel homozygous variant that generates an alternative splice‐donor in intron 4 of SERPINF1 which gives rise to severe bone fragility. The work also demonstrates clinical utility of whole exome sequencing analysis, and consideration of noncoding variants, in the diagnostic setting of rare bone diseases. This article is protected by copyright. All rights reserved
  • Optimizing Sequential and Combined Anabolic and Antiresorptive
           Osteoporosis Therapy

    • Abstract: As osteoporosis therapy options have expanded, and clinical guidelines have begun to embrace the concept of limited treatment courses and “drug holidays”, the choices that physicians must make when initiating, electing to continue, or switching therapies have become more complex. As a result, one of the fundamental issues that must be carefully considered is whether, when, and in what sequence anabolic therapies should be utilized. This review evaluates the current evidence supporting the optimal sequence for the use of anabolic and antiresorptive drugs and assesses the expanding number of clinical trials favoring the initial use of anabolic therapy followed by an antiresorptive agent. This review also explores the evidence suggesting that the effectiveness of anabolic medications are diminished when used in patients that have been previously treated with specific antiresorptive drugs for prolonged periods. Finally, the recent advances in designing combination antiresorptive/anabolic treatment approaches are detailed, with a focus on combined denosumab/teriparatide regimens, which appear to provide the most substantial and clinically relevant skeletal benefits to patients with established osteoporosis. This article is protected by copyright. All rights reserved
  • Semi‐quantitative Evaluation of Muscle Repair by Diffusion Tensor
           Imaging in Mice

    • Abstract: Muscle injury is one of the most common traumas in orthopedic and sports medicine. However, there are only a few treatment options with marginal clinical benefits for this condition. Muscle repair after injury involves multiple and complex processes, such as the inflammation phase, regeneration phase, and remodeling phase. To develop a treatment modality and to examine the efficacy of novel interventions and agents for patients with muscle injuries, it is essential to establish a reliable and sensitive method to monitor the changes in muscle structure and status during muscle repair. Diffusion‐weighted magnetic resonance imaging has been widely used to assess the diffusivity of water molecules in tissue. When it is used in combination with diffusion tensor imaging (DTI), the microstructure of muscle tissue can be indirectly depicted. In the present study, we evaluated the time‐course changes in the diffusivity and anisotropy in muscles by DTI and histology after injury in mice. We found that the diffusivity and anisotropy exhibit distinct kinetics during muscle repair and that these kinetics were significantly altered in mutant mice with a defect in muscle regeneration. Our data show that muscle repair processes can be readily evaluated and monitored by DTI technique and suggest that DTI can be clinically applied for assessing muscle injury and repair in humans. This article is protected by copyright. All rights reserved
  • 62‐year‐old male suffering from uremic leontiasis ossea caused by
           severe secondary hyperparathyroidism

    • Abstract: Secondary hyperparathyroidism (SHPT) is a long‐term complication of chronic kidney disease‐mineral and bone disorders (CKD‐MBD). SHPT is characterized by hyperplasia of the parathyroid glands and abnormal secretion of parathyroid hormones (PTH), calcium and phosphorous metabolic disorders, renal osteodystrophy, vascular and soft tissue calcification, malnutrition, and other multiple system complications, which can seriously affect the quality of life of the patient and increase the risk of cardiovascular disease and mortality rate. Uremic leontiasis ossea (ULO) is a medical condition only rarely encountered clinically. SHPT causes craniofacial bone deformity accompanied by lesions of the nerve, cardiovascular, respiratory, bone, or other systems within the body. The case discussed here is related to severe SHPT. A 62‐year‐old male patient was suffering from leontiasis ossea, pectus excavatum, vascular calcification, spontaneous bone fractures, and lower limb deformities. He was undergoing hemodialysis at the time. He was given a total parathyroidectomy (TPTX) with autograft transplantation (autotransplantation, AT). We further analyzed the multivariate therapeutic effects of TPTX on this patient in order to provide clinical data for standardized treatment of individuals with CKD‐MBD. This article is protected by copyright. All rights reserved
  • Sphingosine‐1‐Phosphate Modulates the Effect of Estrogen in
           Human Osteoblasts

