Abstract
We recently reported that the chondrocyte-specific knockout of discoidin domain receptors 1 (Ddr1) delayed endochondral ossification (EO) in the growth plate by reducing the chondrocyte hypertrophic terminal differentiation, and apoptosis. The biologic and phenotypic changes in chondrocytes in the articular cartilage with osteoarthritis (OA) are similar to the phenomena observed in the process of EO. Additionally, autophagy can promote chondrocyte survival and prevent articular cartilage from degradation in OA. On this basis, we explored the effect of Ddr1 inhibition on OA prevention and further investigated the roles of autophagy in treating OA with a Ddr1 inhibitor (7 rh). The anterior cruciate ligament transection (ACLT)–OA model was used to investigate the role of 7 rh in vivo. Forty 8-week-old mice were randomly assigned to four groups, including the sham group, ACLT group, and two treated groups (ACLT with 7 rh 6.9 nM or 13.8 nM). According to the study design, normal saline or 7 rh were intra-articular (IA) injected into studied knees 3 times per week for 2 weeks and then once per week for 4 weeks. The results showed that 7 rh treatment significantly improved the functional performances (the weight-bearing ability and the running endurance), decreased cartilage degradation, and also reduced the terminal differentiation markers (collagen type X, Indian hedgehog, and matrix metalloproteinase 13). Moreover, 7 rh decreased chondrocyte apoptosis by regulating chondrocyte autophagy through reducing the expression of the mammalian target of rapamycin and enhancing the light chain 3 and beclin-1 expression. These results demonstrated that the IA injection of 7 rh could reduce the chondrocyte apoptosis and promote chondrocyte autophagy, leading to the attenuation of cartilage degradation. Our observations suggested that the IA injection of 7 rh could represent a potential disease-modifying therapy to prevention OA progression.
Highlights
Osteoarthritis (OA) is the most prevalent joint disease worldwide and the leading cause of disability in aged patients
Recent research on parathyroid hormone 1-34 (PTH 1-34) in OA has indicated that the treatment can inhibit the apoptosis of chondrocytes in the growth plate, which can be used to inhibit the apoptosis of chondrocyte in osteoarthritic articular cartilage, thereby reducing cartilage degradation [3,4,5]
In the OA status, the articular chondrocytes become hypertrophic, with changes accompanied by the overexpression of the hypertrophic markers, including alkaline phosphatase, Col X, and Matrix Metalloproteinases 13 (MMP13) and subsequent chondrocyte mineralization and apoptosis, which is similar with the phenotype changes in endochondral ossification (EO) [13]
Summary
Osteoarthritis (OA) is the most prevalent joint disease worldwide and the leading cause of disability in aged patients. Despite some promising disease-modifying therapy undergoing clinical trials, there is no currently effective therapy to prevent the progressive destruction of articular cartilage [1]. The compromising of chondrocyte survival leads to cartilage degradation; as a result, the prevention of chondrocyte death is an important research direction for OA prevention. Recent research on parathyroid hormone 1-34 (PTH 1-34) in OA has indicated that the treatment can inhibit the apoptosis of chondrocytes in the growth plate, which can be used to inhibit the apoptosis of chondrocyte in osteoarthritic articular cartilage, thereby reducing cartilage degradation [3,4,5]
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