Diagnostic Performance of a Panel of miRNAs (OsteomiR) for Osteoporosis in a Cohort of Postmenopausal Women.

A specific signature of 19 circulating miRNAs (osteomiRs) has been reported to be associated with fragility fractures due to postmenopausal osteoporosis. However, it is unknown whether osteoporotic fractures or low BMD phenotypes are independently contributing to changes in osteomiR serum levels. The first aim was to characterize the abundance, sensitivity to hemolysis, and correlation of osteomiR serum levels, the second objective to evaluate the diagnostic accuracy of osteomiRs for osteoporosis according to the WHO criteria and on basis of major osteoporotic fracture history. Fifty postmenopausal women with osteoporosis (with or without fragility fracture) and 50 non-osteoporotic women were included in this cross-sectional study. The diagnostic performance of osteomiRs for osteoporosis based on the WHO definition or fracture history was evaluated using multiple logistic regression and receiver-operator curve (AUC) analysis. The osteomiR® signature is composed of four clusters of miRNAs providing good performance for the diagnosis of osteoporosis in postmenopausal women defined by WHO criteria (AUC = 0.830) and based on history of major osteoporotic fractures (AUC = 0.834). The classification performance for the WHO criteria and for fracture risk is driven by miR-375 and miR-203a, respectively. OsteomiRs, a signature of 19 emerging miRNA bone biomarkers, are measurable in human serum samples. They constitute a panel of independent bone and muscle biomarkers, which in combination could serve as diagnostic biomarkers for osteoporosis in postmenopausal women.

Cathepsin S controls adipocytic and osteoblastic differentiation, bone turnover, and bone microarchitecture.

Cathepsin S is a cysteine protease that controls adipocyte differentiation and has been implicated in vascular and metabolic complications of obesity. Considering the inverse relation of osteoblasts and adipocytes and their mutual precursor cell, we hypothesized that cathepsin S may also affect osteoblast differentiation and bone remodeling. Thus, the fat and bone phenotypes of young (3 months old) and aged (12 or 18 months old) cathepsin S knock-out (KO) and wild-type (WT) mice were determined. Cathepsin S KO mice had a normal body weight at both ages investigated, even though the amount of subscapular and gonadal fat pads was reduced by 20%. Further, cathepsin S deficiency impaired adipocyte formation (-38%, p<0.001), which was accompanied by a lower expression of adipocyte-related genes and a reduction in serum leptin, IL-6 and CCL2 (p<0.001). Micro-CT analysis revealed an unchanged trabecular bone volume fraction and density, while tissue mineral density was significantly lower in cathepsin S KO mice at both ages. Aged KO mice further had a lower cortical bone mass (-2.3%, p<0.05). At the microarchitectural level, cathepsin S KO mice had thinner trabeculae (-8.3%), but a better connected trabecular network (+24%). Serum levels of the bone formation marker type 1 procollagen amino-terminal-propeptide and osteocalcin were both 2-3-fold higher in cathepsin S KO mice as was the mineralized surface. Consistently, osteogenic differentiation was increased 2-fold along with an increased expression of osteoblast-specific genes. Interestingly, serum levels of C-terminal telopeptide of type I collagen were also higher (+43%) in cathepsin S KO mice as were histological osteoclast parameters and ex vivo osteoclast differentiation. Thus, cathepsin S deficiency alters the balance between adipocyte and osteoblast differentiation, increases bone turnover, and changes bone microarchitecture. Therefore, bone and fat metabolisms should be monitored when using cathepsin S inhibitors clinically.