Piezo1 activation suppresses bone marrow adipogenesis to prevent osteoporosis by inhibiting a mechanoinflammatory autocrine loop

Authors:
Top Cited Papers
Open Access
Publisher website
Google Scholar
Abstract
With aging or osteoporosis, bone marrow adipogenesis is increased and inversely correlates with the loss of bone mass. Bone marrow adipocytes are derived from multipotent bone marrow mesenchymal stem cells (BMMSCs), which can differentiate into either fat or bone. BMMSCs are mechanosensitive cells, but how mechanical loading is implicated in the in vivo regulation of bone marrow adipogenesis and its impact on bone remodeling remain poorly understood. Here, we identify the mechanosensitive cationic channel Piezo1 in BMMSCs as a key suppressor of bone marrow adipogenesis by preventing local inflammation, thereby enhancing osteoblast differentiation and bone formation. Mice with a specific Piezo1 invalidation in BMMSCs exhibit osteoporosis and marrow adiposity, together with resistance to the beneficial effects of exercise on bone health. Accordingly, Piezo1-deficient BMMSCs in vitro preferentially differentiate into adipocytes rather than osteoblasts. Invalidation of Piezo1 in BMMSCs enhances the autocrine activation of CCR2 by Ccl2, which further induces lipocalin-2 (Lcn2) production via NF-κB activation, thereby promoting adipocyte differentiation. Conversely, Piezo1 opening induces Klf2 expression through CaMKII, preventing c-Jun activation, Ccl2 production and bone marrow adipogenesis. These findings demonstrate that Piezo1 activation in BMMSCs suppresses bone marrow adipogenesis to maintain bone strength by preventing the Ccl2-Lcn2 inflammatory autocrine loop, thus uncovering a previously unrecognized link between mechanotransduction, inflammation, and cell fate determination.
Funding Information
  • Ministry of Science and Technology of the People's Republic of China (National Key R&D Program of China (2022YFA0806102))
  • Research Grants Council, University Grants Committee (AoE/M/707-18, 17125317, 17120022)
  • National Natural Science Foundation of China (82000832)
  • Food and Health Bureau of the Government of the Hong Kong Special Administrative Region | Health and Medical Research Fund (07182836)
  • Macau Science and Technology Development Fund
  • Fondation de France
  • Fondation pour la Recherche Médicale
  • ANR AdipoPiezo (AAPG ANR 2018) and ANR Piezo1-Athero

This publication has 99 references indexed in Scilit: