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Previous studies have suggested an association between bone mineral density (BMD) and heart failure (HF) risk that may be race-dependent.We evaluated the relationship between BMD and incident HF in a cohort of older adults, the Health, Aging, and Body Composition (Health ABC) study (n = 2835), and next performed a pooled analysis involving a second older cohort, the Cardiovascular Health Study (n = 1268). Hip BMD was measured by dual-energy X-ray absorptiometry in both cohorts and spine BMD by computed tomography in a subset from Health ABC.In Health ABC, lower BMD at the total hip was associated with higher incident HF in Black women after multivariable adjustment. Similar associations were found for BMD at the femoral neck and spine. In both cohorts, pooled analysis again revealed an association between lower total hip BMD and increased risk of HF in Black women (HR = 1.41 per 0.1-g/cmLower BMD was associated with higher risk of HF and especially HFpEF in older Black women and White men, highlighting the need for additional investigation into underlying mechanisms.

NMR measurement: Sample preparation and analysis

Purpose: We hypothesized that in multiple myeloma cells (MMC), high membrane biosynthesis will induce acetate uptake in vitro and in vivo. Here, we studied acetate metabolism and targeting in MMC in vitro and tested the efficacy of 11C-acetate–positron emission tomography (PET) to detect and quantitatively image myeloma treatment response in vivo.Experimental design: Acetate fate tracking using 13C-edited-1H NMR (nuclear magnetic resonance) was performed to study in vitro acetate uptake and metabolism in MMC. Effects of pharmacological modulation of acetate transport or acetate incorporation into lipids on MMC cell survival and viability were assessed. Preclinical mouse MM models of subcutaneous and bone tumors were evaluated using 11C-acetate-PET/CT imaging and tissue biodistribution.Results: In vitro, NMR showed significant uptake of acetate by MMC and acetate incorporation into intracellular metabolites and membrane lipids. Inhibition of lipid synthesis and acetate transport was toxic to MMC, while sparing resident bone cells or normal B cells. In vivo, 11C-acetate uptake by PET imaging was significantly enhanced in subcutaneous and bone MMC tumors compared with unaffected bone or muscle tissue. Likewise, 11C-acetate uptake was significantly reduced in MM tumors after treatment.Conclusions: Uptake of acetate from the extracellular environment was enhanced in MMC and was critical to cellular viability. 11C-Acetate–PET detected the presence of myeloma cells in vivo, including uptake in intramedullary bone disease. 11C-Acetate–PET also detected response to therapy in vivo. Our data suggested that acetate metabolism and incorporation into lipids was crucial to MM cell biology and that 11C-acetate–PET is a promising imaging modality for MM. Clin Cancer Res; 23(2); 416–29. ©2016 AACR.

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Supplementary Figure 1 A) 1H NMR spectra (CPMG) of conditioned medium from human U266 MMC cells upon incubation for 0 (bottom), 4 (middle) or 18 (top) hours with 10 mM acetate. t-But= t-butanol standard, Lac= lactate (1.31-1.32 ppm), A= alanine (3-position at 1.5 ppm), Acetate=acetate (1.91 ppm), Glu=glutamate (2.34-2.38 ppm), Glc = glucose (5.24 ppm). Supplementary Figure 2 A) 1H NMR analysis in CPMG (top) and gHSQC (bottom) sequences of intracellular extracts from U266 upon 8h incubation with 13C-Acetate 10mM with CHC 2.5 mM (left) or vehicle (DMSO, right). Arrows: acetate peak (1.91 ppm) in HSQC sequences (13C-labeled). Supplementary Figure 3 A) Optical (GFP) and 11C-Acetate PET/CT in KaLwRij mice with bi-lateral flank subcutaneous 5TGM1 tumors (T1 and T2): imaging (i) and TAC (ii) of tumors vs. muscle, p

