BMP9 Reduces Bone Loss in Ovariectomized Mice by Dual Regulation of Bone Remodeling.

Bone remodeling is dynamic and is tightly regulated through bone resorption dominated by osteoclasts and bone formation dominated by osteoblasts. Imbalances in this process can cause various pathological conditions, such as osteoporosis. Bone morphogenetic protein 9 (BMP9), a biomolecule produced and secreted by the liver, has many pharmacological effects, including anti-liver fibrosis, antitumor, anti-heart failure, and antidiabetic activities. However, the effects of BMP9 on the regulation of osteoblast and osteoclast functions and the underlying molecular mechanism(s) have not yet been investigated. In this study, BMP9 increased the expression of osteoblastogenic gene markers, such as ALP, Cola1, OCN, RUNX2, and OSX, and ALP activity in MC3T3-E1 cells by upregulating LGR6 and activating the Wnt/ß-catenin pathway. BMP9 also suppressed receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL)-induced osteoclast differentiation of bone marrow macrophages (BMMs) by inhibiting the Akt-NF-κB-NFATc1 pathway. More importantly, in an ovariectomy (OVX) mouse model, BMP9 attenuated bone loss and improved bone biomechanical properties in vivo by increasing bone-forming activity and suppressing bone resorption activity. Accordingly, our current work highlights the dual regulatory effects that BMP9 exerts on bone remodeling by promoting bone anabolic activity and inhibiting osteoclast differentiation in OVX mice. © 2020 American Society for Bone and Mineral Research.

Follicle-stimulating hormone and estradiol are associated with bone mineral density and risk of fractures in men with type 2 diabetes mellitus.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is associated with a higher fracture risk. Sex hormones are important for maintaining skeletal health. It is not clear which sex hormone(s) contribute(s) to bone mineral density (BMD) and fracture risk in males with T2DM. This study investigated the relationships of these parameters in males with T2DM. METHODS: This study involved 482 men with T2DM. BMDs at the lumbar spine (L2-4), femoral neck (FN), and total hip (TH) were measured by dual-energy X-ray absorptiometry (DXA). The 10-year probability of fractures was assessed using the modified Fracture Risk Algorithm (FRAX) tool. Serum levels of sex hormones were measured. RESULTS: Follicle-stimulating hormone (FSH) and estradiol (E2) were associated with BMDs at L2-4 (FSH, ß = -.162, P < .05; E2, ß = .176, P < .001), and E2 was associated with BMD at FN (ß = .137, P < .05) and TH (ß = .140, P < .05). FSH was associated with major osteoporotic fractures (ß = .288, P < .001) and hip fractures (ß = .235, P < .001). Higher FSH was a risk factor for osteoporosis/osteopenia (odds ratios [OR] = 2.92, 95% CI = 1.66-5.14, P < .001), whereas higher E2 was a protective factor (OR = 0.37, 95% CI = 0.22-0.60, P < .001). Patients in the higher tertile of FSH and lower tertile of E2 had an increased risk of osteoporosis/osteopenia (OR = 5.05, 95% CI = 1.37-18.65, P < .05). CONCLUSIONS: For males with T2DM, FSH and E2 are significantly associated with BMD, osteoporosis/osteopenia, and fracture risk.

SIRT2 deficiency prevents age-related bone loss in rats by inhibiting osteoclastogenesis.

Sirtuin 2 (SIRT2) is a deacetylase that belongs to class III family of histone deacetylases (HDACs). Although it is the most abundantly expressed member of HDAC-III in human bone tissues, it is unclear whether SIRT2 plays a role in bone metabolism. In this study, the role of SIRT2 in bone metabolism, and the underlying mechanism were investigated. In in vivo experiments, micro-CT analysis revealed that there were no differences in bone microstructures between SIRT2-KO and WT rats at 12 weeks of age. However, in 36-week-old rats, increased Tb. BMD, bone volume fraction (BV/TV) and trabecular number (Tb. N) of distal femurs were observed in SIRT2-KO rats, when compared with those of WT rats. Moreover, reduced serum ß-CTX was identified in the 36-week old rats. In in vitro studies, inhibition of SIRT2 with its specific inhibitor, AGK2, suppressed the differentiation of bone marrow-derived mononuclear cells (BMMs) into osteoclasts via reduction of the expressions of c-Fos and NFATc1. These results suggest that SIRT2 plays a role in age-related bone loss, probably by regulating osteoclastogenesis.

