miR-21 deficiency inhibits osteoclast function and prevents bone loss in mice

<jats:title>Abstract</jats:title><jats:p>MicroRNAs emerge as critical post-transcriptional regulators in bone metabolism. We have previously reported <jats:italic>in vitro</jats:italic> that miR-21 promotes osteogenesis, while studies have also revealed miR-21 as a regulator of osteoclastogenesis and a promoter of osteoclast differentiation <jats:italic>in vitro</jats:italic>. However, <jats:italic>in vivo</jats:italic> data are still lacking in identifying skeletal function of miR-21, particularly its effects on osteoporosis. Here, using miR-21 knockout (miR-21<jats:sup>−/−</jats:sup>) mice, we investigated effects of miR-21 on bone development, bone remodeling and bone loss. Unexpectedly, miR-21<jats:sup>−/−</jats:sup> mice demonstrated normal skeletal phenotype in development and maintained osteoblastogenesis <jats:italic>in vivo</jats:italic>. Besides, miR-21<jats:sup>−/−</jats:sup> mice showed increased receptor activator of nuclear factor κB ligand (RANKL) and decreased osteoprotegerin (OPG) through miR-21 targeting Sprouty 1 (Spry1). Nevertheless, interestingly, miR-21 deficiency promoted trabecular bone mass accrual physiologically. Furthermore, in pathological states, the protection of bone mass was prominent in miR-21<jats:sup>−/−</jats:sup> mice. These skeletal effects were attributed to inhibition of bone resorption and osteoclast function by miR-21 deficiency through miR-21 targeting programmed cell death 4 (PDCD4), despite the existence of RANKL. As far as we know, this is the first <jats:italic>in vivo</jats:italic> evidence of a pro-osteoclastic microRNA. Together, these findings clarified function of miR-21 in bone metabolism, particularly uncovering osteo-protective potential of miR-21 inactivation in osteoporosis.</jats:p>