The Journal of Bone and Mineral Research (JBMR®), the flagship journal of the American Society for Bone and Mineral Research (ASBMR), enjoys a premiere position in its field and has a global reach. The journal uses a single-blind peer-review process whereby three editors are typically involved in assessing each submission for publication, in addition to external reviewers. Although emphasizing fairness, rigor, and transparency, this process is not immune to the influence of unconscious biases. The gender and geographic diversity of JBMR® authors, editors, and reviewers has increased over the last three decades, but whether such diversity has affected peer-review outcomes is unknown. We analyzed manuscript acceptance rates based on the gender and geographic origin of authors, reviewers, and Associate Editors. The analysis included 1662 original research articles submitted to JBMR® from September 2017 through December 2019. Gender was assigned using probabilities from an online tool and manually validated through internet searches. Predictor variables of manuscript outcome were determined with multivariate logistic regression analysis. The acceptance rate was highest when the first and last authors were of different genders, and lowest when both authors were men. Reviewer gender did not influence the outcome regardless of the genders of the first and last authors. Associate Editors from all geographical regions tended to select reviewers from their same region. The acceptance rate was highest when the Associate Editor was from Europe. Manuscripts with authors from North America and Australia/New Zealand had greater overall odds of acceptance than those from Europe and Asia. Manuscripts reviewed only by Editorial Board (EB) members had a lower acceptance rate than those refereed by non-EB reviewers or a mix of EB and non-EB reviewers. Overall, the geographical origin of authors, reviewers, and editors, as well as reviewers' EB membership may influence manuscript decisions. Yet, the JBMR® peer-review process remains largely free from gender bias. © 2022 American Society for Bone and Mineral Research (ASBMR).

The Active-Controlled Fracture Study in Postmenopausal Women With Osteoporosis at High Risk (ARCH) trial (NCT01631214; https://clinicaltrials.gov/ct2/show/NCT01631214) showed that romosozumab for 1 year followed by alendronate led to larger areal bone mineral density (aBMD) gains and superior fracture risk reduction versus alendronate alone. aBMD correlates with bone strength but does not capture all determinants of bone strength that might be differentially affected by various osteoporosis therapeutic agents. We therefore used quantitative computed tomography (QCT) and finite element analysis (FEA) to assess changes in lumbar spine volumetric bone mineral density (vBMD), bone volume, bone mineral content (BMC), and bone strength with romosozumab versus alendronate in a subset of ARCH patients. In ARCH, 4093 postmenopausal women with severe osteoporosis received monthly romosozumab 210 mg sc or weekly oral alendronate 70 mg for 12 months, followed by open-label weekly oral alendronate 70 mg for ≥12 months. Of these, 90 (49 romosozumab, 41 alendronate) enrolled in the QCT/FEA imaging substudy. QCT scans at baseline and at months 6, 12, and 24 were assessed to determine changes in integral (total), cortical, and trabecular lumbar spine vBMD and corresponding bone strength by FEA. Additional outcomes assessed include changes in aBMD, bone volume, and BMC. Romosozumab caused greater gains in lumbar spine integral, cortical, and trabecular vBMD and BMC than alendronate at months 6 and 12, with the greater gains maintained upon transition to alendronate through month 24. These improvements were accompanied by significantly greater increases in FEA bone strength (p

Mechanical loading on the skeleton stimulates bone formation. Although the exact mechanism underlying this process remains unknown, a growing body of evidence indicates that the Wnt signaling pathway is necessary for the skeletal response to loading. Recently, we showed that Wnts produced by osteoblast lineage cells mediate the osteo-anabolic response to tibial loading in adult mice. Here, we report that Wnt1 specifically plays a crucial role in mediating the mechano-adaptive response to loading. Independent of loading, short-term loss of Wnt1 in the Osx-lineage resulted in a decreased cortical bone area in the tibias of 5-month-old mice. In females, strain-matched loading enhanced periosteal bone formation in Wnt1F/F controls, but not in Wnt1F/F; OsxCreERT2 knockouts. In males, strain-matched loading increased periosteal bone formation in both control and knockout mice; however, the periosteal relative bone formation rate was 65% lower in Wnt1 knockouts versus controls. Together, these findings show that Wnt1 supports adult bone homeostasis and mediates the bone anabolic response to mechanical loading.