    • Abstract: Production of sphingosine‐1‐phosphate (S1P) is linked to 17β‐estradiol (E2) activity in many estrogen‐responsive cells; in bone development the role of S1P is unclear. We studied effects of S1P on proliferation and differentiation of human osteoblasts (hOB). Ten nM E2, 1 µM S1P, or 1 µM of the S1P receptor 1 (S1PR1) agonist SEW2871 increased hOB proliferation at 24h. S1PR 1, 2, and 3 mRNAs are expressed by hOB, but not S1PR4 or S1PR5. Expression of S1PR2 was increased at 7 and 14 days of differentiation, in correspondence with osteoblast related mRNAs. Expression of S1PR1 was increased by E2 or S1P in proliferating hOB, while S1PR2 mRNA was unaffected in proliferating cells; S1PR3 was not affected by E2 or S1P. Inhibiting sphingosine kinase (SPHK) activity with sphingosine kinase inhibitor (Ski) greatly reduced the E2 proliferative effect. Both E2 and S1P increased SPHK mRNA at 24 hours in hOB. S1P promoted osteoblast proliferation via activating MAP kinase activity. Either E2 or S1P increased S1P synthesis in a fluorescent S1P assay. Interaction of E2 and S1P signaling was indicated by up‐regulation of E2 receptor mRNA after S1P treatment. E2 and S1P also promoted alkaline phosphatase expression. During osteoblast differentiation, S1P increased bone‐specific mRNAs, similarly to the effects of E2. However, E2 and S1P showed differences in the activation of some osteoblast pathways. Pathway analysis by gene expression arrays was consistent with regulation of pathways of osteoblast differentiation; collagen and cell adhesion proteins centered on Rho/Rac small GTPase signaling and Map kinase or signal transducer and activator of transcription (Stat) intermediates. Transcriptional activation also included significant increases in superoxide dismutase 1 and 2 transcription by either S1P or E2. We demonstrate that the SPHK system is a co‐mediator for osteoblast proliferation and differentiation which is mainly, but not entirely, complementary to E2, whose effects are mediated by S1PR1 and S1PR2. This article is protected by copyright. All rights reserved
  • Cx43 overexpression in osteocytes prevents osteocyte apoptosis and
           preserves cortical bone quality in aging mice

    • Abstract: Young, skeletally mature mice lacking Cx43 in osteocytes exhibit increased osteocyte apoptosis and decreased bone strength, resembling the phenotype of old mice. Further, the expression of Cx43 in bone decreases with age, suggesting a contribution of reduced Cx43 levels to the age‐related changes in the skeleton. We report herein that Cx43 overexpression in osteocytes achieved by using the DMP1‐8kb promoter (Cx43OT mice) attenuates the skeletal cortical, but not trabecular bone phenotype of aged, 14‐month‐old mice. The percentage of Cx43‐expressing osteocytes was higher in Cx43OT mice, whereas the percentage of Cx43 positive osteoblasts remained similar to wild type (WT) littermate control mice. The percentage of apoptotic osteocytes and osteoblasts was increased in aged WT mice compared to skeletally mature, 6‐month‐old WT mice, and the percentage of apoptotic osteocytes, but not osteoblasts, was decreased in age‐matched Cx43OT mice. Aged WT mice exhibited decreased bone formation and increased bone resorption as quantified by histomorphometric analysis and circulating markers, compared to skeletally mature mice. Further, aged WT mice exhibited the expected decrease in bone biomechanical structural and material properties compared to young mice. Cx43 overexpression prevented the increase in osteoclasts and decrease in bone formation on the endocortical surfaces, and the changes in circulating markers in the aged mice. Moreover, the ability of bone to resist damage was preserved in aged Cx43OT mice both at the structural and material level. All together, these findings suggest that increased Cx43 expression in osteocytes ameliorates age‐induced cortical bone changes by preserving osteocyte viability and maintaining bone formation, leading to improved bone strength. This article is protected by copyright. All rights reserved
  • Redox‐dependent bone alkaline phosphatase dysfunction drives part of the
           complex bone phenotype in mice deficient for Memo1

