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Betaine Downregulates RARRES1 to Alleviate Cartilage Fibrosis and Promote Hyaline Cartilage Repair
Shiqi Wang1, Yang Xue1, Jiarui Zhuang1
1Laboratory for Bone and Joint Disease, Division of Sports Medicine and Adult Reconstructive Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, 321 Zhongshan Road, Nanjing 210008, China.
Abstract:
Cartilage degeneration is the hallmark pathological alteration in osteoarthritis (OA). The irreversible accumulation of fibrotic cartilage compromises joint function and accelerates disease progression. However, reliable biomarkers and therapeutic targets for cartilage fibrosis remain lacking. Through bioinformatic analysis of bulk RNA sequencing and single-cell RNA sequencing datasets, RARRES1 (retinoic acid receptor responder 1) was identified as a key biomarker associated with cartilage degeneration. The functional role of RARRES1 was investigated using a CTGF (Connective tissue growth factor) induced chondrocyte fibrosis model and siRNA-mediated gene knockdown. Subsequently, in vitro and in vivo experiments were conducted, including Western blotting, functional assays, flow cytometry, and pathological staining. RARRES1 was markedly upregulated in the damaged cartilage regions of patients with osteoarthritis, and this finding was confirmed in the chondrocyte fibrosis model. Betaine downregulates RARRES1 and promotes hyaline cartilage repair. Importantly, RGS2 was identified as a critical gene through which betaine exerts its effects on scavenging reactive oxygen species (ROS) accumulation. Our study demonstrates that betaine inhibits RARRES1, thereby appearing to upregulate RGS2 and promote ROS clearance to alleviate fibrotic changes in cartilage. RARRES1 may serve as a biomarker and a potential therapeutic target for cartilage fibrosis.
Insights
Retinoic acid receptor responder 1 (RARRES1) is a biomarker for osteoarthritis cartilage fibrosis. Betaine alleviates fibrosis by downregulating RARRES1 and promoting reactive oxygen species (ROS) clearance via RGS2.
Area of Science:
- Biochemistry
- Molecular Biology
- Biomaterials Science
Background:
- Osteoarthritis (OA) is characterized by cartilage degeneration and irreversible fibrosis, compromising joint function.
- Current diagnostic and therapeutic strategies for cartilage fibrosis are limited.
- Identifying reliable biomarkers and therapeutic targets is crucial for managing OA progression.
Purpose of the Study:
- To identify key biomarkers associated with cartilage degeneration in osteoarthritis.
- To investigate the role of RARRES1 in cartilage fibrosis.
- To explore the therapeutic potential of betaine in mitigating cartilage fibrosis.
Main Methods:
- Bioinformatic analysis of RNA sequencing datasets (bulk and single-cell).
- In vitro chondrocyte fibrosis model induced by CTGF.
- siRNA-mediated gene knockdown of RARRES1.
- In vitro and in vivo experiments including Western blotting, functional assays, flow cytometry, and pathological staining.
Main Results:
- RARRES1 was identified as a key biomarker upregulated in OA cartilage and chondrocyte fibrosis models.
- Betaine treatment downregulated RARRES1 and promoted hyaline cartilage repair.
- RGS2 was identified as a critical mediator for betaine's ROS scavenging effects.
- Betaine inhibited RARRES1, upregulated RGS2, and cleared ROS, alleviating cartilage fibrosis.
Conclusions:
- RARRES1 is a significant biomarker for cartilage fibrosis in osteoarthritis.
- Betaine demonstrates therapeutic potential for cartilage fibrosis by modulating RARRES1 and ROS pathways.
- Targeting RARRES1 and ROS may offer novel strategies for treating osteoarthritis-related cartilage fibrosis.
