Related Experiment Video
Updated: Feb 21, 2026
The Colon-26 Carcinoma Tumor-bearing Mouse as a Model for the Study of Cancer Cachexia
Published on: November 30, 2016
Systemic cachexia and muscle-bone crosstalk drive depression-related joint remodeling and pain
Chen Zhao1,2, Pengcheng Liu3, Jialong Wu1
1Department 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.
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.
Related Concept Videos
01:29Bone Disorders
Bone deposition is also affected by the levels of sex hormones like estrogen and testosterone that promote osteoblast activity and bone matrix synthesis. When the level of these hormones decreases due to aging, it causes a reduction in bone deposition. As a result, bone resorption by osteoclasts...
01:31Osteoclasts in Bone Remodeling
01:28Disorders of the Skeletal Muscle
Musculoskeletal disorders
Musculoskeletal disorders involve injuries and conditions affecting the skeletal muscles and associated connective tissues. These disorders can arise from acute biomechanical stresses or chronic overuse and can occur across different age groups. Common injuries include sprains, fractures, and muscular strains, often resulting from...
01:20The JAK-STAT Signaling Pathway
01:40Bone Remodeling
01:17Hormones and Bone Tissue
Hormones That Influence Osteoblasts and/or Maintain the Matrix
Several hormones are necessary for controlling bone growth and maintaining the bone matrix. The pituitary gland secretes growth hormone (GH), which, as its name implies, controls bone growth. This happens in several ways: first, it triggers chondrocyte...