Associations of serum sex hormone binding globulin with bone mineral densities and higher 10-year probability of fractures in postmenopausal women with type 2 diabetes mellitus.

BACKGROUND: Postmenopause and type 2 diabetes mellitus (T2DM) are associated with higher fracture risk. Sex hormones are important in maintaining woman skeleton health. The relationships of sex hormone(s) with bone mineral density (BMD) and fracture risk are still unclear in diabetic-postmenopausal women. This study aimed to investigate the relationships of sex hormones with BMDs and fracture risk in postmenopausal women with T2DM. METHODS: Two hundred and fourteen postmenopausal women with T2DM were included. BMDs at lumbar spine (L2-4), femoral neck (FN) and total hip (TH) were measured by dual-energy X-ray absorptiometry (DXA). The 10-year probability of fractures was accessed by modified fracture risk algorithm (FRAX) tool. Serum concentrations of sex hormones were measured. RESULTS: Sex hormone binding globulin (SHBG) was a determinant of BMDs at L2-4 (ß=-0.199, P<0.05), TH (ß=-0.233, P<0.05), major osteoporotic fracture (MOF) (ß=0.253, P<0.001) and hip fracture (HF) (ß=0.262, P<0.001). Per SD increase in SHBG caused a 2% increase in the risk of osteoporosis/osteopenia. SHBG in quartile-4 was associated with 4.21 higher risk of osteoporosis/osteopenia compared with SHBG in quartile-1. CONCLUSIONS: In postmenopausal women with T2DM, higher serum SHBG tended to be associated with lower BMDs, and increased the risk of osteoporosis/osteopenia and the fracture risk.

THE ASSOCIATIONS BETWEEN HYPOVITAMINOSIS D, HIGHER PTH LEVELS WITH BONE MINERAL DENSITIES, AND RISK OF THE 10-YEAR PROBABILITY OF MAJOR OSTEOPOROTIC FRACTURES IN CHINESE PATIENTS WITH T2DM.

OBJECTIVE: In the current study, we investigated the vitamin D status, and its relationships with parathyroid hormone (PTH) levels, bone mineral density (BMD), and the 10-year probability of fractures in Chinese patients with type 2 diabetes mellitus (T2DM). METHODS: This was a cross-sectional study of 785 patients. BMDs at the lumbar spine (L2-4), femoral neck (FN), and total hip (TH) were measured by dual-energy X-ray absorptiometry (DXA). Serum levels of 25-hydroxyvitamin D (25(OH)D) and intact PTH were also quantified. The 10-year probability of fracture risk (major osteoporotic fracture [MOF] and hip fracture [HF]) was assessed using the fracture risk assessment tool (FRAX). RESULTS: The prevalence of vitamin D deficiency was 82.3%, and the mean 25(OH)D level was 36.9 ± 15.2 nmol/L. The adequate group had higher BMDs at the FN and TH and lower MOF risk than the inadequate groups. Lower 25(OH)D was associated with higher PTH ( r = -0.126, P<.001). PTH was negatively correlated with BMDs at 3 sites and positively correlated with MOF and HF, but this relationship disappeared in the adequate subgroup. Multivariate stepwise regression analysis revealed that PTH was the determinant of MOF (standard ß = 0.073, P = .010) and HF (standard ß = 0.094, P = .004). CONCLUSION: Our results identified a significantly high rate of vitamin D deficiency among Chinese patients with T2DM. PTH is an important risk factor responsible for the higher 10-year probability of osteoporotic fractures in diabetic patients, especially in those with lower vitamin D levels. ABBREVIATIONS: AKP = alkaline phosphatase; ALB = serum albumin; BMD = bone mineral density; BMI = body mass index; Ca = calcium; CKD = chronic kidney disease; Cr = creatinine; FN = femoral neck; FRAX = fracture risk assessment tool; HbA1c = glycated hemoglobin A1c; HF = hip fracture; L2-4 = lumbar spine; MOF = major osteoporotic fracture; 25(OH)D = 25-hydroxyvitamin D; P = phosphorus; PTH = parathyroid hormone; T2DM = type 2 diabetes mellitus; TH = total hip; UA = uric acid.