    • Abstract: Mediator of ErbB2‐driven cell Motility 1 (MEMO1) is an intracellular redox protein that integrates growth factors signaling with the intracellular redox state. We have previously reported that mice lacking Memo1 displayed higher plasma calcium levels and other alterations of mineral metabolism, but the underlying mechanism was unresolved and the bone phenotype was not described. Here, we show that Cre/lox‐mediated MEMO1 deletion in the whole body of C57Bl/6 mice (Memo cKO) leads to severely altered trabecular bone and lower mineralization, with preserved osteoblast and osteoclast number and activity, but altered osteoblast response to EGF and FGF2. More strikingly, Memo cKO mice display decreased alkaline phosphatase (ALP) activity in serum and in bone, while ALPL expression level is unchanged. Bone intracellular redox state is significantly altered in Memo cKO mice and we inferred that ALP dimerization was reduced in Memo cKO mice. Indeed, if ALP oxidation was similar, we found increased ALP sensitivity to detergent in Memo cKO bone leading to lower ALP dimerization capability. Thus, we report a severe bone phenotype and dysfunctional bone ALP with local alteration of the redox state in Memo cKO mice that mimics partially hypophosphatasia, independent of ALPL mutations. These findings reveal Memo as a key player in bone homeostasis and underline a role of bone redox state in controlling ALP activity. This article is protected by copyright. All rights reserved
  • An N‐ethyl‐N‐nitrosourea (ENU) mutagenized mouse model for autosomal
           dominant non‐syndromic kyphoscoliosis due to vertebral fusion

    • Abstract: Kyphosis and scoliosis are common spinal disorders that occur as part of complex syndromes or as non‐syndromic, idiopathic diseases. Familial and twin studies implicate genetic involvement, although the causative genes for idiopathic kyphoscoliosis remain to be identified. To facilitate these studies, we investigated progeny of mice treated with the chemical mutagen N‐ethyl‐N‐nitrosourea (ENU) and assessed them for morphological and radiographic abnormalities. This identified a mouse with kyphoscoliosis due to fused lumbar vertebrae, which was inherited as an autosomal dominant trait; the phenotype was designated as hereditary vertebral fusion (HVF) and the locus as Hvf. Micro‐computed tomography (CT) analysis confirmed the occurrence of non‐syndromic kyphoscoliosis due to fusion of lumbar vertebrae in HVF mice, consistent with a pattern of blocked vertebrae due to failure of segmentation. Micro‐CT scans also showed the lumbar vertebral column of HVF mice to have generalized disc narrowing, displacement with compression of the neural spine, and distorted transverse processes. Histology of lumbar vertebrae revealed HVF mice to have irregularly shaped vertebral bodies and displacement of intervertebral discs and ossification centers. Genetic mapping using a panel of single nucleotide polymorphic (SNP) loci arranged in chromosome sets and DNA samples from 23 HVF (8 males and 15 females) mice, localized Hvf to chromosome 4A3 and within a 5 Mb region containing 9 protein coding genes, 2 processed transcripts, 3 microRNAs, 5 small nuclear RNAs, 3 large intergenic non‐coding RNAs, and 24 pseudogenes. However, genome sequence analysis in this interval did not identify any abnormalities in the coding exons, or exon‐intron boundaries of any of these genes. Thus, our studies have established a mouse model for a monogenic form of non‐syndromic kyphoscoliosis due to fusion of lumbar vertebrae, and further identification of the underlying genetic defect will help elucidate the molecular mechanisms involved in kyphoscoliosis. This article is protected by copyright. All rights reserved
  • Differential adaptive response of growing bones from two female inbred
           mouse strains to voluntary cage wheel running

    • Abstract: The phenotypic response of bones differing in morphological, compositional, and mechanical traits to an increase in loading during growth is not well understood. Herein, we tested whether bones of two inbred mouse strains that assemble differing sets of traits to achieve mechanical homeostasis at adulthood would show divergent responses to voluntary cage wheel running. Female A/J and C57BL6/J (B6) 4‐week‐old mice were provided unrestricted access to a standard cage wheel for 4 weeks. A/J mice have narrow and highly mineralized femora and B6 mice have wide and less mineralized femora. Both strains averaged 2 – 9.5 km of running per day, with the average‐distance run between strains not significantly different (p = 0.133). Exercised A/J femora showed an anabolic response to exercise with the diaphyses showing a 2.8% greater total area (Tt.Ar, p = 0.06) and 4.7% greater cortical area (Ct.Ar, p = 0.012) compared to controls. In contrast, exercised B6 femora showed a 6.2% (p
  • The interaction of BMP2‐induced defect healing in rat and fixator
           stiffness modulates matrix alignment and contraction

