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Key Points The extracellular calcium-sensing receptor (CaSR) expressed in the parathyroid glands and kidneys modulates blood levels of Ca 2+ ; CaSR is also expressed on bone cells, where it regulates skeletal homeostasis In chondrocytes, CaSR contributes to development of the cartilaginous growth plate, whereas in osteoblasts CaSR is required for the proliferation and differentiation of these cells, and for bone matrix production In young animals, activation of CaSR in osteoclasts inhibits bone resorption, which results in enhanced bone anabolism In old animals, although activation of osteoblasts augments bone formation, this activation also increases the expression of receptor activator of nuclear factor κB ligand and bone resorption by osteoclasts The relationship between activation of CaSR in the skeleton and levels of parathyroid hormone can lead to net bone formation in trabecular bone and net bone resorption in cortical bone Although currently available allosteric modulators of CaSR in the parathyroid gland are beneficial in some clinical conditions, future CaSR-based drugs might be developed that have improved effects on bone The extracellular calcium-sensing receptor (CaSR) is a G protein-coupled receptor that has a key role in Ca 2+ homeostasis via its role in the parathyroid glands and kidneys. New evidence has shown that CaSR also regulates skeletal homeostasis. In this Review, David Goltzman and Geoffrey Hendy discuss the role of CaSR in chondrocytes and development of the cartilagenous growth plate, in osteoblasts and osteoclasts, and effects of CaSR on skeletal development and bone turnover. The extracellular calcium-sensing receptor, CaSR, is a member of the G protein-coupled receptor superfamily and has a critical role in modulating Ca 2+ homeostasis via its role in the parathyroid glands and kidneys. New evidence suggests that CaSR expression in cartilage and bone also directly regulates skeletal homeostasis. This Review discusses the role of CaSR in chondrocytes, through which CaSR contributes to the development of the cartilaginous growth plate, as well as in osteoblasts and osteoclasts, through which CaSR has effects on skeletal development and bone turnover in young and mature animals. The interaction of skeletal CaSR activation with parathyroid hormone (PTH), which is secreted by the parathyroid gland, can lead to net bone formation in trabecular bone or net bone resorption in cortical bone. Allosteric modulators of CaSR are beneficial in some clinical conditions, with effects that are mediated by the ability of these agents to alter levels of PTH and improve Ca 2+ homeostasis. However, further insights into the action of CaSR in bone cells might lead to CaSR-based drugs that maximize not only the effects of the receptor on the parathyroid glands and kidneys but also on bone.

Observational studies have demonstrated an association between decreased vitamin D level and risk of multiple sclerosis (MS); however, it remains unclear whether this relationship is causal. We undertook a Mendelian randomization (MR) study to evaluate whether genetically lowered vitamin D level influences the risk of MS. We identified single nucleotide polymorphisms (SNPs) associated with 25-hydroxyvitamin D (25OHD) level from SUNLIGHT, the largest (n = 33,996) genome-wide association study to date for vitamin D. Four SNPs were genome-wide significant for 25OHD level (p-values ranging from 6 × 10-10 to 2 × 10-109), and all four SNPs lay in, or near, genes strongly implicated in separate mechanisms influencing 25OHD. We then ascertained their effect on 25OHD level in 2,347 participants from a population-based cohort, the Canadian Multicentre Osteoporosis Study, and tested the extent to which the 25OHD-decreasing alleles explained variation in 25OHD level. We found that the count of 25OHD-decreasing alleles across these four SNPs was strongly associated with lower 25OHD level (n = 2,347, F-test statistic = 49.7, p = 2.4 × 10-12). Next, we conducted an MR study to describe the effect of genetically lowered 25OHD on the odds of MS in the International Multiple Sclerosis Genetics Consortium study, the largest genetic association study to date for MS (including up to 14,498 cases and 24,091 healthy controls). Alleles were weighted by their relative effect on 25OHD level, and sensitivity analyses were performed to test MR assumptions. MR analyses found that each genetically determined one-standard-deviation decrease in log-transformed 25OHD level conferred a 2.0-fold increase in the odds of MS (95% CI: 1.7-2.5; p = 7.7 × 10-12; I2 = 63%, 95% CI: 0%-88%). This result persisted in sensitivity analyses excluding SNPs possibly influenced by population stratification or pleiotropy (odds ratio [OR] = 1.7, 95% CI: 1.3-2.2; p = 2.3 × 10-5; I2 = 47%, 95% CI: 0%-85%) and including only SNPs involved in 25OHD synthesis or metabolism (ORsynthesis = 2.1, 95% CI: 1.6-2.6, p = 1 × 10-9; ORmetabolism = 1.9, 95% CI: 1.3-2.7, p = 0.002). While these sensitivity analyses decreased the possibility that pleiotropy may have biased the results, residual pleiotropy is difficult to exclude entirely. A genetically lowered 25OHD level is strongly associated with increased susceptibility to MS. Whether vitamin D sufficiency can delay, or prevent, MS onset merits further investigation in long-term randomized controlled trials.

