Runlin Xing

Increasing evidence has shown that macrophage pyroptosis in different tissues participates in chronic aseptic inflammation and is related to tissue fibrosis. Our last studies also revealed the vital role of synovial fibroblast pyroptosis in the onset and development of knee osteoarthritis (KOA). In this study, we aimed to investigate whether synovial macrophage pyroptosis did occur and whether this form of cell death should be related to synovitis and fibrosis of KOA. In the synovial tissue of KOA model rats, we observed a decrease of caspase1, NLRP3, ASC, and GSDMD caused by macrophage depletion in both the mRNA and protein expressions. Besides, rats treated with the specific caspase1 inhibitor Ac-YVAD-CMK showed less inflammatory reaction and fibrosis, not only in the expression of proinflammatory factors IL-1β, IL-18, and HMGB1 and fibrosis markers TGF-β, PLOD2, COL1A1, and TIMP1 but also in the observation of HE staining, Sirius Red staining, and the transverse diameters of the right knees. Subsequently, we established an LPS+ATP-induced model in macrophages mimicking the inflammatory environment of KOA and inducing macrophage pyroptosis. Macrophages transfected with caspase1 siRNA showed reduced cell death; meanwhile, the relative expression of pyroptosis-related proteins were also downregulated. In addition, the level of fibrotic markers in synovial fibroblasts were significantly decreased after coculture with siRNA GSDMD-transfected macrophages. To conclude, synovial macrophage pyroptosis may occur in the pathological processes of KOA and inhibition of synovial macrophage pyroptosis alleviates synovitis and fibrosis in KOA model rats.

Fibroblast-like synoviocytes (FLSs) are the main effector cells of knee osteoarthritis (KOA) synovial fibrosis. Our last report showed that NLRP1 and NLRP3 inflammasomes may mediate LPS/ATP-induced FLSs pyroptosis in KOA. In the present study, we found an elevated hypoxia-inducible factor-1α (HIF-1α) level in the synovial tissue of KOA model rats, and inhibiting the increase of HIF-1α could improve synovial fibrosis in rats. Subsequently, we established LPS/ATP-induced model in FLSs mimicking the inflammatory environment of KOA. FLSs transfected with siRNA HIF-1α showed a reduced cell death; meanwhile, the relative expression of pyroptosis-related proteins was also downregulated. Additionally, FLSs transfected with or without siRNA GSDMD were exposed to hypoxia. GSDMD silencing can significantly reduce both gene and protein levels of fibrogenic markers transforming growth factor-β (TGF-β), procollagen-lysine, 2-oxoglutarate 5-dioxygenase2 (PLOD2), collagen type I α1 chain (COL1A1), and tissue inhibitor of metalloproteinases 1 (TIMP1). Taken together, our findings indicate that increased HIF-1α is highly involved in the KOA synovial fibrosis. Moreover, elevated HIF-1α may aggravate synovial fibrosis via FLS pyroptosis.

Objective: The aim of this meta-analysis was to clarify the role of Interleukin-1 receptor antagonist gene (IL1-RN) Variable Number of Tandem Repeats (VNTR) polymorphism on the risk of OA by means of metaanalysis. Methods: Eligible articles were retrieved from PubMed, Web of science and Google scholar with a total of 1187 OA cases and 2659 controls. The strength of the association between the IL1-RN VNTR polymorphism and the risk of OA was assessed by odds ratios (ORs) with the corresponding 95% confidence interval (CI) for each study. Results: The meta-analysis of seven published studies retrieved from the literature search showed a significantly increased OA risk in the recessive model analysis (22 vs 2L þ LL: Pb ¼ 0.18, I2 ¼ 32.8, OR(95% CI) ¼ 1.50(1.12, 2.02), P ¼ 0.007), the additive model analysis (22 vs LL: Pb ¼ 0.08, I2 ¼ 46.8, OR(95% CI) ¼ 1.56(1.15, 2.12), P ¼ 0.004) and in the allele contrast model (2 vs L: Pb ¼ 0.02, I2 ¼ 58.8, OR(95% CI) ¼ 1.20(1.05, 1.36), P ¼ 0.007). By subgroup analysis, the IL1-RN VNTR polymorphism was found to be significantly associated with OA susceptibility in Caucasian and Hospital based case-control study (HCC) groups. Conclusion: This meta-analysis showed that IL1-RN VNTR polymorphism may increase the susceptibility to OA. More studies with detailed information are needed to validate our conclusion. Level of evidence: Level III, diagnostic study.

