期刊,Journal of bone and mineral research 2022年37卷6期_国家学术搜索

期刊信息/Journal information

Journal of bone and mineral research

Mary Ann Liebert, Inc

主办单位：Mary Ann Liebert, Inc

国际刊号：0884-0431

Journal of bone and mineral research/Journal Journal of bone and mineral researchSCIISTPAHCI

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Remembering Dr Arnold J Kahn: June 18, 1936–June 16, 2021

Nicola C PartridgeSteven R CummingsAlberta ZalloneZvi Bar‐Shavit...

2页

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New and Unexpected Roles for Primary Cilia in Coordinating Response to Mechanical Load in Articular and Growth Plate Cartilages

Rosa Serra

2页

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Ciliary IFT88 Protects Coordinated Adolescent Growth Plate Ossification From Disruptive Physiological Mechanical Forces

Clarissa R CoveneyHasmik J SamvelyanJadwiga Miotla‐ZarebskaJosephine Carnegie...

16页

查看更多>>摘要：ABSTRACT Compared with our understanding of endochondral ossification, much less is known about the coordinated arrest of growth defined by the narrowing and fusion of the cartilaginous growth plate. Throughout the musculoskeletal system, appropriate cell and tissue responses to mechanical force delineate morphogenesis and ensure lifelong health. It remains unclear how mechanical cues are integrated into many biological programs, including those coordinating the ossification of the adolescent growth plate at the cessation of growth. Primary cilia are microtubule‐based organelles tuning a range of cell activities, including signaling cascades activated or modulated by extracellular biophysical cues. Cilia have been proposed to directly facilitate cell mechanotransduction. To explore the influence of primary cilia in the mouse adolescent limb, we conditionally targeted the ciliary gene Intraflagellar transport protein 88 (Ift88fl/fl) in the juvenile and adolescent skeleton using a cartilage‐specific, inducible Cre (AggrecanCreERT2 Ift88fl/fl). Deletion of IFT88 in cartilage, which reduced ciliation in the growth plate, disrupted chondrocyte differentiation, cartilage resorption, and mineralization. These effects were largely restricted to peripheral tibial regions beneath the load‐bearing compartments of the knee. These regions were typified by an enlarged population of hypertrophic chondrocytes. Although normal patterns of hedgehog signaling were maintained, targeting IFT88 inhibited hypertrophic chondrocyte VEGF expression and downstream vascular recruitment, osteoclastic activity, and the replacement of cartilage with bone. In control mice, increases to physiological loading also impair ossification in the peripheral growth plate, mimicking the effects of IFT88 deletion. Limb immobilization inhibited changes to VEGF expression and epiphyseal morphology in Ift88cKO mice, indicating the effects of depletion of IFT88 in the adolescent growth plate are mechano‐dependent. We propose that during this pivotal phase in adolescent skeletal maturation, ciliary IFT88 protects uniform, coordinated ossification of the growth plate from an otherwise disruptive heterogeneity of physiological mechanical forces. ? 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

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Primary Cilia Direct Murine Articular Cartilage Tidemark Patterning Through Hedgehog Signaling and Ambulatory Load

Danielle RuxKimberly HelbigBiao HanCourtney Cortese...

20页

查看更多>>摘要：ABSTRACT Articular cartilage (AC) is essential for body movement but is highly susceptible to degenerative diseases and has poor self‐repair capacity. To improve current subpar regenerative treatments, developmental mechanisms of AC should be clarified and, specifically, how its postnatal multizone organization is acquired. Primary cilia are cell surface organelles crucial for mammalian tissue morphogenesis. Although their importance for chondrocyte function is appreciated, their specific roles in postnatal AC morphogenesis remain unclear. To explore these mechanisms, we used a murine conditional loss‐of‐function approach (Ift88‐flox) targeting joint‐lineage progenitors (Gdf5Cre) and monitored postnatal knee AC development. Joint formation and growth up to juvenile stages were largely unaffected. However, mature AC (aged 2?months) exhibited disorganized extracellular matrix, decreased aggrecan and collagen II due to reduced gene expression (not increased catabolism), and marked reduction of AC modulus by 30%–50%. In addition, and unexpectedly, we discovered that tidemark patterning was severely disrupted, as was hedgehog signaling, and exhibited specificity based on regional load‐bearing functions of AC. Interestingly, Prg4 expression was markedly increased in highly loaded sites in mutants. Together, our data provide evidence that primary cilia orchestrate postnatal AC morphogenesis including tidemark topography, zonal matrix composition, and ambulation load responses. ? 2022 American Society for Bone and Mineral Research (ASBMR).

