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Chondrocytes reprogram chromatin in hypoxic microenvironments to activate CADM1-AS1/HDAC1 complex-mediated
Weiyu Ni1,2, Tianyuan Gu1,2, Panyang Shen1,2
1Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China.
Nature Communications
|April 10, 2026
Summary
Epigenetic regulation by CADM1-AS1 is vital for cartilage health in osteoarthritis. Modulating this long non-coding RNA reduces cartilage damage, offering a new therapeutic target for osteoarthritis treatment.
Area of Science:
- Epigenetics
- Molecular Biology
- Osteoarthritis Pathogenesis
Background:
- Chondrocyte homeostasis is critical for osteoarthritis treatment.
- Chondrocytes normally exist in a hypoxic environment.
- Epigenetic alterations, specifically histone acetylation, are observed in chondrocytes under hypoxia.
Purpose of the Study:
- To investigate the association between epigenetics and chondrocyte homeostasis.
- To identify epigenetic mechanisms contributing to chondrocyte dysfunction in osteoarthritis.
- To explore CADM1-AS1 as a potential therapeutic target for osteoarthritis.
Main Methods:
- Analysis of histone acetylation in chondrocytes under hypoxic conditions.
- Identification of an enhancer regulating the long non-coding RNA CADM1-AS1.
- Mechanistic studies involving CADM1-AS1, histone deacetylase complexes, and NOS2.
- Conditional knockout of CADM1-AS1 in chondrocytes.
- Exosome-mediated delivery system to modulate CADM1-AS1 expression.
Main Results:
- Significant alterations in histone acetylation were observed in chondrocytes under hypoxic conditions.
- CADM1-AS1 was identified as a key long non-coding RNA essential for cartilage homeostasis.
- CADM1-AS1 recruits histone deacetylase complexes to suppress NOS2 transcription, impacting amino acid metabolism.
- Conditional knockout of CADM1-AS1 accelerated osteoarthritis development in mice.
- A hybrid exosome system effectively modulated CADM1-AS1 expression and reduced cartilage damage.
Conclusions:
- Epigenetic regulation via CADM1-AS1-mediated histone deacetylation plays a crucial role in osteoarthritis pathogenesis.
- CADM1-AS1 is essential for maintaining cartilage homeostasis.
- CADM1-AS1 represents a promising therapeutic target for reducing cartilage damage in osteoarthritis.
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