title: 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.
authors.affiliation: Musculoskeletal Disease Center, JLP VA Medical Center, Loma Linda, California; and Department of Medicine, Loma Linda University, Loma Linda, California.
authors.forename: Subburaman
authors.initials: S
authors.lastname: Mohan
authors.affiliation: Musculoskeletal Disease Center, JLP VA Medical Center, Loma Linda, California; and Department of Medicine, Loma Linda University, Loma Linda, California.
authors.forename: Jon E
authors.initials: JE
authors.lastname: Wergedal
authors.affiliation: Musculoskeletal Disease Center, JLP VA Medical Center, Loma Linda, California; and.
authors.forename: Subhashri
authors.initials: S
authors.lastname: Das
authors.affiliation: Musculoskeletal Disease Center, JLP VA Medical Center, Loma Linda, California; and Department of Medicine, Loma Linda University, Loma Linda, California Chandrasekhar.Kesavan@va.gov.
authors.forename: Chandrasekhar
authors.initials: C
authors.lastname: Kesavan
mesh_terms: D000818:Animals; D024042:Collagen Type I / Q000378:metabolism*; D005260:Female; D005269:Femur / Q000502:physiology; D005786:Gene Expression Regulation; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism; D008297:Male; D018345:Mice, Knockout; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics*; D005810:Multigene Family; D010006:Osteoblasts; D010012:Osteogenesis / Q000235:genetics* / Q000502:physiology; D010805:Physical Conditioning, Animal; D015203:Reproducibility of Results; D013977:Tibia / Q000502:physiology
chemical_list: D024042:Collagen Type I; D035683:MicroRNAs; C543614:Mirn17 microRNA, mouse; C532375:Mirn20 microRNA, mouse; C541873:Mirn92 microRNA, mouse; D007334:Insulin-Like Growth Factor I
keywords: bone formation; conditional knockout; mechanical strain; microRNA; osteoblasts