    • Abstract: Successful fracture healing requires a tight interplay between mechanical and biological cues. In vitro studies illustrated that mechanical loading modulates BMP signaling. However, in the early phases of large bone defect regeneration in vivo the underlying mechanisms leading to this mechanosensation remained unknown.We investigated the interaction of BMP2 stimulation and mechanical boundary conditions in a rat critical‐sized femoral defect model (5 mm) stabilized with three distinctly different external fixator stiffness. Defects were treated with 5 µg rhBMP2 loaded on an absorbable collagen sponge. Early matrix alignment was monitored by second‐harmonic generation imaging. Bony bridging of defects and successive healing was monitored by histology at day 7 and day 14 as well as in vivo microCT at days 10, 21, and 42 postoperative. Femora harvested at day 42 were characterized mechanically assessing torsional load to failure ex vivo.At tissue level, differences between groups were visible at day 14 with manifest bone formation in the microCT. Histologically, we observed prolonged chondrogenesis upon flexible fixation while osteogenesis started earlier after rigid and semi‐rigid fixation. At later time points, there was a boost of bone tissue formation upon flexible fixation whereas other groups already displayed signs of tissue maturation.Based on gene expression profiling we analyzed the mechanobiological interplay. Already at day 3, these analyses revealed differences in expression pattern, specifically of genes involved in extracellular matrix formation. Gene regulation correlating with fixator stiffness was pronounced at day 7 comprising genes related to immunological processes and cellular contraction. The influence of loading on matrix contraction was further investigated and confirmed in a 3D bioreactor.Taken together, we demonstrate an early onset of mechanical conditions influencing BMP2‐induced defect healing and shed light on gene regulatory networks associated with extracellular matrix organization and contraction that seemed to directly impact healing outcomes. This article is protected by copyright. All rights reserved

    • Abstract: Hydration status significantly affects the toughness of bone. In addition to the collagen phase, recent evidence shows that glycosaminoglycans (GAGs) of proteoglycans (PGs) in the extracellular matrix also play a pivotal role in regulating the tissue‐level hydration status of bone, thereby affecting the tissue‐level toughness of bone. In this study, we hypothesized that the amount of GAGs in bone matrix decreased with age and such changes would lead to reduction in bound water and subsequently result in a decrease in the tissue‐level toughness of bone. To test the hypothesis, nanoscratch tests were conducted to measure the tissue‐level toughness of human cadaveric bone specimens, which were procured only from male donors in three different age groups: young (26 ± 6 years old), mid‐aged (52 ± 5 years old) and elderly (73 ± 5 years old), with six donors in each group. Biochemical and histochemical assays were performed to determine the amount and major subtypes of GAGs and proteoglycans in bone matrix. In addition, low‐field NMR measurements were implemented to determine bound water content in bone matrix. The results demonstrated that aging resulted in a statistically significant reduction (17%) of GAGs in bone matrix. Concurrently, a significant deterioration (20%) of tissue‐level toughness of bone with age was observed. Most importantly, the deteriorated tissue‐level toughness of bone was associated significantly with the age‐related reduction (40%) of bound water, which was partially induced by the decrease of GAGs in bone matrix. Furthermore, we identified that chondroitin sulfate (CS) was a major subtype of GAGs and the amount of CS decreased with aging in accompany with a decrease of biglycan that is a major subtype of PGs in bone. The findings of this study suggests that reduction of GAGs in bone matrix is likely one of the molecular origins for age‐related deterioration of bone quality. This article is protected by copyright. All rights reserved

    • Abstract: Tissue engineering is a promising branch of regenerative medicine, but its clinical application remains limited as thorough knowledge of the in vivo repair processes in these engineered implants is limited. Common techniques to study the different phases of bone repair in mice are destructive and thus not optimal to gain insight into the dynamics of this process. Instead, multiphoton‐intravital microscopy allows visualization of (sub)cellular processes at high resolution and frequency over extended periods of time when combined with an imaging window that permits optical access to implants in vivo. In this study, we have developed and validated an ectopic imaging window that can be placed over a tissue‐engineered construct implanted in mice. This approach did not interfere with the biological processes of bone regeneration taking place in these implants, as evidenced by histological and μCT‐based comparison to control ectopic implants. The ectopic imaging window permitted tracking of individual cells over several days in vivo. Furthermore, the use of fluorescent reporters allowed visualization of the onset of angiogenesis and osteogenesis in these constructs. Taken together, this novel imaging window will facilitate further analysis of the spatiotemporal regulation of cellular processes in bone tissue‐engineered implants and provides a powerful tool to enhance the therapeutic potential of bone tissue engineering. This article is protected by copyright. All rights reserved
  • Early signs of bone and cartilage changes induced by treadmill exercise in

