Inhibition of miR-29 activity in the myeloid lineage increases response to calcitonin and trabecular bone volume in mice

Endocrinology. 2021 Jun 30:bqab135. doi: 10.1210/endocr/bqab135. Online ahead of print.ABSTRACTThe miR-29-3p family (miR-29a, miR-29b, miR-29c) of microRNAs is increased during RANKL-induced osteoclastogenesis. In vivo, activation of a miR-29-3p tough decoy inhibitor (TuD) in LysM-cre expressing cells (myeloid lineage) resulted in mice displaying enhanced trabecular and cortical bone volume, due to decreased bone resorption. Calcitonin receptor (Calcr) is a miR-29 target that negatively regulates bone resorption. CALCR was significantly increased in RANKL-treated miR-29-decoy osteoclasts, and these cells were more responsive to the inhibitory effect of calcitonin on osteoclast formation. Further, cathepsin K (Ctsk), which is critical for resorption, was decreased in miR-29-decoy cells. CALCR is a Gs coupled receptor and its activation raises cAMP levels. In turn, cAMP suppresses cathepsin K, and cAMP levels were increased in miR-29-decoy cells. siRNA-mediated knock down of Calcr in miR-29 decoy osteoclasts allowed recovery of cathepsin K levels in these cells. Overall, using a novel knockin tough decoy mouse model, we identified a new role for miR-29-3p in bone homeostasis. In RANKL-driven osteoclastogenesis, as seen in normal bone remodeling, miR-29-3p promotes resorption. Consequently, inhibition of miR-29-3p activity in the myeloid lineage leads to increased trabecular and cortical bone. Further, this study documents an inter-relationship between CALCR and CTSK in osteocla...

Source: Endocrinology - June 30, 2021 Category: Endocrinology Authors: Bongjin Shin Henry C Hrdlicka Anne M Delany Sun-Kyeong Lee Source Type: research