Mmp-13 deletion in cells of the mesenchymal lineage increases bone mass, decreases endocortical osteoclast number, and attenuates the cortical bone loss caused by estrogen deficiency in mice

The protective effect of estrogens against cortical bone loss is mediated via direct actions on mesenchymal lineage cells, but functional evidence for the precise molecular mechanism(s) and the mediators of these effects has only recently began to emerge. We report that the matrix metalloproteinase 13 (MMP-13) is the highest up-regulated gene in calvaria or bone marrow cells from mice lacking the estrogen receptor (ER) alpha in osteoprogenitors. We, therefore, generated mice with conditional Mmp-13 deletion in Prrx1 expressing cells ( Mmp-13 ?Prrx1 ) and compared the effect of estrogen deficiency on their bone phenotype to that of control littermates ( Mmp-13 f/f ). Femur and tibia length was decreased in sham-operated Mmp-13 ?Prrx1 mice as compared to Mmp1 3 f/f . Cortical thickness and trabecular bone volume in the femur and tibia were increased and osteoclast number at the endocortical surfaces was decreased in the sham-operated female Mmp13 ?Prrx1 mice; whereas bone formation rate was unaffected. Ovariectomy (OVX) caused a decrease of cortical thickness in the femur and tibia of Mmp-13 f/f control mice. This effect was attenuated in the Mmp-13 ? Prrx1 mice; but the decrease of trabecular bone caused by OVX was not affected. These results reveal that mesenchymal cell–derived MMP-13 regulates osteoclast number, bone resorption, and bone mass. We have recently reported that the loss of cortical, but not trabecular bone, caused by OVX is also attenuated in Cxcl12 ?Prrx1 mice. Together with the present report, this functional genetic evidence provides proof of principle that increased production of mesenchymal cell-derived factors, such as CXCL12 and MMP-13, are important mediators of the adverse effect of estrogen deficiency on cortical, but not trabecular, bone. Therefore, the mechanisms responsible for the protective effect of estrogens on these two major bone compartments are different.

Vitamin D deficiency is associated with cortical bone loss and fractures in the elderly

Introduction The role of vitamin D on bone microarchitecture and fragility is not clear. Objective To investigate whether vitamin D deficiency (25(OH)D <20 ng/mL) increases cortical bone loss and the severity of fractures. Design Cross-sectional study of 287 elderly women with at least one prevalent low-impact fracture. Methods Biochemistry, X-rays to identify vertebral fractures (VFs) and to confirm non-vertebral fractures (NonVFs), and high-resolution peripheral quantitative computed tomography (HR-pQCT) to evaluate bone microstructure. Results Serum 25(OH)D levels were associated with body mass index (BMI: r = −0.161, P = 0.006), PTH (r = −0.165; P = 0.005), CTX (r = −0.119; P = 0.043) and vBMD at cortical bone (Dcomp: r = 0.132; P = 0.033) and entire bone (D100: r = 0.162 P = 0.009) at the distal radius, but not at the tibia. Age and PTH levels were potential confounding variables, but in the multiple linear regressions only BMI (95% CI: 0.11–4.16; P < 0.01), 25(OH)D (95% CI: −0.007 to 1.70; P = 0.05) and CTX (95% CI: −149.04 to 21.80; P < 0.01) predicted Dcomp, while BMI (95% CI: 1.13–4.18; P < 0.01) and 25(OH)D (95% CI: 0.24–1.52; P < 0.01) predicted D100. NonVFs predominated in patients with 25(OH)D <20 ng/mL (P = 0.013). Logistic regression analysis showed a decrease in the likelihood of presenting grade 2–3 VFs/NonVFs for every increase in 25(OH)D (OR = 0.962, 95% CI: 0.940–0.984; P = 0.001), BMI (OR = 0.932, 95% CI: 0.885–0.981; P = 0.007) and D100 at radius (OR = 0.994, 95% CI: 0.990–0.998; P = 0.005). Conclusion In elderly patients with prevalent fractures, vitamin D deficiency was associated with cortical bone loss and severity of fractures.