Depletion of marrow adipo-CAR cells in mice enhances bone formation by activating bone morphogenetic protein receptor (BMPR) in pre-osteoblasts
Year: 2025
Type: article
Abstract: Diphtheria toxin (DT)-mediated deletion of marrow cells expressing its receptor (DTR), exclusively in adiponectin (Adipoq)-positive cells, results in profound osteosclerosis, a process driven by activation of bone morphogenetic protein receptor (BMPR) signaling. This enhancement of bone mass is associated with removal of Grem1 and Chrdl1, but the cellular source of these BMPR inhibitors, and whether they mediate this unique skeletal event, has not been established. In this study, we found that replacing the depleted BMPR inhibitors, using nanoparticles bearing their mRNAs, attenuates the osteogenic effect of Adipoq-positive cell depletion, confirming the essential role of Grem1 and Chrdl1 in the osteosclerotic process. Depletion of these BMPR inhibitors is accompanied by elimination of Cxcl12 and Lepr, suggesting that the Adipoq-positive subset of Cxcl12-abundant reticular (adipo-CAR) cells are the exclusive producers of Grem1 and Chrdl1 in marrow. While ablation of adipo-CAR cells does not increase osteo-CARs in the marrow, it activates BMPR in Col1*3.6-positive pre-osteoblasts, leading to their proliferation. Deletion of proliferating Col1*3.6-positive cells completely arrests bone formation induced by adipo-CAR cell ablation, suggesting that committed pre-osteoblasts, rather than earlier osteo-CARs, serve as the osteoprogenitors responsible for the new bone formation. The skeletal effects of eliminating marrow cells expressing leptin receptor (Lepr), also a marker of CAR cells, mirrors that induced by depleting those expressing adiponectin, including its initiation by BMPR activation in both male and female mice. Thus, marrow-residing Adipoq/Lepr-positive CAR cells limit excessive skeletal mass by producing BMPR inhibitors, while their depletion leads to significant osteosclerosis through BMPR activation and pre-osteoblast proliferation.
DOI: 10.1093/jbmr/zjaf051
Authors: Wei Zou, Nidhi Rohatgi, Hua Pan, Nitin Kumar Pokhrel, Matthew J Silva, Steven L Teitelbaum
Institution: Washington University in St. Louis
Language: English
Topic: Bone Metabolism and Diseases
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Funders: U.S. Department of Defense, Foundation for Barnes-Jewish Hospital, University of Connecticut, National Institutes of Health, Musculoskeletal Research Center, Washington University in St. Louis, National Cancer Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Arthritis and Musculoskeletal and Skin Diseases
OpenAlex ID: W4408977091