HIF-2α drives osteoarthritis progression via suppression of the HDAC4-ATF4-CHOP signaling axis.

Authors

Pinpin Jiang, Hang Wang, Yujia Li, Yuanyu Zhang, Jingrui Huang, Yukun Xu, Dahai Rong, Danni Ruan, Yao Wang, Jie Yuan, Pengcui Li

Published in

PloS one. Volume 21. Issue 6. Pages e0351847. Epub Jun 18, 2026.

Abstract

Hypoxia-inducible factor-2α (HIF-2α) is a key regulator of cellular adaptation to hypoxia, but its role in osteoarthritis (OA) remains incompletely defined. This study aimed to investigate the contribution of HIF-2α to OA pathogenesis and the underlying molecular mechanisms. Human cartilage specimens were collected to examine HIF-2α expression and components of the histone deacetylase 4 (HDAC4) signaling pathway using Western blotting, quantitative real-time PCR, and immunohistochemistry. An in vitro OA model was established in chondrocytes using interleukin-1β (IL-1β), followed by HIF-2α knockdown with small interfering RNA and overexpression via adenoviral transduction. Chondrocyte apoptosis was assessed by flow cytometry and TUNEL staining. To evaluate in vivo effects, HIF-2α was silenced using an adeno-associated viral vector in a rat OA model induced by anterior cruciate ligament transection (ACLT). Disease progression was assessed by X-ray, computed tomography (CT), FMT® small animal in vivo fluorescence molecular tomography imaging system, Safranin O staining, and immunohistochemistry. HIF-2α expression was significantly increased in cartilage from OA patients and ACLT rats. In vitro, HIF-2α modulation altered HDAC4 expression and downstream apoptotic signaling. Knockdown of HIF-2α reduced chondrocyte apoptosis and attenuated cartilage degeneration in vivo. These findings indicate that HIF-2α promotes OA progression by regulating chondrocyte apoptosis and matrix homeostasis through the HDAC4-ATF4-CHOP pathway. This study identifies a previously unrecognized mechanism linking HIF-2α to OA and highlights its potential as a therapeutic target.

PMID:
42313796
Bibliographic data and abstract were imported from PubMed on 19 Jun 2026.

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