Activating transcription factor 4 (ATF4) is critical for chondrocyte proliferation and bone formation. Exosomes are considered as promising gene-delivery vehicles for the treatment of osteoarthritis (OA). This study utilized the serum-derived exosomes from OA mice as the gene-delivery vehicles for ATF4 gene therapy and explored their therapeutic effects on OA. Meniscus injury-induced OA model was established by the excision of anterior part of medial meniscus in the right knee of C57BL/6J mice. Exosomes were isolated from serum samples of sham and OA mice, and were referred to as sham-Exo and OA-Exo, respectively. ATF4-overexpressing OA-Exo (ATF4-OA-Exo) was developed by introducing ATF4 mRNA into OA-Exo via electroporation. Four weeks after surgery, OA mice received intra-articular injections of sham-Exo, OA-Exo, and ATF4-OA-Exo, respectively. The results showed that intra-articular injection of ATF4-OA-Exo alleviated articular cartilage degeneration or damage and inflammatory response of OA mice. Autophagy was weakened in knee joint cartilage of OA mice, which was partially restored by intra-articular injection of ATF4-OA-Exo. Further in vitro assays revealed that ATF4-OA-Exo promoted chondrocyte autophagy and inhibited chondrocyte apoptosis in the TNF-α-or tunicamycin-treated chondrocytes. Together, ATF4-modified serum exosomes derived from OA mice protect cartilage and alleviate OA progression by inducing autophagy.

Osteoarthritis (OA) is a chronic, debilitating joint disease characterized by progressive destruction of articular cartilage. For a long time, OA has been considered as a degenerative disease, while recent observations indicate the mechanisms responsible for the pathogenesis of OA are multifaceted. Aging is a key factor in its development. Current treatments are palliative and no disease modifying anti-osteoarthritis drugs (DMOADs) are available. In addition to articular cartilage degradation, cellular senescence, synovial inflammation, and epigenetic alterations may all have a role in its formation. Accumulating data demonstrate a clear relationship between the senescence of articular chondrocytes and OA formation and progression. Inhibition of cell senescence may help identify new agents with the properties of DMOADs. Several anti-cellular senescence strategies have been proposed and these include sirtuin-activating compounds (STACs), senolytics, and senomorphics drugs. These agents may selectively remove senescent cells or ameliorate their harmful effects. The results from preclinical experiments and clinical trials are inspiring. However, more studies are warranted to confirm their efficacy, safety profiles and adverse effects of these agents.

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Glucocorticoid (GC)-induced avascular osteonecrosis of femoral head (AOFH) is a devastating complication, and no cures are currently available for it. Previous studies have demonstrated that implantation of bone marrow mesenchymal stem cells (BMMSCs) may prevent the progression of pre-collapse AOFH. Based on previous observations, we hypothesized that GCs induce AOFH via the COX-2 (cyclooxygenase-2)–PGE-2 (prostaglandin E2)–HIF-1α (hypoxia-inducible factor-1α) axis, and that modification of BMMSCs may improve the efficacy of their implantation. BMMSCs isolated from wild-type (WT) mice were treated with dexamethasone (Dex) and the results showed that Dex repressed the expression of COX-2. Femoral head samples harvested from both WT and COX-2 knock-out (COX-2−/−) mice were subjected to micro–computed tomography and histological examinations. Compared with their WT littermates, COX-2−/− mice had larger trabecular separations, diminished microvasculature, and reduced HIF-1α expression in their femoral heads. In vitro angiogenesis assays with tube formation and fetal metatarsal sprouting demonstrated that Dex repressed angiogenesis and PGE-2 antagonized its effects. An AOFH model was successfully established in C57BL/6J mice. In vitro experiment showed that BMMSCs infected with Lentivirus encoding HIF-1α (Lenti-HIF-1α) resulted in a robust increase in the production of HIF-1α protein. Implantation of BMMSCs overexpressing HIF-1α into femoral heads of AOFH mice significantly reduced osteonecrotic areas and enhanced bone repair, thus largely preserving the structural integrity of femoral heads. Our studies provide strong rationales for early intervention with core decompression and implantation of modified BMMSCs for GC-induced AOFH, which may spare patients from expensive and difficult surgical procedures.

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