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

Sukyeong Kim, Sangbin Han, Yeongjae Kim, Hyeon-Seop Kim, Young-Ran Gu, Donghyun Kang, Yongsik Cho, Hyeonkyeong Kim, Jeeyeon Lee, Yeyoung Seo, Moon Jong Chang, Chong Bum Chang, Seung-Baik Kang and Jin-Hong Kim ()
Additional contact information
Sukyeong Kim: Institute for Basic Science
Sangbin Han: Institute for Basic Science
Yeongjae Kim: Institute for Basic Science
Hyeon-Seop Kim: Institute for Basic Science
Young-Ran Gu: Institute for Basic Science
Donghyun Kang: Institute for Basic Science
Yongsik Cho: Institute for Basic Science
Hyeonkyeong Kim: Institute for Basic Science
Jeeyeon Lee: Institute for Basic Science
Yeyoung Seo: Institute for Basic Science
Moon Jong Chang: Seoul National University College of Medicine, Boramae Hospital
Chong Bum Chang: Seoul National University Bundang Hospital
Seung-Baik Kang: Seoul National University College of Medicine, Boramae Hospital
Jin-Hong Kim: Institute for Basic Science

Nature Communications, 2019, vol. 10, issue 1, 1-18

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-019-12910-2

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