    • Abstract: This study aims to investigate the earliest alterations of bone and cartilage tissues as a result of different exercise protocols in the knee joint of Wistar rats. We hypothesize that pre‐training to a continuous intense running protocol would protect the animals from cartilage degeneration. Three groups of animals were used: i) an adaptive (pre‐training) running group that ran for 8 weeks with gradually increasing velocity and time of running followed by a constant running program which was 6 weeks of 1.12 km/h running per day, ii) a non‐adaptive running (constant running) group that initially rested for 8 weeks followed by 6 weeks of constant running and, iii) a non‐ running (control) group. At week 8, 14 and 20 bone and cartilage were analyzed. Both running groups developed mild symptoms of cartilage irregularities, such as chondrocyte hypertrophy and cell clustering in different cartilage zones, in particular after the adaptive running protocol. As a result of physical training in the adaptive running exercise a dynamic response of bone was detected at week 8, where bone growth was enhanced. Conversely, the thickness of epiphyseal trabecular and subchondral bone (at week 14) was reduced due to the constant running in the period between 8 and 14 weeks. Finally, the intermediate differences between the two running groups disappeared after both groups had a resting period (from 14 to 20 weeks). The adaptive running group showed an increase in aggrecan gene expression and reduction of MMP2 expression after the initial 8 weeks running. Thus, the running exercise models in this study showed mild bone and cartilage/chondrocyte alterations that can be considered as early stage osteoarthritis. The pre‐training adaptive protocol before constant intense running did not protect for mild cartilage degeneration. This article is protected by copyright. All rights reserved
  • Phosphorus Balance in Adolescent Girls and the Effect of Supplemental
           Dietary Calcium

    • Abstract: There are limited data on phosphorus balance and the effect of dietary calcium supplements on phosphorus balance in adolescents. The purpose of this study was to determine phosphorus balance and the effect of increasing dietary calcium intake with a supplement on net phosphorus absorption and balance in healthy adolescent girls. This study utilized stored urine, fecal, and diet samples from a previously conducted study that focused on calcium balance. Eleven healthy girls ages 11 to 14 years participated in a randomized crossover study, which consisted of two 3‐week periods of a controlled diet with low (817 ± 19.5 mg/d) or high (1418 ± 11.1 mg/d) calcium, separated by a 1‐week washout period. Phosphorus intake was controlled at the same level during both placebo and calcium supplementation (1435 ± 23.5 and 1453 ± 28.0 mg/d, respectively, p = 0.611). Mean phosphorus balance was positive by about 200 mg/d and was unaffected by the calcium supplement (p = 0.826). Urinary phosphorus excretion was lower with the calcium supplement (535 ± 42 versus 649 ± 41 mg/d, p = 0.013), but fecal phosphorus and net phosphorus absorption were not significantly different between placebo and calcium supplement (553 ± 60 versus 678 ± 63 versus mg/d, p = 0.143; 876 ± 62 versus 774 ± 64 mg/d, p = 0.231, respectively). Dietary phosphorus underestimates using a nutrient database compared with the content measured chemically from meal composites by ∼40%. These results show that phosphorus balance is positive in girls during adolescent growth and that a calcium dietary supplement to near the current recommended level does not affect phosphorus balance when phosphorus intake is at 1400 mg/d, a typical US intake level. © 2017 American Society for Bone and Mineral Research.
  • GATA4 Directly Regulates Runx2 Expression and Osteoblast Differentiation

    • Abstract: GATA4 is a zinc‐finger transcription factor that is a pioneer factor in various tissues and regulates tissue‐specific gene regulation. In vivo deletion of Gata4 using Cre‐recombinase under the control of the Col1a1 2.3 kb promoter showed significantly reduced values for trabecular bone properties by microCT analysis of femur and tibia of 14‐week‐old male and female mice, suggesting GATA4 is necessary for maintaining normal adult bone phenotype. Quantitative PCR analysis revealed higher expression of Gata4 in trabecular bone compared with cortical bone, suggesting a role for GATA4 in maintaining normal trabecular bone mass. In vivo and in vitro, reduction of Gata4 correlates with reduced Runx2 gene expression, along with reduced osteoblast mineralization. To determine if Runx2 is a direct target of GATA4, chromatin immunoprecipitation (ChIP) was performed, and it demonstrated that GATA4 is recruited to the two Runx2 promoters and an enhancer region. Furthermore, when Gata4 is knocked down, the chromatin at the Runx2 region is not open, as detected by DNase assays and ChIP with antibodies to the open chromatin marks H3K4me2 (histone 3 lysine 4 dimethylation) and H3K27ac (histone 3 lysine 27 acetylation) and the closed chromatin mark H3K27me2 (histone 3 lysine 27 trimethylation). Together, the data suggest that GATA4 binds near the Runx2 promoter and enhancer and helps maintain open chromatin to regulate Runx2 expression leading to bone mineralization. © 2017 The
      Authors . JBMR Plus is published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research.
  • Serum Calcium to Phosphorous (Ca/P) Ratio Is a Simple, Inexpensive, and
           Accurate Tool in the Diagnosis of Primary Hyperparathyroidism

