The increase in marrow adipogenesis associated with osteoporosis and age-related osteopenia is well known clinically. However, we are only now beginning to understand the mechanisms that control the differentiation of mesenchymal stem cells to either osteoblasts or adipocytes. Recent work with gene silencing and overexpression has provided insight into critical pathways that determine the fate of these multipotential cells. In vitro and in vivo studies strongly support an inverse relationship between the commitment of bone marrow-derived mesenchymal stem cells or stromal cells to the adipoctye and osteoblast lineage pathways.
Bone formation is regulated by Runx2/Cbfa 1, a member of the runt homology domain transcription factor family while fat formation depends on the peroxisome proliferator-activated receptor gamma (PPARγ). In vitro studies using bone marrow-derived MSCs find that induction of adipocyte differentiation inhibits osteoblastic bone formation. Likewise, agents inducing osteoblast dfferentiation inhibit adipogenesis.
Parathyroid Hormone (PTH) regulates bone formation and resorption. Indeed, intermittent PTH is the most potent bone anabolic agent known and works, in part, by reactivation of quiescent bone surfaces and reducing osteoblast apoptosis. Significantly, continuous PTH infusion increases bone resorption and bone loss. We investigated the possibility that intermittent and continuous PTH treatment also differentially regulates osteogenic and adipocytic lineage commitment of bone marrow stromal progenitor / mesenchymal stem cells (MSC). Intermittent treatment with parathyroid hormone (PTH) as well as a non-peptide small molecule agonist of the PTH1 receptor inhibits adipocyte differentiation in human bone marrow stromal cells. This response may explain, in part, the mechanism that causes the overall bone anabolic action of intermittent PTH.