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Potential Adverse Effect of Nonsteroidal Anti‐Inflammatory Drugs (NSAIDs) on Bisphosphonate Efficacy: An Exploratory Post Hoc Analysis From a Randomized Controlled Trial of Clodronate

Zhangan ZhengHelena JohanssonNicholas C. HarveyMattias Lorentzon...

8页

查看更多>>摘要：ABSTRACT Nonsteroidal anti‐inflammatory drugs (NSAIDs) have been reported to have weak but beneficial effects on bone health, including fracture risk, but many epidemiological studies are likely confounded. We explored the relationship between NSAIDs and fracture risk in a post hoc analysis of a well‐documented, randomized, placebo‐controlled study of the bisphosphonate, clodronate, in which treatment reduced osteoporotic fracture risk by 23%. Concurrent medication use at baseline was used to identify those prescribed oral NSAIDs. Only verified, incident fractures were included in the analysis. A total of 1082 (20.8%) women reported use of NSAIDs at baseline. They were slightly, but significantly, younger (mean 79 versus 80?years, p?=?0.004), heavier (mean 66.7 versus 64.7?kg, p?<?0.001) than nonusers, with slightly higher femoral neck bone mineral density (FN‐BMD, 0.66 versus 0.64?g/cm2, p?<?0.001). In an adjusted model, NSAID use was associated with a significant increase in osteoporotic fracture risk over the 3‐year study period (hazard ratio [HR] 1.27; 95% confidence interval [CI], 1.01–1.62; p?=?0.039). However, this increase in risk was not statistically significant in the placebo group (HR 1.11; 95% CI, 0.81–1.52). In women receiving clodronate, the effect of the bisphosphonate to reduce osteoporotic fracture risk was not observed in those receiving NSAIDs (HR 0.95; 95% CI, 0.65–1.41; p?=?0.81) in contrast to those not using NSAIDs (HR 0.71; 95% CI, 0.58–0.89; p?=?0.002). In a subset with hip BMD repeated at 3?years, BMD loss during clodronate therapy was greater in those women receiving NSAIDs than in nonusers (eg, total hip ?2.75% versus ?1.27%, p?=?0.078; femoral neck ?3.06% versus ?1.12%, p?=?0.028), and was not significantly different from that observed in women receiving placebo. The efficacy of the bisphosphonate, clodronate, to reduce fracture risk was largely negated in those receiving NSAIDs. Although the mechanism is unclear, this clinically significant observation requires exploration in studies of commonly used bisphosphonates. ? 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

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Identification of ENPP1 Haploinsufficiency in Patients With Diffuse Idiopathic Skeletal Hyperostosis and Early‐Onset Osteoporosis

Hajime KatoAnenya J AnshEthan R LesterYuka Kinoshita...

11页

查看更多>>摘要：ABSTRACT Homozygous ENPP1 mutations are associated with autosomal recessive hypophosphatemic rickets type 2 (ARHR2), severe ossification of the spinal ligaments, and generalized arterial calcification of infancy type 1. There are a limited number of reports on phenotypes associated with heterozygous ENPP1 mutations. Here, we report a series of three probands and their families with heterozygous and compound heterozygous ENPP1 mutations. The first case (case 1) was a 47‐year‐old male, diagnosed with early‐onset osteoporosis and low‐normal serum phosphate levels, which invoked suspicion for hypophosphatemic rickets. The second and third cases were 77‐ and 54‐year‐old females who both presented with severe spinal ligament ossification and the presumptive diagnosis of diffuse idiopathic skeletal hyperostosis (DISH). Upon workup, fibroblast growth factor 23 (FGF23) was noted to be relatively high in case 2 and serum phosphorous was low‐normal in case 3, and the diagnoses of X‐linked hypophosphatemic rickets (XLH) and ARHR2 were considered. Genetic testing for genes related to congenital hypophosphatemic rickets was therefore performed, revealing heterozygous ENPP1 variants in cases 1 and 2 (case 1, c.536A>G, p.Asn179Ser; case 2, c.1352A>G, p.Tyr451Cys) and compound heterozygous ENPP1 variants in case 3 constituting the same variants present in cases 1 and 2 (c.536A>G, p.Asn179Ser and c.1352A>G, p.Tyr451Cys). Several in silico tools predicted the two variants to be pathogeneic, a finding confirmed by in vitro biochemical analysis demonstrating that the p.Asn179Ser and p.Tyr451Cys ENPP1 variants possessed a catalytic velocity of 45% and 30% compared with that of wild‐type ENPP1, respectively. Both variants were therefore categorized as pathogenic loss‐of‐function mutations. Our findings suggest that ENPP1 mutational status should be evaluated in patients presenting with the diagnosis of idiopathic DISH, ossification of the posterior longitudinal ligament (OPLL), and early‐onset osteoporosis. ? 2022 American Society for Bone and Mineral Research (ASBMR).