    • Abstract: Primary hyperparathyroidism (PHPT) diagnosis is challenging and is based on serum calcium (Ca) and parathyroid hormone (PTH). Because serum Ca and phosphorous (P) are inversely related in PHPT, we investigated the diagnostic value of the serum Ca/P ratio in the diagnosis of PHPT. We report a single‐center, case‐controlled, retrospective study including 97 patients with documented PHPT and compared them with those of 96 controls (C). The main outcome measures were: serum PTH, 25‐OH vitamin D, Ca, P, albumin, and creatinine. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of the serum Ca/P ratio were calculated. The results were verified using an independent, anonymous set of data extracted from a laboratory database containing over 900 million entries. A total of 35 (36.1%) PHPT patients had normocalcemic PHPT (NCHPT). Ca and PTH were significantly higher in PHPT than in C (p 
  • Cytokine Mixtures Mimicking Secretomes From Mesenchymal Stem Cells Improve
           Medication‐Related Osteonecrosis of the Jaw in a Rat Model

    • Abstract: Recently, several studies have demonstrated that intravenous administration of mesenchymal stem cells (MSCs) improve medication‐related osteonecrosis of the jaw (MRONJ), and paracrine effects of secretomes from MSCs have been hypothesized as the primary contributors. These secretomes in conditioned media from human MSCs (MSC‐CM) were previously demonstrated to promote bone and tissue regeneration. Because MSC‐CM contain cytokines monocyte chemoattractant protein (MCP)‐1, insulin growth factor (IGF)‐1, and vascular endothelial growth factor (VEGF) at relatively higher concentrations than other factors, these cytokines were considered as relevant active factors for tissue regeneration. By mixing the recombinant proteins of MCP‐1, IGF‐1, and VEGF, included at the same concentrations in MSC‐CM, we prepared cytokine mixtures mimicking MSC‐CM and then evaluated its therapeutic effects in a rat MRONJ model. In vitro, cytokine mixtures promoted osteogenic differentiation, migration, and proliferation of rat MSCs. In addition, these maintained osteoclastic function. In vivo, we used a rat MRONJ model to examine therapeutic effects of the cytokine mixtures through intravenous administration. In MSC‐CM or cytokine mixture group, open alveolar sockets in 66% or 67% of the rats with MRONJ, respectively, healed with complete soft tissue coverage and socket bones, whereas in the other groups, the exposed necrotic bone with inflamed soft tissue remained. Histological analysis revealed new bone formation and the appearance of osteoclasts in MSC‐CM or cytokine mixture group; however, osteoclasts were significantly reduced in the other groups. Thus, we concluded that intravenous administration of cytokine mixtures might be an effective therapeutic modality for treating patients with MRONJ. © 2017 The
      Authors JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research
  • Ed Bd, Masthead, Comm List and TOC