The enthesis is a mineralized fibrocartilage transition that attaches tendon to bone and is vital for musculoskeletal function. Despite recent studies demonstrating the necessity of muscle loading for enthesis formation, the mechanisms that regulate enthesis formation and mechanoresponsiveness remain unclear. Therefore, the current study investigated the role of the gap junction protein connexin 43 in these processes by deleting Gja1 (the Cx43 gene) in the tendon and enthesis. Compared with their wild-type (WT) counterparts, mice lacking Cx43 showed disrupted entheseal cell alignment, reduced mineralized fibrocartilage, and impaired biomechanical properties of the supraspinatus tendon entheses during postnatal development. Cx43-deficient mice also exhibited reduced ability to complete a treadmill running protocol but no apparent deficits in daily activity, metabolic indexes, shoulder muscle size, grip strength, and major trabecular bone properties of the adjacent humeral head. To examine enthesis mechanoresponsiveness, young adult mice were subjected to modest treadmill exercise. Gja1 deficiency in the tendon and enthesis reduced entheseal anabolic responses to treadmill exercise: WT mice had increased expression of Sox9, Ihh, and Gli1 and increased Brdu incorporation, whereas Cx43-deficient mice showed no changes or decreased levels with exercise. Collectively, the results demonstrated an essential role for Cx43 in postnatal tendon enthesis formation, function, and response to loading; results further provided evidence implicating a link between Cx43 function and the hedgehog signaling pathway. © 2020 American Society for Bone and Mineral Research.

Pelvic fragility fractures result in significant morbidity and their incidence has increased over the past 30 years. One of the main risk factors in skeletal fragility is bone mineral density (BMD). Most of the current literature has focused on understanding spine and hip BMD. We aimed to measure the BMD of pelvis in a cohort of post-menopausal women and compare it to BMD at other skeletal sites. A questionnaire regarding risk factors for osteoporosis was completed by each participant. DXA scan of the pelvis was performed using research software. Three areas of the pelvis corresponding to common fractures were defined on pelvic DXA: R1 = symphysis public, R2 = inferior public rami, R3 = superior public rami. Pelvic BMD was calculated as the average BMD of R1-3. BMD at each location was reported as mean and standard deviation (SD). ANOVA was used to compare BMD between R1-R3 and pelvis, femoral neck, total hip, and spine. Pearson correlation was used to correlate pelvic BMD to BMD of proximal femur and spine. BMD was compared in four participant groups: 1- osteoporosis in spine and hip, 2- osteoporosis in spine only, 3-osteoporosis in hip only, and 4- no osteoporosis in spine and hip. The effect of diabetes and obesity on BMD at various skeletal sites was analyzed. Among the one hundred postmenopausal women enrolled in the study, age was: 64 ± 8, 31% were obese (BMI ≥ 30), and 8% had a diagnosis of type 2 diabetes. Pelvic area R3 had significantly higher BMD than R1 or R2 (p0.001). Pelvic BMD (0.50 ± 0.16) was significantly lower than total hip (0.70 ± 0.20) and spine BMD (0.97 ± 0.19) (p0.001). Pelvic BMD correlated with BMD at other skeletal locations, with the highest correlation with total hip (total hip: R2: 0.70, femoral neck R2: 0.50, spine R2: 0.65). Pelvic BMD was significantly lower in patients with osteoporosis of both hip and spine compared to the group without osteoporosis at both locations (p = 0.02). Obesity and type 2 diabetes were both associated with significantly higher BMD at pelvis, spine, and total hip. Pelvic BMD is lower than at other skeletal sites and is highly correlated with total hip area bone density. Obesity and type 2 diabetes are associated with higher pelvic BMD. To establish guidelines for the treatment pelvic BMD, studies defining the association of pelvic BMD with pelvic fracture risk are needed.

