Overexpression of miR17 ~ 92 in Myeloid Cells in Mice Increased Bone Mass Through Reduced Bone Resorption and Increased Bone Formation in Sex-Dependent Manner.

Abstract

This study assessed the feasibility of miR17 ~ 92-based antiresorptive strategy by determining the effects of conditional transgenic (cTG) overexpression of miR17 ~ 92 in myeloid cells on bone and osteoclasts. Osteoclasts of male and female cTG mutant mice each showed 3- to fivefold overexpression of miR17 ~ 92 cluster genes compared to those of age- and sex-matched wildtype (WT) littermates. Male but not female cTG mutant mice had more trabecular and cortical bones as well as lower bone resorption reflected by reduction in osteoclast number and resorbing surface. Osteoclasts of male but not female cTG mutants showed decreased bone resorption activity. Consistent with suppression of osteoclast maturation, osteoclasts of male cTG mutants were smaller, contained less nuclei, showed reduced levels of mRNA of genes associated with osteoclast differentiation and fusion, and formed more diffused actin ring. Osteoclastic overexpression of miR17 ~ 92 also increased bone formation, but the increase was much larger in males than in females. The increase in male mutants was due to higher mineral apposition rate, and conversely, it was caused by increasing bone-forming surface in female mutants. In summary, osteoclastic overexpression of miR17 ~ 92 increased bone mass through reduction in bone resorption along with coupled increase in bone formation in male-specific manner. Although the osteoclastic overexpression of miR17 ~ 92-induced suppression of bone resorption and increases in bone formation support the feasibility of miR17 ~ 92-based antiresorptive strategies, the male-specific sexual disparity in skeletal responses to osteoclastic overexpression of miR17 ~ 92 could limit its clinical utility as it may not be used in women with postmenopausal osteoporosis.