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Effect of Denosumab Compared With Risedronate on Bone Strength in Patients Initiating or Continuing Glucocorticoid Treatment

Piet GeusensMelissa SAM BeversBert RietbergenOsvaldo D Messina...

11页

查看更多>>摘要：ABSTRACT In a randomized clinical trial in patients initiating glucocorticoid therapy (GC‐I) or on long‐term therapy (GC‐C), denosumab every 6 months increased spine and hip bone mineral density at 12 and 24?months significantly more than daily risedronate. The aim of this study was to evaluate the effects of denosumab compared with risedronate on bone strength and microarchitecture measured by high‐resolution peripheral quantitative computed tomography (HR‐pQCT) in GC‐I and GC‐C. A subset of 110 patients had high‐resolution peripheral quantitative computed tomography (HR‐pQCT) scans of the distal radius and tibia at baseline and at 12 and 24?months. Cortical and trabecular microarchitecture were assessed with standard analyses and failure load (FL) with micro‐finite element analysis. At the radius at 24?months, FL remained unchanged with denosumab and significantly decreased with risedronate in GC‐I (?4.1%, 95% confidence interval [CI] ?6.4, ?1.8) and, in GC‐C, it significantly increased with denosumab (4.3%, 95% CI 2.1, 6.4) and remained unchanged with risedronate. Consequently, FL was significantly higher with denosumab than with risedronate in GC‐I (5.6%, 95% CI 2.4, 8.7, p?<?0.001) and in GC‐C (4.1%, 95% CI 1.1, 7.2, p?=?0.011). We also found significant differences between denosumab and risedronate in percentage changes in cortical and trabecular microarchitectural parameters in GC‐I and GC‐C. Similar results were found at the tibia. To conclude, this HR‐pQCT study shows that denosumab is superior to risedronate in terms of preventing FL loss at the distal radius and tibia in GC‐I and in increasing FL at the radius in GC‐C, based on significant differences in changes in the cortical and trabecular bone compartments between treatment groups in GC‐I and GC‐C. These results suggest that denosumab could be a useful therapeutic option in patients initiating GC therapy or on long‐term GC therapy and may contribute to treatment decisions in this patient population. ? 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

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An Osteoporosis Susceptibility Allele at 11p15 Regulates SOX6 Expression by Modulating TCF4 Chromatin Binding

Dong‐Li ZhuXiao‐Feng ChenXiao‐Rong ZhouShou‐Ye Hu...

9页

查看更多>>摘要：ABSTRACT Osteoporosis is an age‐related complex disease clinically diagnosed with bone mineral density (BMD). Although several genomewide association studies (GWASs) have discovered multiple noncoding genetic variants at 11p15 influencing osteoporosis risk, the functional mechanisms of these variants remain unknown. Through integrating bioinformatics and functional experiments, a potential functional single‐nucleotide polymorphism (SNP; rs1440702) located in an enhancer element was identified and the A allele of rs1440702 acted as an allelic specificities enhancer to increase its distal target gene SOX6 (~600 Kb upstream) expression, which plays a key role in bone formation. We also validated this long‐range regulation via conducting chromosome conformation capture (3C) assay. Furthermore, we demonstrated that SNP rs1440702 with a risk allele (rs1440702‐A) could increase the activity of the enhancer element by altering the binding affinity of the transcription factor TCF4, resulting in the upregulation expression of SOX6 gene. Collectively, our integrated analyses revealed how the noncoding genetic variants (rs1440702) affect osteoporosis predisposition via long‐range gene regulatory mechanisms and identified its target gene SOX6 for downstream biomarker and drug development. ? 2022 American Society for Bone and Mineral Research (ASBMR).

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Suppression of Sost/Sclerostin and Dickkopf‐1 Augment Intervertebral Disc Structure in Mice

Paul NiziolekDaniel EdwardsRoy ChoiErica L Clinkenbeard...

