Progenitor recruitment and adipogenic lipolysis contribute to the anabolic actions of parathyroid hormone on the skeleton

Abstract

Intermittent administration of parathyroid hormone (PTH) stimulates bone formation in vivo and also suppresses the volume ofbonemarrowadipose tissue (BMAT). Incontrast, a calorie-restricted(CR) diet causes bone loss and inducesBMATin both mice andhumans.We used theCRmodel to testwhetherPTHwould reduceBMAT inmiceby both altering cell fate and inducing lipolysis ofmarrowadipocytes. Eight-week-oldmicewere placedon a control (Ctrl) diet or CR diet. At 12 wk, CR and Ctrl mice were injected daily with PTH (CR/PTH or Ctrl/PTH) or vehicle for 4wk.Two other cohortswereCRand simultaneously injected (CR+ PTHorCR+Veh) for 4wk.CRmice hadlowbonemass and increasedBMATin theproximal tibias.PTHsignificantly increased bonemass inall cohorts despite calorie restrictions. Adipocyte density and size were markedly increased with restriction of calories. PTH reduced adipocyte numbers in CR + PTH mice, whereas adipocyte size was reduced in CR/PTH-treated mice. In contrast, osteoblast number was increased 3-8-fold with PTH treatment. In vitro, bone marrow stromal cells differentiated into adipocytes and, treated with PTH, exhibited increased production of glycerol and fatty acids. Moreover, in cocultures of bonemarrowadipocyte and osteoblast progenitors, PTHstimulated the transfer of fatty acids to osteoblasts. In summary, PTHadministration toCRmice increased bonemass by shifting lineage allocation toward osteogenesis and inducing lipolysis of mature marrow adipocytes. The effects of PTH on bone marrow adiposity could enhance its anabolic actions by providing both more cells and more fuel for osteoblasts during bone formation.