2. Academic Validation
  3. Tankyrase inhibition preserves osteoarthritic cartilage by coordinating cartilage matrix anabolism via effects on SOX9 PARylation

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

  • Nat Commun. 2019 Oct 25;10(1):4898. doi: 10.1038/s41467-019-12910-2.
Sukyeong Kim 1 2,  Sangbin Han 1 2,  Yeongjae Kim 1 2,  Hyeon-Seop Kim 1 2,  Young-Ran Gu 1 2,  Donghyun Kang 1 2,  Yongsik Cho 1 2,  Hyeonkyeong Kim 1 2,  Jeeyeon Lee 1 2,  Yeyoung Seo 1 2,  Moon Jong Chang 3,  Chong Bum Chang 4,  Seung-Baik Kang 3,  Jin-Hong Kim 5 6 7
Affiliations

Affiliations

  • 1 Center for RNA Research, Institute for Basic Science, 08826, Seoul, South Korea.
  • 2 Department of Biological Sciences, College of Natural Sciences, Seoul National University, 08826, Seoul, South Korea.
  • 3 Department of Orthopaedic Surgery, Seoul National University College of Medicine, Boramae Hospital, 07061, Seoul, South Korea.
  • 4 Department of Orthopaedic Surgery, Seoul National University Bundang Hospital, 13620, Seongnam, South Korea.
  • 5 Center for RNA Research, Institute for Basic Science, 08826, Seoul, South Korea. [email protected].
  • 6 Department of Biological Sciences, College of Natural Sciences, Seoul National University, 08826, Seoul, South Korea. [email protected].
  • 7 Interdisciplinary Program in Bioinformatics, Seoul National University, 08826, Seoul, South Korea. [email protected].
PMID: 31653858 DOI: 10.1038/s41467-019-12910-2
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-19351
    99.73%, PARP Inhibitor