Fig 2: ER stress-induced osteoarthritic changes in the knee joint. Knee joints of aged ERp57 cKO animals display severe OA cartilage degeneration with enhanced MMP3, MMP9, ADAMTS4, and ADAMTS5 expression and osteophyte formation. These changes are preceded by reduced compressive stiffness of the cartilage ECM and increased apoptotic cell death. Both effects are likely induced by ER stress that cannot be adequately compensated by the UPR.

Fig 3: IL-1ß-induced ATDC5 cells’ behavior cultured with GLP hydrogel compared with GGA hydrogel.a, b The FCM results and statistical analysis results for the percentage of apoptosis. c–h Immunofluorescent images for SOX9, Bcl-2, and BAX protein expression as well as the statistical stained positively area from the images. Sox9 is the characteristic gene to indicate the ECM expression, Bcl-2 and Bax genes are the anti-apoptosis and the apoptosis-promoting genes of the cells. i–n The RT-qPCR results of the mRNA expression levels for Sox9, Col2a1, Acan, Adamts5, iNOS, and COX2. o, p The ELISA results for inflammatory mediators, IL-6 and TNF-a. q, r The Western Blot results for the expression of proteins (p-PI3K, PI3K, p-AKT/AKT, ADAMTS5) of IL-1ß-induced ATDC5 cells cultured with hydrogels and the corresponding statistical analysis results. Data are presented as means ± SD of at least three replicate experiments. Unpaired two-tailed Student’s t tests was used to calculate significant difference, *p < 0.05, **p < 0.01. GGA gallic acid-grafted gelatin, GLP GGA@Lipo@PTH (1–34).

Fig 4: Osteoarthritis rats were treated with different intensities of treadmill exercise. Real-time PCR and immunohistochemistry (IHC) were performed to measure relative inflammatory genes/proteins in OA. (A,B) Expression of collagen II in CG and OAM were higher than OAH and OAG by IHC. (A,C) Expression of MMP-13 in CG and OAM were lower than OAH and OAG by IHC. (A,D) Expression of ADAMTS5 in CG and OAM were lower than OAH and OAG by IHC. (A,E) The percentage of NF-kappaB positive cell in CG and OAM were lower than OAH and OAG by IHC. (A,F) Expression of HDAC3 in CG and OAM were lower than OAH and OAG by IHC. (A,G) mRNA of collagen II in CG and OAM were higher than OAH and OAG by real-time PCR analysis. (A,H) mRNA of MMP-13 in CG and OAM were lower than OAG and mRNA of MMP-13 in CG was lower than OAH by real-time PCR analysis. (A,I) mRNA of ADAMTS5 in CG and OAM were lower than OAH and OAG by real-time PCR analysis. (A,J) mRNA of HDAC3 in CG and OAM were lower than OAH and OAG by real-time PCR analysis. (A,K) mRNA of NF-kappaB in CG and OAM were lower than OAH and OAG by real-time PCR analysis; ***p < 0.001;**p < 0.01; *p < 0.05 vs. CG, ###p < 0.001; ##p < 0.01; #p < 0.05 vs. OAM; n = 3 rats for each group in IHC and n = 6 rats for each group in real-time PCR, means with SEM.

Fig 5: PPM1A ablation prevented cartilage catabolism and SMAD2 dephosphorylation in chondrocytes responding to DMM surgery.(A) IHC expression of MMP-13 in knee joints from WT mice and PPM1A−/− mice at 8 weeks after DMM surgery. Scale bar: 50 μm. (B) Quantification for MMP-13 expression in chondrocytes from WT and KO mice at 8 weeks following operation. (C) Representative images of Adamts-5 IHC expression from WT mice and PPM1A−/− mice at 8 weeks after DMM surgery. Scale bar: 50 μm. (D) IHC quantification for Adamts-5 expression in chondrocytes from mice at 8 weeks. (E) Representative images of p-SMAD2 expression in articular chondrocytes from WT mice and PPM1A−/− mice at 8 weeks after DMM surgery. Scale bar: 50 μm. (F) IHC quantification for p-SMAD2 expression in chondrocytes from mice at 8 weeks following sham or DMM surgery. (G) TUNEL staining for apoptosis chondrocytes in articular cartilage from WT mice and PPM1A−/− mice at 8 weeks after operation. Scale bar: 200 μm. (H) Quantification for TUNEL positive cells in articular cartilage. Data were presented as means ± SD and statistical analyses were performed by 2-way ANOVA with Šidák post hoc test, n ≥ 3 mice per group. **P < 0.01.