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

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.