Deletion of phospholipase D1 decreases bone mass and increases fat mass via modulation of Runx2, β-catenin-osteoprotegerin, PPAR-γ and C/EBPα signaling axis

Dong Woo Kang, Won Chan Hwang, Yu Na Noh, Xiangguo Che, Soung Hoon Lee, Younghoon Jang, Kang Yell Choi, Je Yong Choi, Do Sik Min

Research output: Contribution to journalArticlepeer-review

Abstract

In osteoporosis, mesenchymal stem cells (MSCs) prefer to differentiate into adipocytes at the expense of osteoblasts. Although the balance between adipogenesis and osteogenesis has been closely examined, the mechanism of commitment determination switch is unknown. Here we demonstrate that phospholipase D1 (PLD1) plays a key switch in determining the balance between bone and fat mass. Ablation of Pld1 reduced bone mass but increased fat in mice. Mechanistically, Pld1/− MSCs inhibited osteoblast differentiaion with diminished Runx2 expression, while osteoclast differentiation was accelerated in Pld1−/− bone marrow-derived macrophages. Pld1−/− osteoblasts showed decreased expression of osteogenic makers. Increased number and resorption activity of osteoclasts in Pld1−/− mice were corroborated with upregulation of osteoclastogenic markers. Moreover, Pld1−/− osteoblasts reduced β-catenin mediated-osteoprotegerin (OPG) with increased RANKL/OPG ratio which resulted in accelerated osteoclast differentiation. Thus, low bone mass with upregulated osteoclasts could be due to the contribution of both osteoblasts and osteoclasts during bone remodeling. Moreover, ablation of Pld1 further increased bone loss in ovariectomized mice, suggesting that PLD1 is a negative regulator of osteoclastogenesis. Furthermore, loss of PLD1 increased adipogenesis, body fat mass, and hepatic steatosis along with upregulation of PPAR-γ and C/EBPα. Interestingly, adipocyte-specific Pld1 transgenic mice rescued the compromised phenotypes of fat mass and adipogenesis in Pld1 knockout mice. Collectively, PLD1 regulated the bifurcating pathways of mesenchymal cell lineage into increased osteogenesis and decreased adipogenesis, which uncovered a previously unrecognized role of PLD1 in homeostasis between bone and fat mass.

Original languageEnglish
Article number166084
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1867
Issue number5
DOIs
Publication statusPublished - 2021 May 1

Bibliographical note

Funding Information:
This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government ( NRF-2018R1A2B3002179 ) and by the Yonsei University Research Fund of 2019-22-0193 .

Publisher Copyright:
© 2021 The Authors

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Molecular Biology

Fingerprint

Dive into the research topics of 'Deletion of phospholipase D1 decreases bone mass and increases fat mass via modulation of Runx2, β-catenin-osteoprotegerin, PPAR-γ and C/EBPα signaling axis'. Together they form a unique fingerprint.

Cite this