It has been reported that 1,25 dihydroxyvitamin D [1,25(OH)2D] deficiency leads to the loss of mandibular bone, however the mechanism is unclear. We investigated whether the Sirt1/FOXO3a signaling pathway is involved in this process. Using a 1,25(OH)2D deficiency model induced by genetic deletion in mice of 25-hydroxyvitamin D-1α hydroxylase [1α(OH)ase-/- mice]. We first documented a sharp reduction of expression levels of Sirt1 in the 1α(OH)ase-/- mice in vivo. Next, we demonstrated dose-dependent upregulation of Sirt1 by treatment with exogenous 1,25(OH)2D3 in vitro. We then identified a functional VDR binding site in the Sirt1 promoter. By crossing Prx1-Sirt1 transgenic mice with 1α(OH)ase-/- mice we demonstrated that the overexpression of Sirt1 in mesenchymal stem cells (MSCs) greatly improved the 1α(OH)ase-/- mandibular bone loss phenotype by increasing osteoblastic bone formation and reducing osteoclastic bone resorption. In mechanistic studies, we showed, in 1α(OH)ase-/- mice, decreases of Sirt1 and FoxO3a, an increase in oxidative stress as reflected by a reduction of the antioxidant enzymes peroxiredoxin1 (Prdx1), SOD1 and SOD2 expression, and an increase of markers for osteocyte senescence and senescence associated secretory phenotypes (SASP), including β-galactosidase (β-gal), p16, p53 and p21. The targeted overexpression of Sirt1 in the 1α(OH)ase-/- mice restored the expression levels of these molecules. Finally, we demonstrated that a Sirt1 agonist can upregulate FOXO3a activity by increasing deacetylation and nuclear translocation. Overall, results from this study support the concept that targeted increases in Sirt1/FOXO3a signaling levels can greatly improve the bone loss caused by 1,25(OH)2D deficiency.

Osteoporosis and sarcopenia are common comorbid diseases, yet their shared mechanisms are largely unknown. We found that genetic variation near FAM210A was associated, through large genome-wide association studies, with fracture, bone mineral density (BMD), and appendicular and whole body lean mass, in humans. In mice, Fam210a was expressed in muscle mitochondria and cytoplasm, as well as in heart and brain, but not in bone. Grip strength and limb lean mass were reduced in tamoxifen-inducible Fam210a homozygous global knockout mice (TFam210a −/−), and in tamoxifen-inducible Fam210 skeletal muscle cell-specific knockout mice (TFam210aMus −/−). Decreased BMD, bone biomechanical strength, and bone formation, and elevated osteoclast activity with microarchitectural deterioration of trabecular and cortical bones, were observed in TFam210a −/− mice. BMD of male TFam210aMus −/− mice was also reduced, and osteoclast numbers and surface in TFam210aMus −/− mice increased. Microarray analysis of muscle cells from TFam210aMus −/− mice identified candidate musculoskeletal modulators. FAM210A, a novel gene, therefore has a crucial role in regulating bone structure and function, and may impact osteoporosis through a biological pathway involving muscle as well as through other mechanisms.

