Tankyrase inhibition preserves osteoarthritic cartilage by coordinating cartilage matrix anabolism via effects on SOX9 PARylation

• Published in: Nature communications 2019-10, Vol.10 (1), p.4898-18, Article 4898
• Main Authors: Kim, Sukyeong, Han, Sangbin, Kim, Yeongjae, Kim, Hyeon-Seop, Gu, Young-Ran, Kang, Donghyun, Cho, Yongsik, Kim, Hyeonkyeong, Lee, Jeeyeon, Seo, Yeyoung, Chang, Moon Jong, Chang, Chong Bum, Kang, Seung-Baik, Kim, Jin-Hong
• Format: Article
• Language: English
• Subjects: 13/51; 38/89; 38/91; 631/553/1833; 631/80/458/2389; 64/60; 692/699/1670/407; 82/58; 96/100; 96/106; 96/44; 96/63; 96/95; Adenosine diphosphate; ADP-ribosylation; Animals; Arthritis; Biodegradation; Biomedical materials; Cartilage; Cartilage (articular); Cartilage diseases; Cartilage, Articular - drug effects; Cartilage, Articular - metabolism; Cartilage, Articular - physiology; Chondrocytes - metabolism; Computer Simulation; Enzyme Inhibitors; Extracellular Matrix - drug effects; Extracellular Matrix - metabolism; Factor analysis; Gene Knockdown Techniques; Genes; HEK293 Cells; Humanities and Social Sciences; Humans; Mesenchymal Stem Cell Transplantation; Mice; multidisciplinary; Orthopedics; Osteoarthritis; Osteoarthritis - genetics; Osteoarthritis - metabolism; Osteoarthritis, Knee - genetics; Osteoarthritis, Knee - metabolism; Poly ADP Ribosylation - drug effects; Poly ADP Ribosylation - physiology; Principal components analysis; Proteins; Rats; Regeneration; Regeneration - genetics; Regulation; Science; Science (multidisciplinary); Sox9 protein; SOX9 Transcription Factor - drug effects; SOX9 Transcription Factor - metabolism; Stem cell transplantation; Stem cells; Tankyrases - antagonists & inhibitors; Tankyrases - genetics; Tankyrases - metabolism; Transcription factors; Transplantation
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-12910-2

Osteoarthritis (OA) is a prevalent degenerative disease, which involves progressive and irreversible destruction of cartilage matrix. Despite efforts to reconstruct cartilage matrix in osteoarthritic joints, it has been a difficult task as adult cartilage exhibits marginal repair capacity. Here we report the identification of tankyrase as a regulator of the cartilage anabolism axis based on systems-level factor analysis of mouse reference populations. Tankyrase inhibition drives the expression of a cartilage-signature matrisome and elicits a transcriptomic pattern that is inversely correlated with OA progression. Furthermore, tankyrase inhibitors ameliorate surgically induced OA in mice, and stem cell transplantation coupled with tankyrase knockdown results in superior regeneration of cartilage lesions. Mechanistically, the pro-regenerative features of tankyrase inhibition are mainly triggered by uncoupling SOX9 from a poly(ADP-ribosyl)ation (PARylation)-dependent protein degradation pathway. Our findings provide insights into the development of future OA therapies aimed at reconstruction of articular cartilage. Osteoarthritis results from the progressive destruction of cartilage matrix. Here, Kim et al. identify tankyrase as a regulator of cartilage matrix anabolism, and find that tankyrase inhibition, by preventing SOX9 PARylation, protects from cartilage destruction in a mouse model of osteoarthritis.