Osteoarthritis
Figure 3 Fbxw7 loss in chondrocyte accelerates mouse OA development. (A) Representative images of IHC staining of FBXW7 in articular cartilage of Fbxw7 KO and Control mice aged 3 months. Scale bar: 50 µm. (B) Representative images of H&E staining (first row), safranin O/fast green staining (second row) and IHC staining of p16 INK4a (third row) and p21 (fourth row) in articular cartilage of Fbxw7 KO and Control mice aged 18 months. Scale bars: 100 µm (first and second rows) and 50 µm (third and fourth rows). (C,D) Quantitative analysis of the OARSI scale and p16 INK4a -positive and p21-positive chondrocytes in Fbxw7 KO mice and Controls. n=10 per group. (E) Representative images of safranin O/fast green staining and immunofluorescence staining of Colx, COL2A1, aggrecan and TUNEL in chondrocytes of Fbxw7 KO and Controls at 4 and 8 weeks after DMM surgery. Scale bars: 100 µm (first row) and 50 µm (rest rows). (F) OARSI scale and quantification of Colx, ACAN and TUNEL-positive chondrocytes based on staining results in (E). n=10 per group. Data are shown as mean±SD. Statistical analyses were conducted using Student’s t-test (D), three-way analysis of variance followed by Tukey’s multiple comparison test (F) or non-parametric Mann-Whitney U tests (OARSI score) (C). Boxed area is enlarged in the bottom right corner. *P<0.05, **P<0.01. Con, control; DMM, destabilisation of the medial meniscus; FBXW7, F-box and WD repeat domain containing 7; IHC, immunohistochemical; NS, not significant; OA, osteoarthritis; OARSI, Osteoarthritis Research Society International; TUNEL, terminal deoxynucleotidyl transferase dUTP nick end labelling.
of DTP3 on OA were further verified in Fbxw7 KO mouse in which MKK7 was highly expressed in chondrocytes (figure 6C and online supplemental figure S10C,D). Taken together, these data suggest that FBXW7 loss promotes chondrocyte senescence and OA development partially through MKK7–JNK activation. DISCUSSION Ageing and mechanical overload play important roles in OA development. This study for the first time established a mech- anistic association between these two critical risk factors for
Inhibition of MKK7–JNK signalling delays chondrocyte senescence and OA development To further verify the role of MKK7 in OA development induced by mechanical overloading in vivo, DTP3 was injected intraperi- toneally to inhibit MKK7 after DMM surgery. The results showed a reduction in p-JNK-positive cells in articular cartilage by DTP3 injection and significant alleviation of the cartilage destruction and the OARSI score compared with the vehicle-treated mice. Catabolic factor expression and chondrocyte senescence and apoptosis were markedly reduced by DTP3 treatment (figure 6B and online supplemental figure S10A,B). These protective effects
Zhang H, et al . Ann Rheum Dis 2022; 81 :676–686. doi:10.1136/annrheumdis-2021-221513
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