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Updated: May 3, 2026
Software-Assisted Quantitative Measurement of Osteoarthritic Subchondral Bone Thickness
Published on: March 18, 2022
ATF-4 deficiency increases ER stress and induces osteoarthritis formation in mice
Peng-Yu Xie1, Shan-Shan Li1, Xu Liang1
1Department of Rheumatology, First Affiliated Hospital of Zhengzhou University, No.1 Jianshe Dong Road, Zhengzhou, 450052, China.
Abstract:
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.
Insights
Activating transcription factor 4 (ATF-4) is crucial for maintaining knee joint health. Its deficiency leads to osteoarthritis, but restoring ATF-4 can protect against joint damage.
Area of Science:
- Skeletal Biology
- Molecular Biology
- Pathogenesis of Osteoarthritis
Background:
- Osteoarthritis (OA) is a significant cause of morbidity with no current disease-modifying drugs.
- Understanding OA pathogenesis is key to developing effective treatments.
- Activating transcription factor 4 (ATF-4) is involved in cellular processes like ER stress and autophagy, crucial for skeletal health.
Purpose of the Study:
- To investigate the role of Activating transcription factor 4 (ATF-4) in the pathogenesis of osteoarthritis.
- To determine if ATF-4 deficiency exacerbates joint damage and OA development.
- To explore the therapeutic potential of ATF-4 in osteoarthritis.
Main Methods:
- Utilized Atf-4 deficient (Atf-4-/-) mice and wild-type (WT) littermates.
- Induced meniscal injury in mice to study OA development.
- Performed in vitro studies on articular chondrocytes from Atf-4-/- and WT mice.
- Administered ATF-4 into the joint cavity of Atf-4-/- mice.
Main Results:
- Meniscal injury in Atf-4-/- mice led to complete knee joint destruction and spontaneous OA-like lesions with aging.
- Articular chondrocytes from Atf-4-/- mice showed increased ER stress, decreased proliferation, and enhanced apoptosis compared to WT.
- Re-introduction of ATF-4 significantly reduced joint damage in Atf-4-/- mice.
Conclusions:
- ATF-4 is essential for the normal function of articular chondrocytes and maintaining knee joint integrity.
- ATF-4 deficiency accelerates OA pathogenesis.
- Targeting ATF-4 presents a potential therapeutic strategy for osteoarthritis.
