Chondrocyte mTORC1 activation stimulates miR-483-5p via HDAC4 in osteoarthritis progression

Hua Wang, Haiyan Zhang, Qiuyi Sun, Jian Yang, Chun Zeng, Changhai Ding, Daozhang Cai, Anling Liu, Xiaochun Bai

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Abstract

The hyperactivation of the mechanistic target of rapamycin complex 1 (mTORC1) in chondrocytes has been shown to accelerate the severity of destabilization of the medial meniscus-induced and age-related osteoarthritis (OA) phenotypes with aberrant chondrocyte hypertrophy and angiogenesis. Meanwhile, we previously reported that miR-483-5p is essential for the initiation and development of OA by stimulating chondrocyte hypertrophy and angiogenesis. The connection between mTORC1 and miR-483-5p activation in OA progression, however, remains unclear. In this study, we elucidated their relationship and identified the underlying mechanisms. The expression of miR-483-5p in the articular cartilage of cartilage-specific TSC1 knockout mice was assessed compared with control mice using the Agilent Mouse miRNA (8*60K) V19.0 array and real-time polymerase chain reaction (RT-PCR). The functional effects of the stimulation of miR-483-5p via histone deacetylase 4 (HDAC4) by mTORC1 in OA development, subsequently modulating its downstream targets matrilin 3 and tissue inhibitor of metalloproteinase 2, were examined by immunostaining, western blotting, and real-time PCR. This study revealed that miR-483-5p was responsible for mTORC1 activation-stimulated OA. Mechanistically, mTORC1 controls the HDAC4-dependent expression of miR-483-5p to stimulate chondrocyte hypertrophy, extracellular matrix degradation, and subchondral bone angiogenesis, and it consequently initiates and accelerates the development of OA. Our findings revealed a novel mTORC1-HDAC4-miR-483-5p pathway that is critical for OA development.

Original languageEnglish (US)
Pages (from-to)2730-2740
Number of pages11
JournalJournal of Cellular Physiology
Volume234
Issue number3
DOIs
StatePublished - Mar 2019

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All Science Journal Classification (ASJC) codes

  • Physiology
  • Clinical Biochemistry
  • Cell Biology

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