Abstract
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-13ΔPrrx1) and compared the effect of estrogen deficiency on their bone phenotype to that of control littermates (Mmp-13f/f). Femur and tibia length was decreased in sham-operated Mmp-13ΔPrrx1 mice as compared to Mmp-13f/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 Mmp-13ΔPrrx1 mice; whereas bone formation rate was unaffected. Ovariectomy (OVX) caused a decrease of cortical thickness in the femur and tibia of Mmp-13f/f control mice. This effect was attenuated in the Mmp-13ΔPrrx1 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 Cxcl12ΔPrrx1 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.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Grant Supporters: This work was supported by the Department of Veterans Affairs (I01 BX001405), the National Institutes of Health (P01 AG013918, R01 AR056679, P20 GM125503), and the UAMS Tobacco Funds and Translational Research Institute (1UL1RR029884).
Conflict of Interest Statement: The authors declare no conflicts.