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The unique role of bone marrow adipose tissue in ovariectomy-induced bone loss in mice

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Abstract

Background

Accumulation of bone marrow adipose tissue (BMAT) is always seen in osteoporosis induced by estrogen deficiency. Herein, we aimed to investigate the mechanisms and consequences of this phenomenon by establishing a mouse model of osteoporosis caused by ovariectomy (OVX)-mimicked estrogen deficiency.

Methods

Micro-CT, osmium tetroxide staining, and histological analyses were performed to examine the changes in bone microstructure, BMAT and white adipose tissue (WAT) in OVX mice compared to sham mice. The osteogenesis and adipogenesis of primary bone marrow stromal cells (BMSCs) isolated from sham and OVX mice were compared in vitro. The molecular phenotypes of BMAT and WAT were determined and compared by quantitative PCR (qPCR). Bone marrow adipocyte-conditioned medium (BMA CM) was prepared from sham or OVX mice for coculture assays, and BMSCs or bone marrow monocytes/macrophages (BMMs) were isolated and subjected to osteoblast and osteoclast differentiation, respectively. Cell staining and qPCR were used to assess the effects of BMAT on bone metabolism.

Results

OVX-induced estrogen deficiency induced reductions in both cortical and trabecular bone mass along with an expansion of BMAT volume. At the cellular level, loss of estrogen inhibited BMSC osteogenesis and promoted BMSC adipogenesis, whereas addition of estradiol exerted the opposite effects. In response to estrogen deficiency, despite the common proinflammatory molecular phenotype observed in both fat depots, BMAT, unlike WAT, unexpectedly exhibited an increase in adipocyte differentiation and lipolytic activity as well as the maintenance of insulin sensitivity. Importantly, BMAT, but not WAT, presented increased mRNA levels of both BMP receptor inhibitors (Grem1, Chrdl1) and Rankl following OVX. In addition, treatment with BMA CM, especially from OVX mice, suppressed the osteoblast differentiation of BMSCs while favoring the osteoclast differentiation of BMMs.

Conclusion

Our study illustrates that OVX-induced estrogen deficiency results in bone loss and BMAT expansion by triggering imbalance between the osteogenesis and adipogenesis of BMSCs. Furthermore, expanded BMAT, unlike typical WAT, may negatively regulate bone homeostasis through paracrine inhibition of osteoblast-mediated bone formation and promotion of osteoclast-mediated bone resorption.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (No. 82273294); the Science and Technology Department of Sichuan Province (2022YFS0136); the Chengdu Bureau of Science and Technology (2022-YF05-01316-SN); the National Natural Science Foundation of China (No.82204847); Key Research and Development Project of Science and Technology Department of Sichuan Province (2023YFS0332); and the 1.3.5 project for discipline of excellence, West China Hospital, Sichuan University (No. 2020HXFH008, No. ZYJC18003).

Author contributions

X.Y designed this research. J.L., L.L., L.L., C.W., Y.X. and L.T. were responsible for the experiments. Among them, J.L., L.L., L.L. and C.W. were in charge of the animal experiments, cellular experiments, and molecular experiments. Y.X. and L.T. were mainly responsible for the histopathological part. J.L., L.L., H.L. and X.Y. were responsible for the revision of the whole article. J.L. and L.L. contributed equally to this work. All authors contributed to the article and approved the submitted version.

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Authors and Affiliations

  1. Laboratory of Endocrinology and Metabolism, Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu, 610041, China

    Jiao Li, Lingyun Lu, Lu Liu, Cui Wang, Ying Xie, Li Tian & Xijie Yu

  2. Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, 610041, China

    Jiao Li & Hong Li

  3. Department of Integrated Traditional Chinese and Western medicine, West China Hospital, Sichuan University, Chengdu, 610041, China

    Lingyun Lu

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Li, J., Lu, L., Liu, L. et al. The unique role of bone marrow adipose tissue in ovariectomy-induced bone loss in mice. Endocrine 83, 77–91 (2024). https://doi.org/10.1007/s12020-023-03504-6

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