Purpose Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome of abnormal phosphate and vitamin D metabolism caused by typically small endocrine tumors that secrete fibroblast growth factor 23 (FGF23). TIO is characterized clinically by progressive musculoskeletal pain, fatigue, proximal muscle weakness, and multiple fractures, leading to long-term disability. Misdiagnosis and delayed diagnosis are common because of the nonspecific symptoms, and several years may elapse before patients receive an accurate diagnosis and appropriate treatment. Thus, it is vital that awareness of the appropriate recognition and management of TIO is increased among healthcare professionals who may encounter patients with suspected TIO. Methods A roundtable meeting was held on 10 January 2020 in Dallas, TX, USA, to gather perspectives on the diagnosis and treatment of TIO. The following topics were considered: clinical presentation, patient history, differential diagnosis, laboratory assessment, imaging, venous sampling, and treatment. Results This report provides a summary of our collective experiences in the management of TIO. Main conclusions Laboratory tests are mandatory to expedite TIO diagnosis and should include measurement of fasting serum phosphorus, renal phosphate reabsorption, serum 1,25-dihydroxyvitamin D, and serum FGF23 levels. Functional and anatomical imaging are essential to locate the FGF23-secreting tumor(s) causing TIO. Surgical resection is often a curative treatment when the tumor can be localized; however, better management of patients who cannot be operated on with targeted therapies is needed. Further efforts to increase awareness of TIO within the medical community, and education on recommended diagnostic and treatment pathways are required to improve the management of this debilitating disease.

High fracture rate and high circulating levels of the Wnt inhibitor, sclerostin, have been reported in diabetic patients. We studied the effects of Wnt signaling activation on bone health in a mouse model of insulin‐deficient diabetes. We introduced the sclerostin‐resistant Lrp5 A214V mutation, associated with high bone mass, in mice carrying the Ins2 Akita mutation (Akita), which results in loss of beta cells, insulin deficiency, and diabetes in males. Akita mice accrue less trabecular bone mass with age relative to wild type (WT). Double heterozygous Lrp5 A214V/Akita mutants have high trabecular bone mass and cortical thickness relative to WT animals, as do Lrp5 A214V single mutants. Likewise, the Lrp5 A214V mutation prevents deterioration of biomechanical properties occurring in Akita mice. Notably, Lrp5 A214V/Akita mice develop fasting hyperglycemia and glucose intolerance with a delay relative to Akita mice (7 to 8 vs. 5 to 6 weeks, respectively), despite lack of insulin production in both groups by 6 weeks of age. Although insulin sensitivity is partially preserved in double heterozygous Lrp5 A214V/Akita relative to Akita mutants up to 30 weeks of age, insulin‐dependent phosphorylated protein kinase B (pAKT) activation in vitro is not altered by the Lrp5 A214V mutation. Although white adipose tissue depots are equally reduced in both compound and Akita mice, the Lrp5 A214V mutation prevents brown adipose tissue whitening that occurs in Akita mice. Thus, hyperactivation of Lrp5‐dependent signaling fully protects bone mass and strength in prolonged hyperglycemia and improves peripheral glucose metabolism in an insulin independent manner. Wnt signaling activation represents an ideal therapeutic approach for diabetic patients at high risk of fracture. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Introduction Peripheral neuropathy occurs in two thirds of patients with diabetes mellitus (DM). It can lead to severe pathological changes in the feet, and it increases the risk of fracture more than any other diabetic complication. The objective of this review is to analyze available literature on the effect of peripheral neuropathy on BMD of the foot, spine, or hip. We hypothesize that the presence of diabetic neuropathy leads to lower BMD in adults with diabetes. Methods Original studies investigating the effects of diabetic neuropathy on bone density were searched for inclusion in this systematic review. Studies were eligible if they met the following criteria: 1) participants included adults with either Type 1 DM or Type 2 DM; 2) Method used for the diagnosis of neuropathy described in the manuscript 3) DXA scan, ultrasound, or CT scan was used to measure proximal femur, spine, or foot bone mineral density were reported, and 4) bone parameters were analyzed based on the presence and absence of neuropathy. Results Among the 5 studies that met eligibility criteria, 4 did not find a significant effect of neuropathy on BMD. One study showed a significant negative impact of neuropathy on calcaneal BMD in patients with type 1 diabetes. The meta-analysis did not show a significant effect of peripheral neuropathy on BMDs of proximal femur, spine, and calcaneus in diabetic adults. Conclusion Our study shows no evidence that peripheral neuropathy affects bone density or bone turnover in DM. However, this conclusion should be taken with caution since only a very limited number of studies were available for inclusion in the analysis and included both type 1 and type 2 DM patients. Improved measures of peripheral neuropathy and more advanced imaging technologies are needed to better assess the effect of diabetes on bone health.