Objective The aim of this meta-analysis was to clarify the role of Matrix metalloproteinase 1 (MMP-1) -1607 1G/2G (rs1799750) polymorphism on the osteoarthritis (OA) risk. Methods Articles were selected by retrieving the Web of Science, Embase and Pubmed. The strength of the association between -1607 1G/2G polymorphism and OA risk was assessed by odds ratios (ORs) with the corresponding 95% confidence interval (CI) for each study. Results No significant association between -1607 1G/2G polymorphism and OA risk was found in all the models overall (2G2G vs 1G1G, OR (95%CI) = 0.69 (0.36–1.32), P = 0.54; 2G2G + 2G1G vs 1G1G, OR (95%CI) = 0.88 (0.47–1.63), P = 0.69; 2G2G vs 2G1G + 1G1G, OR (95%CI) = 1.30 (0.68–2.47), P = 0.41; 2 G vs 1G, OR (95%CI) = 0.90 (0.86–1.54), P = 0.66). By subgroup analysis, significant association was found in the “< 60 years” group (2G2G vs 1G1G, OR (95%CI) = 3.46 (2.13–5.62), P = 0.00; 2G2G + 2G1G vs 1G1G, OR (95%CI) = 0.49 (0.31–0.79), P = 0.00; 2G2G vs 2G1G + 1G1G, OR (95%CI) = 2.74 (1.80–4.16, P = 0.00; 2 G vs 1G, OR (95%CI) = 0.56 (0.35–0.89), P = 0.01). Conclusions This meta-analysis showed that -1607 1G/2G polymorphism may increase the susceptibility to OA among the younger populations (<60 years). More studies with detailed information are needed to validate our conclusion. Level of Evidence Level I Diagnostic Study. ER -

Brucine is the active component in traditional Chinese medicine “Ma-Qian-Zi” (Strychnos nux-vomica Linn), with capabilities of analgesic, anti-inflammatory, anti-tumor and so on. It is crucial how to break through the impact of cuticle skin which reduces the penetration of drugs to improve drug transmission rate. The aim of this study is to improve the local drug concentration by using ultrasound. We used fresh porcine skin to study the effects of ultrasound on the transdermal absorption of brucine under the influence of various acoustic parameters, including frequency, amplitude and irradiation time. The transdermal conditions of yellow-green fluorescent nanoparticles and brucine in skin samples were observed by laser confocal microscopy and ultraviolet spectrophotometry. The results show that under ultrasonic conditions, the permeability of the skin to the fluorescent label and brucine (e.g., the depth and concentration of penetration) is increased compared to its passive diffusion permeability. The best ultrasound penetration can make the penetration depth of more than 110 microns, fluorescent nanoparticles and brucine concentration increased to 2-3 times. This work will provide supportive data on how the brucine is better used for transdermal drug delivery (TDD).

High-turnover type bone metabolism derangement has been considered to be one of the major causes of osteoarthritis (OA). Bisphosphonates can attach to hydroxyapatite binding sites on bony surfaces, particularly those which are undergoing active bone resorption. To evaluate the effectiveness of bisphosphonates in OA treatment, literature databases were searched from inception to February 28, 2016 for clinical studies of bisphosphonates for OA treatment. All randomized controlled trials in which bisphosphonates therapy was compared with a placebo or a conventional medication, were selected. 15/1145 studies were eligible for analysis, which included 3566 participants. Bisphosphonates therapy improved pain, stiffness and function significantly in OA assessed by the Western Ontario and McMaster Universities Arthritis Index scale (MD = 4.59; 95 % CI 2.83–6.34; P < 0.00001; MD = 1.43; 95 % CI 0.83–2.23; P = 0.0005; MD = 2.01; 95 % CI 1.27–2.75; P < 0.00001). Bisphosphonates also reduced osteophyte score significantly (MD = −0.51; 95 % CI −0.84 to −0.19; P = 0.002). However, no significant differences were found in subjective improvement, osteoarthritis progression, the number of required acetaminophen treatment or joint replacement. In conclusion, bisphosphonates therapy is effective in relieving pain,stiffness and accelerating functional recovery in OA. Limitations of the studies we analysed included the differences in duration of bisphosphonates use, the doses and types of bisphosphonates and the lack of long-term data on OA joint structure modification after bisphosphonates therapy. More targeted studies are required to evaluate on the effectiveness of bisphosphonates for OA treatment.