Emerging observational data suggest that vitamin D deficiency is associated with the onset and progression of knee osteoarthritis (OA). However, the relationship between vitamin D level and OA and the role of vitamin D supplementation in the prevention of knee OA are controversial. To address these issues, we analyzed the articular cartilage phenotype of 6- and 12-month-old wild-type and 1α(OH)ase mice and found that 1,25(OH) D deficiency accelerated the development of age-related spontaneous knee OA, including cartilage surface destruction, cartilage erosion, proteoglycan loss and cytopenia, increased OARSI score, collagen X and Mmp13 positive chondrocytes, and increased chondrocyte senescence with senescence-associated secretory phenotype (SASP). 1,25(OH) D supplementation rescued all knee OA phenotypes of 1α(OH)ase mice , and 1,25(OH) D rescued IL-1β-induced chondrocyte OA phenotypes , including decreased chondrocyte proliferation and cartilage matrix protein synthesis, and increased oxidative stress and cell senescence. We also demonstrated that VDR was expressed in mouse articular chondrocytes, and that VDR knockout mice exhibited knee OA phenotypes. Furthermore, we demonstrated that the down-regulation of Sirt1 in articular chondrocytes of 1α(OH)ase mice was corrected by supplementing 1,25(OH) D or overexpression of Sirt1 in mesenchymal stem cells (MSCs) and 1,25(OH) D up-regulated Sirt1 through VDR mediated transcription. Finally, we demonstrated that overexpression of Sirt1 in MSCs rescued knee OA phenotypes in 1α(OH)ase mice. Thus, we conclude that 1,25(OH) D via VDR-mediated gene transcription, plays a key role in preventing the onset of aging-related knee OA in mouse models by up-regulating Sirt1, an aging-related gene that promotes articular chondrocyte proliferation and extracellular matrix protein synthesis, and inhibits senescence and SASP.

Abstract SummaryMost of the published epidemiology on osteoporosis is derived from White populations; still many countries have increasing ethno-culturally diverse populations, leading to gaps in the development of population-specific effective fracture prevention strategies. We describe differences in prevalent fracture and bone mineral density patterns in Canadians of different racial/ethnic backgrounds. Introduction We described prevalent fracture and bone mineral density (BMD) patterns in Canadians by their racial/ethnic backgrounds.MethodsFor this cross-sectional analysis, we used the Canadian Longitudinal Study on Aging baseline data (2011–2015) of 22,091 randomly selected participants of Black, East Asian, South or Southeast Asian (SSEA) and White race/ethnic backgrounds, aged 45–85 years with available information on the presence or absence of self-reported prevalent low trauma fractures and femoral neck BMD (FNBMD) measurement. Logistic and linear regression models examined associations of race/ethnic background with fracture and FNBMD, respectively. Covariates included sex, age, height, body mass index (BMI), grip strength and physical performance score.ResultsWe identified 11,166 women and 10,925 men. Self-reported race/ethnic backgrounds were: 139 Black, 205 East Asian, 269 SSEA and 21,478 White. White participants were older (mean 62.5 years) than the other groups (60.5 years) and had a higher BMI (28.0 kg/m2) than both Asian groups, but lower than the Black group. The population-weighted prevalence of falls was 10.0%, and that of low trauma fracture was 12.0% ranging from 3.3% (Black) to 12.3% (White), with Black and SSEA Canadians having lower adjusted odds ratios (aOR) of low trauma fractures than White Canadians (Black, aOR = 0.3 [95% confidence interval: 0.1–0.7]; SSEA, aOR = 0.5 [0.3–0.8]). The mean (SD) FNBMD varied between groups: Black, 0.907 g/cm2 (0.154); East Asian, 0.748 g/cm2 (0.119); SSEA, 0.769 g/cm2 (0.134); and White, 0.773 g/cm2 (0.128). Adjusted linear regressions suggested that Black and both Asian groups had higher FNBMD compared to White.ConclusionOur results support the importance of characterizing bone health predictors in Canadians of different race/ethnic backgrounds to tailor the development of population-specific fracture prevention strategies.

