Marrow adipose tissue (MAT) accumulation is a hallmark of many skeletal diseases, such as osteoporosis and disuse osteopenia. Previous work has shown that the mitogen-activated protein kinase (MAPK) pathway promotes osteogenesis and inhibits marrow adipogenesis in vitro through phosphorylation of runt-related transcription factor 2 (RUNX2) and peroxisome proliferator-activated receptor γ (PPARγ), respectively. Now, a new study evaluating the in vivo significance of these findings shows that the phosphorylation state of PPARγ controls bone formation and marrow adiposity in mouse models.

Micro-CT imaging revealed that mice with the PPARγ-S112A mutation (which prevents MAPK-dependent PPARγ phosphorylation) had markedly lower trabecular bone volume than wild-type mice; this was accompanied by reduced bone formation and osteoblast activity, independent of osteoclastic resorption. By contrast, PPARγ-S112A mice had greater than threefold increases in MAT volume, upregulation of adipocyte differentiation markers and elevated serum levels of adiponectin.

Bone marrow stromal cells isolated from PPARγ-S112A mice preferentially differentiated into adipocytes; consistently, these cells had elevated levels of total PPARγ and decreased levels of total and phosphorylated RUNX2. Furthermore, bone marrow-derived mesenchymal stem cells (MSCs) from PPARγ-S112A mice had a reduced ability to form osteoblast colonies and an increased capacity to form adipocyte colonies in vitro, indicating that PPARγ-S112 phosphorylation influences MSC lineage allocation.

“These findings provide in vivo support for our hypothesis concerning the role of MAPK signalling in lineage switching between osteoblasts and adipocytes and bone and/or MAT formation,” concludes lead investigator Renny Franceschi. “Blocking RUNX2 phosphorylation is also of equal importance, a goal that is being actively pursued by us”.