Background: Osteoporosis and heart failure (HF) are age-related disorders that share some pathogenetic features and may influence each other. Previous studies have suggested an association between bone mineral density (BMD) and HF risk, which may be race-dependent. We sought to further investigate race- and sex-specific associations of BMD with HF in a longitudinal study of older adults. Methods: We evaluated the relationship between BMD and HF in the Health, Aging, and Body Composition study, a sample of community-dwelling adults aged 70-79. BMD was measured by dual-energy X-ray absorptiometry (DXA) of the total hip and femoral neck, and in half the cohort by computed tomography of the spine. Analyses were stratified a priori by sex and race, and Cox models were used to estimate risk after adjustment for potential confounders. Results: Of 2835 participants, 572 (49% women, 42% black) developed HF during a median follow up of 12.2 years. Lower BMD of the total hip by DXA was associated with higher risk of HF in black women (adj. HR 1.84 [95% CI, 1.43 - 2.37] per SD decrement), with suggestion of lower risk in black men that was not significant (adj. HR 0.81 [0.64 - 1.02]). Corresponding analyses failed to reveal significant associations in white women (adj. HR 0.86 [0.71-1.04]) or white men (adj. HR 1.10 [0.93 - 1.30]). There were a significant interaction of total hip BMD by sex among blacks (p=0.002), but not whites (p=0.363), as well as by race among women (p=0.026) and men (p=0.049). Relationships of BMD of the femoral neck were similar in all groups. Likewise, lower volumetric BMD of the spine was associated with higher risk in black women (adj. HR 1.34 [1.02 - 1.77] per SD decrement), but there were no significant associations in black men (adj. HR 0.91 [0.78 - 1.18]), white women (adj. HR 0.83 [0.64 - 1.08]), or white men (adj. HR 1.17 [0.95 - 1.44]). Conclusions: Among a biracial cohort of older adults, lower BMD was associated with higher risk of HF in black women, with no clear evidence of an association in white women or in men of either race. Further research is needed to understand the factors that may account for the particular association in black women, and whether these can be leveraged for therapeutic intervention.

Cancer-associated fibroblasts (CAFs) are a heterogeneous population of mesenchymal cells supporting tumor progression, whose origin remains to be fully elucidated. Osterix (Osx) is a marker of osteogenic differentiation, expressed in skeletal progenitor stem cells and bone-forming osteoblasts. We report Osx expression in CAFs and by using Osx-cre;TdTomato reporter mice we confirm the presence and pro-tumorigenic function of TdTOSX+ cells in extra-skeletal tumors. Surprisingly, only a minority of TdTOSX+ cells expresses fibroblast and osteogenic markers. The majority of TdTOSX+ cells express the hematopoietic marker CD45, have a genetic and phenotypic profile resembling that of tumor infiltrating myeloid and lymphoid populations, but with higher expression of lymphocytic immune suppressive genes. We find Osx transcript and Osx protein expression early during hematopoiesis, in subsets of hematopoietic stem cells and multipotent progenitor populations. Our results indicate that Osx marks distinct tumor promoting CD45- and CD45+ populations and challenge the dogma that Osx is expressed exclusively in cells of mesenchymal origin.

Nitrogen-containing bisphosphonates (N-BPs), such as alendronate, are the most widely prescribed medications for diseases involving bone, with nearly 200 million prescriptions written annually. Recently, widespread use of N-BPs has been challenged due to the risk of rare but traumatic side effects such as atypical femoral fracture (AFFs) and osteonecrosis of the jaw (ONJ). N-BPs bind to and inhibit farnesyl diphosphate synthase (FDPS), resulting in defects in protein prenylation. Yet it remains poorly understood what other cellular factors might allow N-BPs to exert their pharmacological effects. Here, we performed genome-wide studies in cells and patients to identify the poorly characterized gene, ATRAID. Loss of ATRAID function results in selective resistance to N-BP-mediated loss of cell viability and the prevention of alendronate-mediated inhibition of prenylation. ATRAID is required for alendronate inhibition of osteoclast function, and ATRAID-deficient mice have impaired therapeutic responses to alendronate in both postmenopausal and senile (old age) osteoporosis models. Lastly, we performed exome sequencing on patients taking N-BPs that suffered ONJ or an AFF. ATRAID is one of three genes that contain rare non-synonymous coding variants in patients with ONJ or AFF that is also differentially expressed in poor outcome groups of patients treated with N-BPs. We functionally validated this patient variation in ATRAID as conferring cellular hypersensitivity to N-BPs. Our work adds key insight into the mechanistic action of N-BPs and the processes that might underlie differential responsiveness to N-BPs in people.One Sentence SummaryATRAID is essential for responses to the commonly prescribed osteoporosis drugs nitrogen-containing bisphosphonates.OverlineBONE

