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Functional characterization of activin A-activin receptor IIB pathway in osteoarthritis
- Author(s)
- 전지민
- Advisor
- 양시영
- Department
- 일반대학원 의생명과학과
- Publisher
- The Graduate School, Ajou University
- Publication Year
- 2020-08
- Language
- eng
- Alternative Abstract
- Osteoarthritis (OA) is a degenerative joint disease involving various pathogenic factors. To date, the treatment of OA has been limited to pain relief through drugs, physiotherapy, and surgical intervention. However, methods to completely stop disease progression or to regenerate damaged cartilage are yet to be developed. Here, I studied two aspects concerning the prevention and treatment of OA by identifying the genes, proteins, and natural products that induce cartilage degeneration or regulate cartilage regeneration. In part I, I identified activin receptor IIB (encoded by ACVR2B) as a therapeutic target and a novel receptor that plays a crucial role in the pathogenesis of OA. The pathogenesis of OA is a result of the interaction of various pathogenic cytokines and growth factors with their cognate receptors; however, the actual pathogenic receptors/ligands involved remains unclear. In vitro and in vivo analyses demonstrated that activin receptor IIB inhibition attenuated osteoarthritic cartilage destruction by regulating the expression of matrix metallopeptidase 3 (Mmp3), Mmp13, and cyclooxygenase 2 (Cox2). Furthermore, a soluble form of activin receptor IIB fusion protein (sACVR2B-Fc) protected against osteoarthritic cartilage destruction. Among the activin receptor IIB ligands, activin A significantly regulates catabolic factor expression and cartilage destruction in OA pathogenesis. NOX4 and AP-1 were identified as essential mediators and transcription factors involved in activin receptor IIB -activin A expression, thereby amplifying the expression of catabolic factors. In part II, I demonstrated the role of 3’-sialyllactose as a prophylactic agent in osteoarthritic cartilage destruction. 3’-sialyllactose has specific physiological functions in various tissues; however, its effects on osteoarthritic development remain unknown. In in vitro and in vivo studies, 3’-sialyllactose restored the synthesis of Col2a1 and accumulation of a sulfated proteoglycan, a critical factor for cartilage regeneration in osteoarthritic development. Additionally, in vitro, biochemical and histological analysis demonstrated that 3’-sialyllactose was inhibited by the expression of MMP3, MMP13, and Cox2 induced by IL-1β, IL-6, IL-17, and TNF-α, thereby indicating a role in the attenuation of cartilage degradation. In conclusion, the activin receptor IIB-induced catabolic cascade was shown to play a critical role in the progression of OA, and 3’-sialyllactose protected against osteoarthritic cartilage degradation. These results suggest that activin receptor IIB ligand traps may have therapeutic implications in OA pathogenesis, and 3’-sialyllactose may be considered a naturally-occurring therapeutic compound for the prevention of OA. These results indicate that the soluble form (sACVR2B-Fc) and 3’-sialyllactose may serve as potential targets and could be manipulated to ameliorate the progression of osteoarthritic cartilage degradation.
- Fulltext
- Appears in Collections:
- Graduate School of Ajou University > Department of Biomedical Sciences > 4. Theses(Ph.D)
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