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 of bone marrow adipose tissue (BMAT). In contrast, a calorie‐restricted (CR) diet causes bone loss and induces BMAT in both mice and humans. We used the CR model to test whether PTH would reduce BMAT in mice by both altering cell fate and inducing lipolysis of marrow adipocytes. Eight‐week‐old mice were placed on 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 4 wk. Two other cohorts were CR and simultaneously injected (CR + PTH or CR + Veh) for 4 wk. CR mice had low bone mass and increased BMAT in the proximal tibias. PTH significantly increased bone mass in all 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 bone marrow adipocyte and osteoblast progenitors, PTH stimulated the transfer of fatty acids to osteoblasts. In summary, PTH administration to CR mice increased bone mass 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.—Maridas, D. E., Rendina‐Ruedy, E., Helderman, R. C., DeMambro, V. E., Brooks, D., Guntur, A. R., Lanske, B., Bouxsein, M. L., Rosen, C. J. Progenitor recruitment and adipogenic lipolysis contribute to the anabolic actions of parathyroid hormone on the skeleton. FASEB J. 33, 2885–2898 (2019). http://www.fasebj.org

The role of osteoblasts in energy homeostasis

“…This hormone induces lipolysis in adipocytes 169 and has been shown to reduce bone marrow adiposity when administered to mice 170,171 . In vitro work using an elegant co-culture system containing adipocytes and osteoblast progenitors demonstrated that after lipolysis, fatty acids are transferred from adipocytes to cells of the osteoblast lineage 171 . Although additional studies will be necessary, the transferred fatty acids could be speculated to be metabolized as an energy source.…”

Reporting Guidelines, Review of Methodological Standards, and Challenges Toward Harmonization in Bone Marrow Adiposity Research. Report of the Methodologies Working Group of the International Bone Marrow Adiposity Society

“…Teriparatide treatment in osteopenic women reduces BMAT (229) and animal studies showed that this effect can be recapitulated by genetic deletion of the parathyroid hormone receptor in skeletal stromal cells (56). Interestingly, additional studies from the Rosen lab showed that the effect of PTH is not only on the differentiation of the SSC into the adipocytic lineage, but that Parathyroid Hormone (PTH) can also induce lipolysis in BM adipocytes (230). In addition, growth hormone (GH) is an important regulator of skeletal growth and growth hormone deficiency or resistance has been associated with changes in BMAT.…”

Dual Effects of Lipid Metabolism on Osteoblast Function

“…While additional studies will be necessary, this paradigm is congruent with findings from Maridas et. al (105) that tracked the transfer of fatty acids from adipocytes to bone marrow stromal cells as well as the established ability of PTH to induce lipolysis in adipocytes (106). Likewise, the reduction in marrow adipose tissue volume after intermittent PTH treatment suggests that marrow adipocytes represent an energy reserve that provides fatty acids to fuel the anabolic activity of osteoblasts (105,107).…”

“…al (105) that tracked the transfer of fatty acids from adipocytes to bone marrow stromal cells as well as the established ability of PTH to induce lipolysis in adipocytes (106). Likewise, the reduction in marrow adipose tissue volume after intermittent PTH treatment suggests that marrow adipocytes represent an energy reserve that provides fatty acids to fuel the anabolic activity of osteoblasts (105,107). The finding that PTH can increase bone mass even under conditions of caloric restriction suggests that the relationship between PTH activity and metabolism is more complex and worthy of further study (105).…”