Pelvic fractures represent 7% of all fragility fractures; they account for 5% of the cost of osteoporotic fracture care, and are commonly (> 50%) associated with loss of independence in the elderly. The incidence of pelvic fractures has increased significantly over the past 3 decades. However, little is known about the relationship between bone mineral density (BMD) and pelvic fractures. We have conducted a pilot cross-sectional study to establish a method of measuring pelvic BMD and to correlate BMD of the pelvis with BMD at other skeletal sites. Postmenopausal women without a history of pelvis and hip fragility fractures were enrolled. Hip, spine, and pelvis DXA scans were obtained using a Hologic DXA machine. Pelvic BMD was calculated using Hologic Research Software from 3 areas of the pelvis (R1: public symphysis, R2: inferior pubic ramus, and R3: superior pubic ramus), corresponding to common fracture locations. Pelvis BMD was the average of the 3 pelvis sites. Pelvic BMD measurement precision error was calculated using the root mean square method (Recommended by International Society of Clinical Densitometry (ISCD)). Statistical analysis was used to compare BMD at different sites. Alpha error was set at 0.05. Of 73 postmenopausal women who were enrolled in the study (average age 64 years, average 15 years postmenopausal), 3% had chronic kidney disease, 7% had type 2 DM, 3% were on corticosteroids and none were smokers. BMD of femoral neck assessed on pelvic DXA was not significantly different from femoral neck BMD measured on standard DXA (P=0.09). To assess pelvis BMD measurement precision, 15 patients underwent 3 separate pelvic DXA images after repositioning. BMD precision error was 0.011g/cm2 which is slightly lower than the precision total hip BMD at our center (0.007 g/cm2). BMD of R1, R2, and R3 pelvic areas were measured as 0.44±0.15, 0.41± 0.15, and 0.62 ±0.19 g/cm2, respectively. Notably, BMD of R3 was significantly higher than the other 2 areas (P

Highlights • N-cadherin in osteolineage, Osterix+ cells restrains extraskeletal tumor growth. • Osterix+ cells are present in the stromal microenvironment of extraskeletal tumors. • Osterix+ cells are present in normal tissues frequent sites of metastasis. • N-cadherin modulates pro-tumorigenic signaling in tumor associated Osterix+ cells., Tumor growth and metastases are dependent on interactions between cancer cells and the local environment. Expression of the cell–cell adhesion molecule N-cadherin (Ncad) is associated with highly aggressive cancers, and its expression by osteogenic cells has been proposed to provide a molecular “dock” for disseminated tumor cells to establish in pre-metastatic niches within the bone. To test this biologic model, we conditionally deleted the Ncad gene (Cdh2) in osteolineage cells using Osx-cre (cKO). Contrary to expectations, the metastatic breast cancer cell line PyMT-BO1 was able to form tumors in bone and to induce osteolysis in cKO as well as in control mice. Despite absence of Ncad, bone marrow stromal cells isolated from cKO mice were able to engage in direct cell–cell interactions with tumor cells expressing either N- or E-cadherin. However, subcutaneous PyMT-BO1 and B16F10 tumors grew larger in cKO relative to control littermates. Cell tracking experiments using the Ai9 reporter revealed the presence of Osx+ and Ncad+ cells in the stroma of extra-skeletal tumors and in a small population of lung cells. Gene expression analysis by RNAseq of Osx+ cells isolated from extra-skeletal tumors revealed alterations of pro-tumorigenic signaling pathways in cKO cells relative to control Osx+ cells. Thus, Ncad in Osx+ cells is not necessary for the establishment of bone metastases, but in extra-skeletal tumors it regulates pro-tumorigenic support by the microenvironment.

