Zou Wei, Rohatgi Nidhi, Pan Hua, Pokhrel Nitin Kumar, Silva Matthew J, Teitelbaum Steven L
Division of Anatomic and Molecular Pathology, Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, United States.
Division of Rheumatology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, United States.
J Bone Miner Res. 2025 May 24;40(5):688-698. doi: 10.1093/jbmr/zjaf051.
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 Col13.6-positive pre-osteoblasts, leading to their proliferation. Deletion of proliferating Col13.6-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.
白喉毒素（DT）介导的仅在脂联素（Adipoq）阳性细胞中表达其受体（DTR）的骨髓细胞缺失，会导致严重的骨硬化，这一过程由骨形态发生蛋白受体（BMPR）信号通路的激活驱动。骨量的这种增加与Gremlin1（Grem1）和Chordin样蛋白1（Chrdl1）的清除有关，但这些BMPR抑制剂的细胞来源以及它们是否介导这一独特的骨骼事件尚未明确。在本研究中，我们发现使用携带其mRNA的纳米颗粒替代耗尽的BMPR抑制剂，可减弱Adipoq阳性细胞缺失的成骨作用，证实了Grem1和Chrdl1在骨硬化过程中的关键作用。这些BMPR抑制剂的耗尽伴随着趋化因子配体12（Cxcl12）和瘦素受体（Lepr）的消除，表明富含Cxcl12的网状细胞（adipo-CAR）中的Adipoq阳性亚群是骨髓中Grem1和Chrdl1的唯一产生者。虽然adipo-CAR细胞的消融不会增加骨髓中的成骨CAR细胞，但它会激活I型胶原蛋白α3.6（Col13.6）阳性前成骨细胞中的BMPR，导致其增殖。增殖的Col13.6阳性细胞的缺失完全阻止了adipo-CAR细胞消融诱导的骨形成，这表明定向的前成骨细胞而非早期的成骨CAR细胞是负责新骨形成的骨祖细胞。消除表达瘦素受体（Lepr）的骨髓细胞（Lepr也是CAR细胞的标志物）的骨骼效应，与耗尽表达脂联素的细胞所诱导的效应相似，包括在雄性和雌性小鼠中均由BMPR激活引发。因此，驻留在骨髓中的Adipoq/Lepr阳性CAR细胞通过产生BMPR抑制剂来限制骨骼质量过度增加，而它们的缺失则通过BMPR激活和前成骨细胞增殖导致显著的骨硬化。