  • Genetic Risk Factors for Atypical Femoral Fractures (AFFs): A Systematic

    • Abstract: Atypical femoral fractures (AFFs) are uncommon and have been associated particularly with long‐term antiresorptive therapy, including bisphosphonates. Although the pathogenesis of AFFs is unknown, their identification in bisphosphonate‐naïve individuals and in monogenetic bone disorders has led to the hypothesis that genetic factors predispose to AFF. Our aim was to review and summarize the evidence for genetic factors in individuals with AFF. We conducted structured literature searches and hand‐searching of conference abstracts/reference lists for key words relating to AFF and identified 2566 citations. Two individuals independently reviewed citations for (i) cases of AFF in monogenetic bone diseases and (ii) genetic studies in individuals with AFF. AFFs were reported in 23 individuals with the following 7 monogenetic bone disorders (gene): osteogenesis imperfecta (COL1A1/COL1A2), pycnodysostosis (CTSK), hypophosphatasia (ALPL), X‐linked osteoporosis (PLS3), osteopetrosis, X‐linked hypophosphatemia (PHEX), and osteoporosis pseudoglioma syndrome (LRP5). In 8 cases (35%), the monogenetic bone disorder was uncovered after the AFF occurred. Cases of bisphosphonate‐naïve AFF were reported in pycnodysostosis, hypophosphatasia, osteopetrosis, X‐linked hypophosphatemia, and osteoporosis pseudoglioma syndrome. A pilot study in 13 AFF patients and 268 controls identified a greater number of rare variants in AFF cases using exon array analysis. A whole‐exome sequencing study in 3 sisters with AFFs showed, among 37 shared genetic variants, a p.Asp188Tyr mutation in the GGPS1 gene in the mevalonate pathway, critical to osteoclast function, which is also inhibited by bisphosphonates. Two studies completed targeted ALPL gene sequencing, an ALPL heterozygous mutation was found in 1 case of a cohort of 11 AFFs, whereas the second study comprising 10 AFF cases did not find mutations in ALPL. Targeted sequencing of ALPL, COL1A1, COL1A2, and SOX9 genes in 5 cases of AFF identified a variant in COL1A2 in 1 case. These findings suggest a genetic susceptibility for AFFs. A large multicenter collaborative study of well‐phenotyped AFF cases and controls is needed to understand the role of genetics in this uncommon condition. © 2017 The
      Authors JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.
  • Primary Osteoporosis in Young Adults: Genetic Basis and Identification of
           Novel Variants in Causal Genes

    • Abstract: Genetic determinants contribute to osteoporosis and enhance the risk of fracture. Genomewide association studies of unselected population‐based individuals or families have identified polymorphisms in several genes related to low bone density, but not in osteoporotic patients with Z‐score 
  • Parathyroid Hormone Signaling in Osteocytes

    • Abstract: Osteocytes are the most abundant cell type in bone and play a central role in orchestrating skeletal remodeling, in part by producing paracrine‐acting factors that in turn influence osteoblast and osteoclast activity. Recent evidence has indicated that osteocytes are crucial cellular targets of parathyroid hormone (PTH). Here, we will review the cellular and molecular mechanisms through which PTH influences osteocyte function. Two well‐studied PTH target genes in osteocytes are SOST and receptor activator of NF‐κB ligand (RANKL). The molecular mechanisms through which PTH regulates expression of these two crucial target genes will be discussed. Beyond SOST and RANKL, PTH/PTH‐related peptide (PTHrP) signaling in osteocytes may directly influence the way osteocytes remodel their perilacunar environment to influence bone homeostasis in a cell‐autonomous manner. Here, I will highlight novel, additional mechanisms used by PTH and PTHrP to modulate bone homeostasis through effects in osteocytes. © 2017 The
      Authors . JBMR Plus is published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research.
  • A Novel Distal Enhancer Mediates Inflammation‐, PTH‐, and Early Onset
           Murine Kidney Disease‐Induced Expression of the Mouse Fgf23 Gene

    • Abstract: Fibroblast growth factor 23 (FGF23) production is regulated by both calciotropic hormones and inflammation. Consistent with this, elevated FGF23 levels are associated with inflammatory markers as well as parathyroid hormone (PTH) in various disease states, including chronic kidney disease (CKD). However, the molecular mechanisms underpinning Fgf23 transcription in response to these regulators are largely unknown. We therefore utilized chromatin immunoprecipitation followed by DNA sequencing (ChIP‐seq) data from an osteocyte cell line to identify potential regulatory regions of the Fgf23 gene. Based on ChIP‐seq analysis of enhancer‐associated histone modifications, including H3K4 methylation and H3K9 acetylation, we discovered several potential enhancers for Fgf23, one of which was located 16kb upstream of the gene's transcriptional start site. Deletion of this putative enhancer from the mouse genome using CRISPR‐Cas9 technology led to lower bone, thymus, and spleen expression of Fgf23 mRNA without altering circulating levels of the intact hormone, although as previously reported, only bone displayed significant basal expression. Nevertheless, lack of the −16kb enhancer blunted FGF23 upregulation in a tissue‐specific manner by the acute inflammatory inducers lipopolysaccharide (LPS), interleukin‐1‐beta (IL‐1β), and tumor necrosis factor‐alpha (TNFα) in bone, non‐osseous tissues, and in circulation. Lack of the −16kb enhancer also inhibited PTH‐induced bone Fgf23 mRNA. Moreover, the absence of this Fgf23 enhancer in an oxalate diet‐induced murine CKD model prevented the early onset induction of osseous, renal, and thymic Fgf23 mRNA levels and led to a significant blunting of elevated circulating intact FGF23 levels. These results suggest that −16kb enhancer mediates the induction of Fgf23 by inflammation and PTH and facilitates the increase in FGF23 expression in a murine model of CKD. As exemplified herein, these Fgf23 enhancer‐deleted mice will provide a unique model in which to study the role of FGF23 expression in inflammatory diseases. © 2017 The
      Authors . JBMR Plus is published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research.
  • Sclerostin Antibody Treatment Stimulates Bone Formation to Normalize Bone
           Mass in Male Down Syndrome Mice