Skeletal complications are common features of neonatal-onset multisystem inflammatory disease (NOMID), a disorder caused by NLRP3-activating mutations. NOMID mice in which NLRP3 is activated globally exhibit several characteristics of the human disease, including systemic inflammation and cartilage dysplasia, but the mechanisms of skeletal manifestations remain unknown. In this study, we find that activation of NLRP3 in myeloid cells, but not mesenchymal cells triggers chronic inflammation, which ultimately, causes growth plate and epiphyseal dysplasia in mice. These responses are IL-1 signaling-dependent, but independent of PARP1, which also functions downstream of NLRP3 and regulates skeletal homeostasis. Mechanistically, inflammation causes severe anemia and hypoxia in the bone environment, yet down-regulates the HIF-1α pathway in chondrocytes, thereby promoting the demise of these cells. Thus, activation of NLRP3 in hematopoietic cells initiates IL-1β-driven paracrine cascades, which promote abnormal growth plate development in NOMID mice.

N-cadherin inhibits osteogenic cell differentiation and canonical Wnt/β-catenin signaling in vitro. However, in vivo both conditional Cdh2 ablation and overexpression in osteoblasts lead to low bone mass. We tested the hypothesis that N-cadherin has different effects on osteolineage cells depending upon their differentiation stage. Embryonic conditional osteolineage Cdh2 deletion in mice results in defective growth, low bone mass, and reduced osteoprogenitor number. These abnormalities are prevented by delaying Cdh2 ablation until 1 month of age, thus targeting only committed and mature osteoblasts, suggesting they are the consequence of N-cadherin deficiency in osteoprogenitors. Indeed, diaphyseal trabecularization actually increases when Cdh2 is ablated postnatally. The sclerostin-insensitive Lrp5A214V mutant, associated with high bone mass, does not rescue the growth defect, but it overrides the low bone mass of embryonically Cdh2-deleted mice, suggesting N-cadherin interacts with Wnt signaling to control bone mass. Finally, bone accrual and β-catenin accumulation after administration of an anti-Dkk1 antibody are enhanced in N-cadherin-deficient mice. Thus, although lack of N-cadherin in embryonic and perinatal age is detrimental to bone growth and bone accrual, in adult mice loss of N-cadherin in osteolineage cells favors bone formation. Hence, N-cadherin inhibition may widen the therapeutic window of osteoanabolic agents. © 2017 American Society for Bone and Mineral Research.

An increasing evidence base suggests that low bone mineral density (BMD) and fractures are associated with cardiovascular disease (CVD). We conducted a systematic review and meta-analysis summarizing the evidence of low BMD and fractures as risk factors for future CVD. Two independent authors searched major databases from inception to 1st August 2016 for longitudinal studies reporting data on CVD incidence (overall and specific CVD) and BMD status and fractures. The association between low BMD, fractures and CVD across longitudinal studies was explored by calculating pooled adjusted hazard ratios (HRs)?±?95% confidence intervals (CIs) with a random-effects meta-analysis. Twenty-eight studies (18 regarding BMD and 10 fractures) followed-up a total of 1,107,885 participants for a median of 5 years. Taking those with higher BMD as the reference, people with low BMD were at increased risk of developing CVD during follow-up (11 studies; HR?=?1.33; 95%CI: 1.27-1.38; I2?=?53%), after adjusting for a median of 8 confounders. This finding was confirmed using a decrease in one standard deviation of baseline BMD (9 studies; HR?=?1.16; 95%CI: 1.09-1.24; I2?=?69%). The presence of fractures at baseline was associated with an increased risk of developing CVD (HR?=?1.20; 95%CI: 1.06-1.37; I2?=?91%). Regarding specific CVD, low BMD was associated with an increased risk of developing coronary artery disease, cerebrovascular conditions, and CVD associated death. Fractures at baseline was associated with an increased risk of cerebrovascular conditions and death due to CVD. In conclusion, low BMD and fractures are associated with a small, but significant increased risk of CVD risk and possibly death.