
==== Front
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10.21203/rs.3.rs-4809633/v1
10.21203/rs.3.rs-4809633
preprint
1
Article
Bone marrow adipogenic lineage precursors are the major regulator of bone resorption in adult mice
Qin Ling https://orcid.org/0000-0002-2582-0078

Lu Jiawei
He Qi
Wang Huan
Yao Lutian
Duffy Michael
Guo Hanli
Braun Corben
Lin Yuewei
Zhou Yilu
Liang Qiushi
Bandyopadhyay Shovik
Tan Kai
Choi Yongwon https://orcid.org/0000-0002-1007-7998

Liu Sherry
28 8 2024
rs.3.rs-4809633https://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License, which allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use.
https://www.researchsquare.com/article/rs-4809633/v1
nihpp-rs4809633v1.pdf
Abstract

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, lineage tracing, and in situ hybridization revealed that Adipoq+ cells contain not only MALPs but also late mesenchymal progenitors capable of osteogenic differentiation. However, RANKL mRNA was 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 within 1 month 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.
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