Parathyroid Hormone Directs Bone Marrow Mesenchymal Cell Fate

Intermittent PTH administration builds bone mass and prevents fractures, but its mechanism of action is unclear. We genetically deleted the PTH/PTHrP receptor (PTH1R) in mesenchymal stem cells using Prx1Cre and found low bone formation, increased bone resorption, and high bone marrow adipose tissue (BMAT). Bone marrow adipocytes traced to Prx1 and expressed classic adipogenic markers and high receptor activator of nuclear factor kappa B ligand (Rankl) expression. RANKL levels were also elevated in bone marrow supernatant and serum, but undetectable in other adipose depots. By cell sorting, Pref1+RANKL+ marrow progenitors were twice as great in mutant versus control marrow. Intermittent PTH administration to control mice reduced BMAT significantly. A similar finding was noted in male osteoporotic patients. Thus, marrow adipocytes exhibit osteogenic and adipogenic characteristics, are uniquely responsive to PTH, and secrete RANKL. These studies reveal an important mechanism for PTH’s therapeutic action through its ability to direct mesenchymal cell fate. [Display omitted] •PTH1R regulates lineage allocation in the marrow•Bone marrow adipocytes compose a unique adipose depot and produce RANKL•PTH reduced marrow adipogenesis in mice and humans Fan et al. show that PTH regulates mesenchymal stem cell fate between bone and adipocyte in the marrow. Bone marrow adipocytes have distinct origins and properties from other adipocytes and are responsive to PTH, underlying the reduction in marrow adiposity in mouse models and idiopathic osteoporosis patients treated with PTH.