2. Academic Validation
  3. Systemic cachexia and muscle-bone crosstalk drive depression-related joint remodeling and pain

Systemic cachexia and muscle-bone crosstalk drive depression-related joint remodeling and pain

  • Int J Surg. 2026 Feb 19;112(4):9427-9447. doi: 10.1097/JS9.0000000000004653.
Chen Zhao 1 2,  Pengcheng Liu 3,  Jialong Wu 1,  Ran Duan 4,  Weiqi Li 5,  Jianfei Zhang 6,  Xuzhuo Chen 1
Affiliations

Affiliations

  • 1 Department of Oral Surgery, Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 2 Department of Orthopedics, Shanghai Key Laboratory of Orthopedics Implant, the Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 3 Department of Orthopedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 4 Department of Reconstructive and Plastic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University, Shanghai, China.
  • 5 State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, P.R. China.
  • 6 Department of Oral & Cranio-maxillofacial Surgery, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai, China.
PMID: 41711199 DOI: 10.1097/JS9.0000000000004653
Abstract

Background: Joint pain is common in patients with depression, but its structural basis and molecular mechanisms remain unclear. This study aimed to investigate the underlying pathological changes and signaling pathways contributing to depression-related joint pain.

Materials and methods: Using inflammatory and chronic stress-induced mouse models of depression, we evaluated osteoclast activation, subchondral bone remodeling, and associated behavioral alterations. Molecular and genetic analyses were conducted to examine the role of the Lbp-Tlr4-Netrin-1 signaling axis and key metabolic genes including Gdf-15, LepR, and PPARγ, specifically in adipose tissue, bone marrow, and osteoclasts. Additionally, we assessed the impact of muscle degeneration on joint pathology, and conditionally deleted TGF-β1 in muscle satellite cells to determine its role in joint preservation.

Results: Depression-induced joint pain was associated with increased osteoclast activity and extensive subchondral bone remodeling. The Lbp-Tlr4-Netrin-1 axis was highly upregulated in depressed subchondral bone, and its inhibition alleviated both pain-like behaviors and excessive bone resorption while mitigating depression-related weight loss. Deletion of Gdf-15, LepR, and PPARγ revealed that lipid metabolism genes significantly affect both depressive behavior and pain. Depression promoted TGF-β-mediated mesenchymal stem cell senescence and adipogenic differentiation, resembling pathological changes seen in aging and obesity. Notably, simple weight gain without metabolic correction worsened joint damage. Muscle wasting due to depression also contributed to joint pathology, and deletion of TGF-β1 in satellite cells improved joint integrity.

Conclusions: Depression-related joint pain is not merely a psychological phenomenon but a complex organic disorder with defined structural and molecular underpinnings. It involves dysregulated lipid metabolism, aging-associated pathways, and multi-organ interactions between fat, muscle, bone, and the nervous system.

Keywords

chronic stress model; depression-related joint pain; lipid metabolism; muscle–bone crosstalk.

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