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, Jin Hong Kim

Research output: Contribution to journalArticle

1 Citation (Scopus)

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.

Original languageEnglish
Article number4898
JournalNature Communications
Volume10
Issue number1
DOIs
StatePublished - 1 Dec 2019

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Tankyrases
adenosine diphosphate
cartilage
Cartilage
Adenosine Diphosphate
Osteoarthritis
matrices
mice
transplantation
Articular Cartilage
Stem Cell Transplantation
factor analysis
stem cells
regulators
Proteolysis
Statistical Factor Analysis
Factor analysis
Stem cells
Regeneration
regeneration

Cite this

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. / Tankyrase inhibition preserves osteoarthritic cartilage by coordinating cartilage matrix anabolism via effects on SOX9 PARylation. In: Nature Communications. 2019 ; Vol. 10, No. 1.
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Tankyrase inhibition preserves osteoarthritic cartilage by coordinating cartilage matrix anabolism via effects on SOX9 PARylation. / 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.

In: Nature Communications, Vol. 10, No. 1, 4898, 01.12.2019.

Research output: Contribution to journalArticle

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AU - Kim, Sukyeong

AU - Han, Sangbin

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AU - Kim, Hyeon Seop

AU - Gu, Young Ran

AU - Kang, Donghyun

AU - Cho, Yongsik

AU - Kim, Hyeonkyeong

AU - Lee, Jeeyeon

AU - Seo, Yeyoung

AU - Chang, Moon Jong

AU - Chang, Chong Bum

AU - Kang, Seung Baik

AU - Kim, Jin Hong

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