Lu Jiawei, He Qi, Wang Huan, Yao Lutian, Duffy Michael, Guo Hanli, Braun Corben, Zhou Yilu, Liang Qiushi, Lin Yuewei, Bandyopadhyay Shovik, Tan Kai, Choi Yongwen, Liu X Sherry, Qin Ling
Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
Department of Spine Surgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200092, China.
Bone Res. 2025 Mar 19;13(1):39. doi: 10.1038/s41413-025-00405-4.
Bone resorption by osteoclasts is a critical step in bone remodeling, a process important for maintaining bone homeostasis and repairing injured bone. We previously identified a bone marrow mesenchymal subpopulation, marrow adipogenic lineage precursors (MALPs), and showed that its production of RANKL stimulates bone resorption in young mice using Adipoq-Cre. To exclude developmental defects and to investigate the role of MALPs-derived RANKL in adult bone, we generated inducible reporter mice (Adipoq-CreER Tomato) and RANKL deficient mice (Adipoq-CreER RANKLflox/flox, iCKO). Single cell-RNA sequencing data analysis and lineage tracing revealed that Adipoq cells contain not only MALPs but also some mesenchymal progenitors capable of osteogenic differentiation. In situ hybridization showed that RANKL mRNA is only detected in MALPs, but not in osteogenic cells. RANKL deficiency in MALPs induced at 3 months of age rapidly increased trabecular bone mass in long bones as well as vertebrae due to diminished bone resorption but had no effect on the cortical bone. Ovariectomy (OVX) induced trabecular bone loss at both sites. RANKL depletion either before OVX or at 6 weeks post OVX protected and restored trabecular bone mass. Furthermore, bone healing after drill-hole injury was delayed in iCKO mice. Together, our findings demonstrate that MALPs play a dominant role in controlling trabecular bone resorption and that RANKL from MALPs is essential for trabecular bone turnover in adult bone homeostasis, postmenopausal bone loss, and injury repair.
破骨细胞介导的骨吸收是骨重塑过程中的关键步骤，该过程对于维持骨稳态和修复受损骨骼至关重要。我们之前鉴定出一种骨髓间充质亚群，即骨髓脂肪生成谱系前体细胞（MALPs），并利用Adipoq-Cre证明其产生的RANKL可刺激幼鼠的骨吸收。为排除发育缺陷并研究MALPs来源的RANKL在成年骨中的作用，我们构建了诱导型报告基因小鼠（Adipoq-CreER Tomato）和RANKL缺陷小鼠（Adipoq-CreER RANKLflox/flox，iCKO）。单细胞RNA测序数据分析和谱系追踪显示，Adipoq细胞不仅包含MALPs，还包含一些能够向成骨细胞分化的间充质祖细胞。原位杂交表明，仅在MALPs中检测到RANKL mRNA，而成骨细胞中未检测到。3月龄时诱导MALPs中的RANKL缺陷，由于骨吸收减少，长骨和椎骨的小梁骨量迅速增加，但对皮质骨无影响。卵巢切除（OVX）在两个部位均诱导小梁骨丢失。在OVX之前或OVX后6周消耗RANKL可保护并恢复小梁骨量。此外，iCKO小鼠钻孔损伤后的骨愈合延迟。总之，我们的研究结果表明，MALPs在控制小梁骨吸收中起主导作用，并且MALPs来源的RANKL对于成年骨稳态、绝经后骨丢失和损伤修复中的小梁骨周转至关重要。
