| First Author | Ge C | Year | 2018 |
| Journal | Bone | Volume | 107 |
| Pages | 1-9 | PubMed ID | 29107124 |
| Mgi Jnum | J:256978 | Mgi Id | MGI:6112767 |
| Doi | 10.1016/j.bone.2017.10.023 | Citation | Ge C, et al. (2018) Genetic inhibition of PPARgamma S112 phosphorylation reduces bone formation and stimulates marrow adipogenesis. Bone 107:1-9 |
| abstractText | A common feature of many skeletal diseases is the accumulation of marrow fat. A reciprocal relationship exists between osteogenesis and adipogenesis in bone marrow that is mediated by the relative activity of PPARgamma and RUNX2 transcription factors. The ERK/MAPK pathway is an important inducer of MSC differentiation to osteoblasts and an inhibitor of adipogenesis that functions by phosphorylating RUNX2 and PPARgamma. To begin to assess the importance of this regulation in vivo, we examined the consequences of blocking one arm of this pathway, PPARgamma S112 phosphorylation, by evaluating the bone phenotype of PPARgamma S112A mutant mice. This mutation prevents MAPK phosphorylation and inhibition of PPARgamma transcriptional activity. Both male and female PPARgamma S112A mice had decreased tibial and vertebral BV/TV and decreased trabecular bone relative to wild type littermates. These results were explained by a decrease in bone formation and osteoblast activity in the absence of changes in resorption. In contrast, marrow adipose tissue, adipocyte markers and serum adiponectin were all dramatically increased. Bone marrow stromal cells isolated from PPARgamma S112A mice had elevated PPARgamma and preferentially differentiated to adipocytes while total and phosphorylated RUNX2 and osteoblastogenesis were inhibited, indicating that the PPARgamma S112A mutation affects bone in a cell autonomous manner. Changes in osteoblast/adipocyte lineage allocation in MSC cultures were also seen where CFU-OBs were reduced with a parallel increase in CFU-AD. This study emphasizes the importance of PPARgamma phosphorylation in controlling bone mass and marrow adiposity and demonstrates how a regulatory mutation in PPARgamma previously associated with peripheral fat metabolism can have broader effects on bone homeostasis that may in turn affect whole body energy metabolism. |