    • Abstract: Down syndrome (DS), characterized by trisomy of human chromosome 21, is associated with a variety of endocrine disorders as well as profound skeletal abnormalities. The low bone mass phenotype in DS is defined by low bone turnover due to decreased osteoclast and osteoblast activity, decreasing the utility of antiresorptive agents in people with DS. Sclerostin antibody (SclAb) is a therapeutic candidate currently being evaluated as a bone anabolic agent. Scl, the product of the sclerostin gene (SOST), inhibits bone formation through its inhibition of Wnt signaling. SclAb increases bone mass by suppressing the action of the endogenous inhibitor of bone formation, Scl. To examine the effects of SclAb on the DS bone phenotype, 8‐week‐old male wild‐type (WT) andTs65Dn DS mice were treated with 4 weekly iv injections of 100 mg/kg SclAb. Dual‐energy X‐ray absorptiometry (DXA), microCT, and dynamic histomorphometry analyses revealed that SclAb had a significant anabolic effect on both age‐matched WT littermate controls and Ts65Dn DS mice that was osteoblast mediated, without significant changes in osteoclast parameters. SclAb treatment significantly increased both cortical and trabecular bone mass at multiple sites; SclAb treatment resulted in the normalization of Ts65Dn bone mineral density (BMD) to WT levels in the proximal tibia, distal femur, and whole body. Ex vivo bone marrow cultures demonstrated that SclAb increased the recruitment of the mesenchymal progenitors into the osteoblast lineage, as indicated by increased alkaline phosphatase–positive colonies, with no effect on osteoclast differentiation. Together, in the setting of a murine model of DS and decreased bone turnover, SclAb had a potent anabolic effect. SclAb stimulated bone formation and increased osteoblastogenesis without affecting osteoclastogenesis or bone resorption. These data suggest that SclAb is a promising new therapy to improve bone mass and reduce fracture risk in the face of the low bone mass and turnover prevalent in the DS population. © 2017 The
      Authors JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.
  • Flare‐Up After Maxillofacial Surgery in a Patient With Fibrodysplasia
           Ossificans Progressiva: An [18F]‐NaF PET/CT Study and a Systematic

    • Abstract: Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder leading to progressive heterotopic ossifications (HO) of muscles, tendons, and ligaments, which can be induced by trauma or by surgery. Despite strong medical advice to the contrary, an FOP patient insisted on surgery to alleviate her complete trismus, which caused an unbearable impact on her quality of life (QOL). The entire trismus history of this FOP patient is presented. [18F]‐NaF position emission tomography/computed tomography (PET/CT) scans were introduced as an imaging method for heterotopic bone formation activity. To place our findings into context, a systematic review on jaw surgery in FOP was performed. After falling down the stairs, a 9‐year‐old patient developed mobility impairment of her left‐sided jaw. During the following 13 years bone scintigraphy showed persistent activity of the disease leading to progressive left‐sided zygomatico‐mandibular fusion by HO, resulting in complete trismus. Within 1 month after HO removal on the left side and a matching right coronoidectomy, [18F]‐NaF PET/CT demonstrated a substantial flare‐up activity followed by new HO in both masseter and temporalis muscles. Despite recurrent HO and trismus her QOL increased due to a stable increased interincisal opening of 5.5 mm. Although systematic review reveals a 100% risk of HO recurrence after jaw surgery, information on improved QOL is scarce. In conclusion, surgery in FOP may be beneficial for QOL despite new HO formation. Assessment of disease activity using [18F]‐NaF PET/CT is possible before HO is evident on CT and may serve as a new and quantitative marker of the disease. © 2017 The
      Authors . JBMR Plus Published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research.
School of Mathematical and Computer Sciences
Heriot-Watt University
Edinburgh, EH14 4AS, UK
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Fax: +00 44 (0)131 4513327
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