Purpose: Oxidative stress-induced chondrocyte apoptosis and extracellular matrix (ECM) degradation plays an important role in the progression of osteoarthritis (OA). Bardoxolone methyl (BM), a semisynthetic triterpenoid, exerts strong effect against oxidative stress. The purpose of the present study was to determine the effectiveness of bardoxolone-methyl (BM) in preventing oxidative stress-induced chondrocyte apoptosis and extracellular ECM degradation in vitro and the role of alleviating OA progression in vivo. Methods: Oxidative damage was induced by 25 mM tert-butyl hydroperoxide (TBHP) for 24 h in rat chondrocytes. 0.025 and 0.05 μM bardoxolone-methyl (BM) were used in vitro treatment. Ex-vivo cartilage explant model was established to evaluate the effect of BM on oxidative stress-induced ECM degradation. The mouse OA model was induced by surgical destabilization of the medial meniscus. Results: In vitro, 0.025 and 0.05 μM BM reduced TBHP-induced excessive ROS generation, improved cell viability, increased malondialdehyde level and decreased superoxide dismutase level. 0.025 and 0.05 μM BM prevented TBHP-induced mitochondrial damage and apoptosis in chondrocytes BM activated heme oxygenase-1 (HO-1)/NADPH quinone oxidoreductase 1 (NOQ1) signaling pathway through targeting nuclear factor erythroid derived-2-related factor 2 (Nrf2). Additionally, BM treatment enhanced the expression levels of aggrecan and collagen II and inhibited the expression levels of matrix metalloproteinase 9 (MMP 9), MMP 13, Bax and cleaved-caspase-3. BM increased proteoglycan staining area and IOD value in ex vivo cultured experiment cartilage explants and improved the OARSI score, stands, max contact mean intensity, print area and duty cycle in mouse OA model. Conclusion: BM prevented oxidative stress-induced chondrocyte apoptosis and ECM degradation in vitro and alleviated OA in vivo, suggesting that BM serves as an effective drug for treatment with OA.

Osteoarthritis (OA) is the most prevalent type of degenerative joint disease, and its pathological progression is highly associated with oxidative stress. Natural antioxidants can attenuate oxidative stress and chondrocyte injury, suggesting that antioxidants have potential applications in the management of OA. Ellagic acid (EA), a natural polyphenol derived from fruits or nuts, exerts antioxidant and anti-inflammatory effects in diseases related to oxidative stress. Herein, we investigated the effects of EA on interleukin-1β (IL-1β)-induced oxidative stress and degeneration in C28/I2 human chondrocytes. EA efficiently suppressed IL-1β-induced oxidative stress and ameliorated oxidative stress-induced dysfunction of chondrocytes, as indicated by the promotion of cartilage matrix secretion. Moreover, EA remarkably suppressed cell apoptosis and senescence, and reduced the expression of proinflammatory factors and metalloproteinases, suggesting that EA could alleviate chondrocyte injury under oxidative stress. Mechanistically, EA upregulated the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) as well as its downstream targets NADPH quinone oxidoreductase 1 and heme oxygenase-1. ML385, a specific Keap1/Nrf2 pathway inhibitor, blocked the antioxidant and chondroprotective effects of EA. Our findings demonstrated that EA could attenuate oxidative stress and exert protective effects on chondrocytes by upregulating the Keap1/Nrf2 signaling pathway. Graphical abstract

A series of adjustable long chain branching poly(L-lactide)s (b-PLAs) was prepared by reactive processing of linear PLA using pyromellitic dianhydride (PMDA) and polyfunctional epoxy ether (PFE) as the branching agent and their vascular stents were fabricated via 3D-printing. Fourier-transform infrared (FTIR) spectroscopy and gel permeation chromatography (GPC) results indicated that the chain branching reaction occurs and the average molecular weight increases obviously after the chain branching reaction. Rheological tests on the b-PLAs demonstrated that they are composed of a symmetric- or asymmetric-star, or tree-like chain configuration. The volume fraction of the branching structure of the chains increased from 0.03 to 0.3 with increasing branching agent content. The effects of the branching structure on the melt crystallization behavior of b-PLAs were investigated by means of differential scanning calorimetry (DSC). The isothermal crystallization results showed that the half-time of crystallization (t_1/2) of the samples decreased from 16.8 min for linear PLA to 2.3 min when the branching agent content was 2 wt% at 106 °C. Also, as observed from polarized optical microscopy experiments, the nucleation density of the b-PLAs significantly increased with increasing volume fraction of the branching structure because the enrichment of segments around the branching structure facilitated nucleation, thus the b-PLA samples have a higher probability to form a primary nucleus than linear PLA. Moreover, mechanical testing demonstrated that forming the branching structure enabled the effective modification of the mechanical properties of PLA. The microstructures with a smaller spherulite size and higher crystallinity of the b-PLAs improved their tensile strength and modulus from 45.7 MPa and 1.63 GPa to 77.2 MPa and 3.41 GPa, respectively. Furthermore, the radial force performance of the 3D printed b-PLA vascular stents was enhanced from 4.8 to 13.7 N by the branching structure of the chains. The CCK-8 assay results indicated that the osteoblast activity of b-PLA is higher than that of linear PLA, and the scanning electron microscopy (SEM) results also indicated that b-PLA was covered and flattened with a better attachment morphology for the osteoblasts than PLA. Therefore, the b-PLAs with a long chain branching structure could effectively facilitate cell growth, proliferation, and differentiation.

Extracellular acidification occurs under physiologic and pathologic conditions, such as exercise, ischemia, and inflammation. It has been shown that acidosis has various adverse effects on bone. In recent years there has been increasing evidence which indicates that ovarian cancer G protein-coupled receptor 1 (OGR1) is a pH-sensing receptor and mediates a variety of extracellular acidification-induced actions on bone cells and other cell types. Recent studies have shown that OGR1 is involved in the regulation of osteoclast differentiation, survival, and function, as well as osteoblast differentiation and bone formation. Moreover, OGR1 also regulates acid-induced apoptosis of endplate chondrocytes in intervertebral discs. These observations demonstrate the importance of OGR1 in skeletal development and metabolism. Here, we provide an overview of OGR1 regulation ofosteoclasts, osteoblasts, and chondrocytes, and the molecular actions of OGR1 induced by extracellular acidification in the maintenance of bone health.

Green and biodegradable materials with great mechanical properties and biocompatibility will offer new opportunities for next-generation high-performance biological materials. Herein, the novel oriented shish kebab crystals of a novel poly(trimethylene carbonate-lactide-glycolide) (PTLG) vascular stent are first reported to be successfully fabricated through a feasible solid-state drawing process to simultaneously enhance the mechanical performance and biocompatibility. The crystal structure of this self-reinforced vascular stent was transformed from spherulites to a shish kebab crystal, which indicates the mechanical interlocking effect and prevents the lamellae from slipping with a significant improvement of mechanical strength to 333 MPa. Meanwhile, it is different from typical biomedical polymers with smooth surface structures, and the as-obtained PTLG vascular stent exhibits a bionic surface morphology with a parallel micro groove and ridge structure. These ridges and grooves were attributed to the reorganization of cytoskeleton fiber bundles following the direction of blood flow shear stress. The structure and parameters of these morphologies were highly similar to the inner surface of blood vessels of the human, which facilitates cell adhesion growth to improve its proliferation, differentiation, and activity on the surface of PTLG.