Conditional disruption of miR17-92 cluster in collagen type I-producing osteoblasts results in reduced periosteal bone formation and bone anabolic response to exercise

Abstract

In this study, we evaluated the role of the microRNA (miR)17-92 cluster in osteoblast lineage cells using a Cre-loxP approach in which Cre expression is driven by the entire regulatory region of the type I collagen α2 gene. Conditional knockout (cKO) mice showed a 13-34% reduction in total body bone mineral content and area with little or no change in bone mineral density (BMD) by DXA at 2, 4, and 8 wk in both sexes. Micro-CT analyses of the femur revealed an 8% reduction in length and 25-27% reduction in total volume at the diaphyseal and metaphyseal sites. Neither cortical nor trabecular volumetric BMD was different in the cKO mice. Bone strength (maximum load) was reduced by 10% with no change in bone toughness. Quantitative histomorphometric analyses revealed a 28% reduction in the periosteal bone formation rate and in the mineral apposition rate but with no change in the resorbing surface. Expression levels of periostin, Elk3, Runx2 genes that are targeted by miRs from the cluster were decreased by 25-30% in the bones of cKO mice. To determine the contribution of the miR17-92 cluster to the mechanical strain effect on periosteal bone formation, we subjected cKO and control mice to 2 wk of mechanical loading by four-point bending. We found that the periosteal bone response to mechanical strain was significantly reduced in the cKO mice. We conclude that the miR17-92 cluster expressed in type I collagen-producing cells is a key regulator of periosteal bone formation in mice.

Mechanical Stress Regulates Bone Metabolism Through MicroRNAs

“…) (Wei et al, ), indicating that miR‐21 is a mechanosensitive associated miRNA in the regulation of bone formation under mechanical loading. Moreover, expression of MiR‐20a and miR‐92a increased 1.3‐ and 2.1‐folds respectively in the mechanically loaded tibia compared to the unloaded tibia following 2 weeks of four‐point bending in C57BL/6J mice (Mohan et al, ).…”

“…The response of bone tissue cells to a mechanical stress stimulus is adversely affected when critical miRNAs are missing. Mohan et al () reported that conditional disruption of the miR17‐92 cluster in collagen type I‐producing osteoblasts reduced the bone mineral density and bone strength, decreased bone formation rate significantly, and down‐regulated the gene expression of periostin, Elk3, and Runx2. Furthermore, the periosteal bone response to mechanical strain was obviously decreased due to conditional knockout of miR17‐92 cluster (Mohan et al, ).…”

“…Mohan et al () reported that conditional disruption of the miR17‐92 cluster in collagen type I‐producing osteoblasts reduced the bone mineral density and bone strength, decreased bone formation rate significantly, and down‐regulated the gene expression of periostin, Elk3, and Runx2. Furthermore, the periosteal bone response to mechanical strain was obviously decreased due to conditional knockout of miR17‐92 cluster (Mohan et al, ). MiR‐365 has been reported as the first identified mechanically responsive miRNA which can regulate chondrocyte differentiation directly by targeting HDAC4.…”

IGF‐1 signaling mediated cell‐specific skeletal mechano‐transduction

“…54 Another study indicated that in osteoblasts conditional disruption of miR17-92 cluster, which is activated by IGF-1 stimulation, results in reduced periosteal bone formation and bone anabolic response to exercise. 55 In vitro data support these vivo observations. Inhibition of IGF-1with the antagonist IGFBP-4 blunted fluid-flow stress-induced proliferation in the osteoblastic cell line MC3T3-E1.…”

“…We further assessed the skeletal response of osteoblast‐specific IGF‐1R deficient mice to unloading and reloading, and found that the recovery of periosteal bone formation with reloading was completely inhibited in the conditional IGF‐1R knockout mice . Another study indicated that in osteoblasts conditional disruption of miR17‐92 cluster, which is activated by IGF‐1 stimulation, results in reduced periosteal bone formation and bone anabolic response to exercise …”