Prolonged skeletal unloading through bedrest results in bone loss similar to that observed in elderly osteoporotic patients, but with an accelerated timeframe. This rapid effect on weight-bearing bones is also observed in astronauts who can lose up to 2% of their bone mass per month spent in Space. Despite the important implications for Spaceflight travelers and bedridden patients, the exact mechanisms involved in disuse osteoporosis have not been elucidated. Parathyroid hormone-related protein (PTHrP) regulates many physiological processes including skeletal development, and has been proposed as a mechanosensor. To investigate the role of PTHrP in microgravity-induced bone loss, trabecular and calvarial osteoblasts (TOs and COs) from Pthrp +/+ and -/- mice were subjected to actual Spaceflight for 6 days (Foton M3 satellite). Pthrp +/+, +/- and -/- osteoblasts were also exposed to simulated microgravity for periods varying from 6 days to 6 weeks. While COs displayed little change in viability in 0g, viability of all TOs rapidly decreased in inverse proportion to PTHrP expression levels. Furthermore, Pthrp+/+ TOs displayed a sharp viability decline after 2 weeks at 0g. Microarray analysis of Pthrp+/+ TOs after 6 days in simulated 0g revealed expression changes in genes encoding prolactins, apoptosis/survival molecules, bone metabolism and extra-cellular matrix composition proteins, chemokines, insulin-like growth factor family members and Wnt-related signalling molecules. 88% of 0g-induced expression changes in Pthrp+/+ cells overlapped those caused by Pthrp ablation in normal gravity, and pulsatile treatment with PTHrP1-36 not only reversed a large proportion of 0g-induced effects in Pthrp+/+ TOs but maintained viability over 6-week exposure to microgravity. Our results confirm PTHrP efficacy as an anabolic agent to prevent microgravity-induced cell death in TOs.

Gastric cancer (GC) is one of the most common malignancies, and is the second leading cause of cancer-related deaths worldwide. Macrophages infiltrated in the tumor microenvironment (TME) called tumor-associated macrophages (TAMs) are key orchestrators in TME. In GC, it has been reported that infiltration of TAMs is associated with epithelial-mesenchymal transition (EMT)-related proteins in human GC tissues, but the exactly mechanism has not been clarified. In the present study, we aimed to elucidate the underlying mechanism of TAMs on GC cells. THP-1 cells were used to investigate the effects of TAMs on GC cells. The effects of invasion and migration induced by coculture with TAMs were investigated by Transwell invasion and wound healing assays. The expression of EMT-related genes and forkhead box Q1 (FOXQ1) were examined in MKN45 and MKN74 cells after being co-cultured with TAMs. The density of TAMs and the expression of FOXQ1 were analyzed by immunohistochemistry in GC tissues. Our results revealed that, co-culture with TAMs promoted the invasion and migration of GC cells. Co-culture with TAMs induced EMT in GC cells. FOXQ1 is essential for TAM-induced EMT and metastasis in GC cells. Furthermore, silencing of FOXQ1 blocked the effect of TAM-enhanced EMT and metastasis of GC cells. High expression of CD68 was correlated with positive FOXQ1 expression (r=0.613; P<0.001) in clinical GC samples. Our data provided evidence that TAMs promote EMT, invasion and migration of GC cells via FOXQ1. Therefore, the TAM/FOXQ1 axis may represent a novel target for GC cells.

Vitamin D signaling regulates cell proliferation and differentiation, and epidemiological data suggest that it functions as a cancer chemopreventive agent, although the underlying mechanisms are poorly understood. Vitamin D signaling can suppress expression of genes regulated by c-MYC, a transcription factor that controls epidermal differentiation and cell proliferation and whose activity is frequently elevated in cancer. We show through cell- and animal-based studies and mathematical modeling that hormonal 1,25-dihydroxyvitamin D (1,25D) and the vitamin D receptor (VDR) profoundly alter, through multiple mechanisms, the balance in function of c-MYC and its antagonist the transcriptional repressor MAD1/MXD1. 1,25D inhibited transcription of c-MYC–regulated genes in vitro, and topical 1,25D suppressed expression of c-MYC and its target setd8 in mouse skin, whereas MXD1 levels increased. 1,25D inhibited MYC gene expression and accelerated its protein turnover. In contrast, it enhanced MXD1 expression and stability, dramatically altering ratios of DNA-bound c-MYC and MXD1. Remarkably, F-box protein FBW7, an E3-ubiquitin ligase, controlled stability of both arms of the c-MYC/MXD1 push–pull network, and FBW7 ablation attenuated 1,25D regulation of c-MYC and MXD1 turnover. Additionally, c-MYC expression increased upon VDR knockdown, an effect abrogated by ablation of MYC regulator β-catenin. c-MYC levels were widely elevated in vdr ⁻/⁻ mice, including in intestinal epithelium, where hyperproliferation has been reported, and in skin epithelia, where phenotypes of VDR-deficient mice and those overexpressing epidermal c-MYC are similar. Thus, 1,25D and the VDR regulate the c-MYC/MXD1 network to suppress c-MYC function, providing a molecular basis for cancer preventive actions of vitamin D.