14页

查看更多>>摘要：ABSTRACT Intervertebral disc (IVD) degeneration is a leading cause of low back pain, characterized by accelerated extracellular matrix breakdown and IVD height loss, but there is no approved pharmacological therapeutic. Deletion of Wnt ligand competitor Lrp5 induces IVD degeneration, suggesting that Wnt signaling is essential for IVD homeostasis. Therefore, the IVD may respond to neutralization of Wnt ligand competitors sost(gene)/sclerostin(protein) and/or dickkopf‐1 (dkk1). Anti‐sclerostin antibody (scl‐Ab) is an FDA‐approved bone therapeutic that activates Wnt signaling. We aimed to (i) determine if pharmacological neutralization of sclerostin, dkk1, or their combination would stimulate Wnt signaling and augment IVD structure and (ii) determine the prolonged adaptation of the IVD to global, persistent deletion of sost. Nine‐week‐old C57Bl/6J female mice (n?=?6–7/group) were subcutaneously injected 2×/week for 5.5?weeks with scl‐Ab (25?mg/kg), dkk1‐Ab (25?mg/kg), 3:1 scl‐Ab/dkk1‐Ab (18.75:6.25?mg/kg), or vehicle (veh). Separately, IVD of sost KO and wild‐type (WT) mice (n?=?8/group) were harvested at 16?weeks of age. First, compared with vehicle, injection of scl‐Ab, dkk1‐Ab, and 3:1 scl‐Ab/dkk1‐Ab similarly increased lumbar IVD height and β‐catenin gene expression. Despite these similarities, only injection of scl‐Ab alone strengthened IVD mechanical properties and decreased heat shock protein gene expressions. Genetically and compared with WT, sost KO enlarged IVD height, increased proteoglycan staining, and imbibed IVD hydration. Notably, persistent deletion of sost was compensated by upregulation of dkk1, which consequently reduced the cell nuclear fraction for Wnt signaling co‐transcription factor β‐catenin in the IVD. Lastly, RNA‐sequencing pathway analysis confirmed the compensatory suppression of Wnt signaling and revealed a reduction of cellular stress‐related pathways. Together, suppression of sost/sclerostin or dkk1 each augmented IVD structure by stimulating Wnt signaling, but scl‐Ab outperformed dkk1‐Ab in strengthening the IVD. Ultimately, postmenopausal women prescribed scl‐Ab injections to prevent vertebral fracture may also benefit from a restoration of IVD height and health. ? 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

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Renal Clearance of Fibroblast Growth Factor‐23 (FGF23) and its Fragments in Humans

Shilpa SharmaRonit KatzCharles GinsbergAlexander Bullen...

9页

查看更多>>摘要：ABSTRACT Relative abundance of fibroblast growth factor‐23 (FGF23) measured by the C‐terminal (cFGF23, which measures both intact FGF23 and C‐terminal fragments) versus intact (iFGF23, measures only intact hormone) assays varies by kidney function in humans. Differential kidney clearance may explain this finding. We measured cFGF23 and iFGF23 in the aorta and bilateral renal veins of 162 patients with essential hypertension undergoing renal angiography. Using multivariable linear regression, we examined factors associated with aorta to renal vein reduction of FGF23 using both assays. Similar parameters and with addition of urine concentrations of cFGF23 and iFGF23 were measured in six Wistar rats. Mean ± standard deviation (SD) age was 54?±?12?years, 54% were women, and mean creatinine clearance was 72?±?48?mL/min/100?g. The human kidney reduced the concentrations of both cFGF23 (16%?±?12%) and iFGF23 (21%?±?16%), but reduction was higher for iFGF23. Greater kidney creatinine and PTH reductions were each independently associated with greater reductions of both cFGF23 and iFGF23. The greater kidney reduction of iFGF23 compared to cFGF23 appeared stable and consistent across the range of creatinine clearance evaluated. Kidney clearance was similar, and urine concentrations of both assays were low in the rat models, suggesting kidney metabolism of both cFGF23 and iFGF23. Renal reduction of iFGF23 is higher than that of creatinine and cFGF23. Our data suggest that FGF23 is metabolized by the kidney. However, the major cell types involved in metabolization of FGF23 requires future study. Kidney clearance of FGF23 does not explain differences in C‐terminal and intact moieties across the range of kidney function. ? 2022 American Society for Bone and Mineral Research (ASBMR).

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NSTL
Wiley