Cell Metab. 2017 Jan 25. pii: S1550-4131(17)30036-0. doi: 10.1016/j.cmet.2017.01.001. [Epub ahead of print]

Parathyroid Hormone Directs Bone Marrow Mesenchymal Cell Fate.

Fan Y¹, Hanai JI², Le PT³, Bi R⁴, Maridas D³, DeMambro V³, Figueroa CA³, Kir S⁵, Zhou X⁶, Mannstadt M⁷, Baron R⁸, Bronson RT⁹, Horowitz MC¹⁰, Wu JY¹¹, Bilezikian JP¹², Dempster DW¹³, Rosen CJ¹⁴, Lanske B¹⁵.

Abstract

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.