Stress causes lipid droplet accumulation in chondrocytes by impairing microtubules

Jia Yu; Qian Liu; Yuejiao Zhang; Lingfeng Xu; Xiaohua Chen; Feng He; Mian Zhang; Hongxu Yang; Shibing Yu; Xin Liu; Yaoping Wu; Meiqing Wang

doi:10.1016/j.joca.2024.08.015

Stress causes lipid droplet accumulation in chondrocytes by impairing microtubules

Osteoarthritis Cartilage. 2024 Dec 25:S1063-4584(24)01506-1. doi: 10.1016/j.joca.2024.08.015. Online ahead of print.

Authors

Jia Yu¹, Qian Liu², Yuejiao Zhang³, Lingfeng Xu⁴, Xiaohua Chen⁵, Feng He⁶, Mian Zhang⁷, Hongxu Yang⁸, Shibing Yu⁹, Xin Liu¹⁰, Yaoping Wu¹¹, Meiqing Wang¹²

Affiliations

¹ Department of Oral Anatomy and Physiology and TMD, College of Stomatology, the Fourth Military Medical University. Xi'an, China. Electronic address: 476216482@qq.com.
² Department of Stomatology, Air Force Medical Center, PLA, the Fourth Military Medical University, Beijing, China. Electronic address: 13259776870@163.com.
³ Shanghai Key Laboratory of Craniomaxillofacial Development and Diseases, Shanghai Stomatological Hospital, Fudan University, Shanghai, China. Electronic address: 1064382106@qq.com.
⁴ Department of Oral Anatomy and Physiology and TMD, College of Stomatology, the Fourth Military Medical University. Xi'an, China. Electronic address: 1226017982@qq.com.
⁵ Department of Oral Anatomy and Physiology and TMD, College of Stomatology, the Fourth Military Medical University. Xi'an, China. Electronic address: 1457143049@qq.com.
⁶ Department of Oral Anatomy and Physiology and TMD, College of Stomatology, the Fourth Military Medical University. Xi'an, China. Electronic address: 809389273@qq.com.
⁷ Department of Oral Anatomy and Physiology and TMD, College of Stomatology, the Fourth Military Medical University. Xi'an, China. Electronic address: zhangmian1986@aliyun.com.
⁸ Department of Oral Anatomy and Physiology and TMD, College of Stomatology, the Fourth Military Medical University. Xi'an, China. Electronic address: yanghongxushmily@163.com.
⁹ Department of Oral Anatomy and Physiology and TMD, College of Stomatology, the Fourth Military Medical University. Xi'an, China. Electronic address: yushibin@fmmu.edu.cn.
¹⁰ Department of Stomatology, the 960th Hospital of People's Liberation Army, Jinan, China. Electronic address: 15249067958@163.com.
¹¹ Department of Joint Surgery, Shenzhen Hospital of Southern Medical University, Shenzhen, China. Electronic address: Horikawadavid@vip.sina.com.
¹² Department of Oral Anatomy and Physiology and TMD, College of Stomatology, the Fourth Military Medical University. Xi'an, China; Shanghai Key Laboratory of Craniomaxillofacial Development and Diseases, Shanghai Stomatological Hospital, Fudan University, Shanghai, China. Electronic address: mqwang@fmmu.edu.cn.

PMID: 39730095
DOI: 10.1016/j.joca.2024.08.015

Abstract

Objective: Abnormal mechanical stress is intimately coupled with osteoarthritis (OA). Microtubules play a vital role in the regulation of mechanotransduction and intracellular transport. The purpose of the present study was to investigate the impact of stress-induced microtubule impairment on intracellular transport and lipid droplet (LD) accumulation in chondrocytes.

Method: Rats were subjected to unilateral anterior crossbite (UAC), which is inducible for degeneration of temporomandibular joint (TMJ) cartilage. Chondrocytes derived from rat TMJ cartilage were subjected to fluid flow shear stress (FFSS) and analyzed via LCMS/MS-based proteomics. The microtubule destabilization agent nocodazole and/or the microtubule stabilizer docetaxel were used in the UAC and FFSS models.

Results: In both FFSS- and UAC-treated chondrocytes, decreased acetylated α-Tubulin (ac-Tubulin) expression and LD accumulation were observed. Proteomic data revealed increased levels of the LD-associated protein perilipin 3 (Plin3) and decreased levels of cytoskeleton components in FFSS-treated chondrocytes. Live-cell imaging revealed that the colocalization of LDs with lysosomes was significantly decreased after FFSS treatment. Impairment of microtubules by nocodazole reduced the protein level of ac-Tubulin and disrupted the Hsc70-mediated interaction between Plin3 and Lamp2a, as shown by co-IP assays. In contrast, docetaxel reversed the suppression of ac-Tubulin expression, reduced the accumulation of LDs, and decreased the expression of Plin3 in chondrocytes exposed to FFSS and UAC, and docetaxel ameliorated UAC-induced osteoarthritic lesions in the TMJ cartilage.

Conclusion: Microtubule impairment under aberrant stress conditions disrupts intracellular transport and blocks lipophagy, causing LD accumulation in chondrocytes. Microtubule stabilization could be a new approach for treating stress-induced cartilage degeneration.

Keywords: Chondrocyte; Lipid; Mechanic-stress; Osteoarthritis; Temporomandibular joint.