2. Academic Validation
  3. ADRM1/RPN13 attenuates cartilage extracellular matrix degradation via enhancing UCH37-mediated ALK5 deubiquitination

ADRM1/RPN13 attenuates cartilage extracellular matrix degradation via enhancing UCH37-mediated ALK5 deubiquitination

  • Int J Biol Macromol. 2023 Jul 3;125670. doi: 10.1016/j.ijbiomac.2023.125670.
Meisong Zhu 1,  Zhiyou Cao 1,  Fengbo Mo 1,  Shoujie Shi 1,  Jiawei Hu 1,  Qiang Xu 1,  Kun Quan 1,  Jianhui Liang 1,  Wei Li 1,  Xin Hong 1,  Bin Zhang 1,  Xuqiang Liu 1,  Min Dai 2
Affiliations

Affiliations

  • 1 Department of Orthopedics, The First Affiliated Hospital of Nanchang University, Artificial Joints Engineering and Technology Research Center of Jiangxi Province, Nanchang, Jiangxi province 330006, China.
  • 2 Department of Orthopedics, The First Affiliated Hospital of Nanchang University, Artificial Joints Engineering and Technology Research Center of Jiangxi Province, Nanchang, Jiangxi province 330006, China. Electronic address: daiminyisheng@163.com.
PMID: 37406898 DOI: 10.1016/j.ijbiomac.2023.125670
Abstract

Osteoarthritis (OA) is the most common age-related joint disorder with no effective therapy, and its specific pathological mechanism remains to be fully clarified. Adhesion-regulating molecule 1 (ADRM1) has been proven to be involved in OA progression as a favorable gene. However, the exact mechanism of ADRM1 involved in OA were unknown. Here, we showed that the ADRM1 expression decreased in human OA cartilage, destabilization of the medial meniscus (DMM)-induced mouse OA cartilage, and interleukin (IL)-1β-induced primary mouse articular chondrocytes. Global knockout (KO) ADRM1 in cartilage or ADRM1 inhibitor (RA190) could accelerate the disorders of extracellular matrix (ECM) homeostasis, thereby accelerated DMM-induced cartilage degeneration, whereas overexpression of ADRM1 protected mice from DMM-induced OA development by maintaining the homeostasis of articular cartilage. The molecular mechanism study revealed that ADRM1 could upregulate ubiquitin carboxy-terminal hydrolase 37 (UCH37) expression and bind to UCH37 to activate its deubiquitination activity. Subsequently, increased and activated UCH37 enhanced activin receptor-like kinase 5 (ALK5) deubiquitination to stabilize ALK5 expression, thereby maintaining ECM homeostasis and attenuating cartilage degeneration. These findings indicated that ADRM1 could attenuate cartilage degeneration via enhancing UCH37-mediated ALK5 deubiquitination. Overexpression of ADRM1 in OA cartilage may provide a promising OA therapeutic strategy.

Keywords

ADRM1; ALK5; Chondrocyte; Osteoarthritis; UCH37.

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