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<p>Although osteoarthritis (OA) is a leading cause of morbidity, no disease-modifying osteoarthritis drugs (DMOADs) are currently available. An in-depth understanding of OA pathogenesis may help the development of novel and effective treatments. Activating transcription factor 4 (ATF-4) plays a critical role in skeletal biology as it is closely involved in ER stress, autophagy, cell senescence, etc. Our study showed that meniscal injury in Atf-4 deficient (<i>Atf-4</i><sup><i>−/−</i></sup>) mice resulted in complete destruction of mouse knee joints. In addition, these mice developed spontaneous OA-like lesions with aging. In vitro study demonstrated that the ER stress was increased and proliferation was decreased in articular chondrocytes from <i>Atf-4</i><sup><i>−/−</i></sup> mice compared to wild-type (WT) chondrocytes, which enhanced apoptosis of <i>Atf-4</i><sup><i>−/−</i></sup> chondrocytes. Re-introduction of ATF-4 into the joint cavity of <i>Atf-4</i><sup><i>−/−</i></sup> mice significantly alleviated joint damage. Taken together, our study demonstrates that ATF-4 is a critical molecule for normal functionality of articular chondrocytes and its modification may facilitate the identification of novel therapeutic targets.</p>

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ATF-4 deficiency increases ER stress and induces osteoarthritis formation in mice

  • 期刊论文

  • 发表日期：

    2025年7月12日

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  • Peng-Yu Xie,
  • Shan-Shan Li,
  • Xu Liang,
  • Hang Ma,
  • Ying-Chao Yang,
  • Tian-Fang Li

摘要

Although osteoarthritis (OA) is a leading cause of morbidity, no disease-modifying osteoarthritis drugs (DMOADs) are currently available. An in-depth understanding of OA pathogenesis may help the development of novel and effective treatments. Activating transcription factor 4 (ATF-4) plays a critical role in skeletal biology as it is closely involved in ER stress, autophagy, cell senescence, etc. Our study showed that meniscal injury in Atf-4 deficient (Atf-4−/−) mice resulted in complete destruction of mouse knee joints. In addition, these mice developed spontaneous OA-like lesions with aging. In vitro study demonstrated that the ER stress was increased and proliferation was decreased in articular chondrocytes from Atf-4−/− mice compared to wild-type (WT) chondrocytes, which enhanced apoptosis of Atf-4−/− chondrocytes. Re-introduction of ATF-4 into the joint cavity of Atf-4−/− mice significantly alleviated joint damage. Taken together, our study demonstrates that ATF-4 is a critical molecule for normal functionality of articular chondrocytes and its modification may facilitate the identification of novel therapeutic targets.