Osteoarthritis (OA) is mainly caused by ageing, strain, trauma, and congenital joint abnormalities, resulting in articular cartilage degeneration. During the pathogenesis of OA, the changes in subchondral bone (SB) are not only secondary manifestations of OA, but also an active part of the disease, and are closely associated with the severity of OA. In different stages of OA, there were microstructural changes in SB. Osteocytes, osteoblasts, and osteoclasts in SB are important in the pathogenesis of OA. The signal transduction mechanism in SB is necessary to maintain the balance of a stable phenotype, extracellular matrix (ECM) synthesis, and bone remodelling between articular cartilage and SB. An imbalance in signal transduction can lead to reduced cartilage quality and SB thickening, which leads to the progression of OA. By understanding changes in SB in OA, researchers are exploring drugs that can regulate these changes, which will help to provide new ideas for the treatment of OA.

Cite this article: Bone Joint Res 2023;12(9):536–545.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by symmetrical and chronic polyarthritis. Fibroblast-like synoviocytes are mainly involved in joint inflammation and cartilage and bone destruction by inflammatory cytokines and matrix-degrading enzymes in RA. Approaches that induce various cellular growth alterations of synoviocytes are considered as potential strategies for treating RA. However, since synoviocytes play a critical role in RA, the mechanism and hyperplastic modulation of synoviocytes and their motility need to be addressed. In this review, we focus on the alteration of synoviocyte signalling and cell fate provided by signalling proteins, various antioxidant molecules, enzymes, compounds, clinical candidates, to understand the pathology of the synoviocytes, and finally to achieve developed therapeutic strategies of RA.

Cite this article: Bone Joint Res 2021;10(4):285–297.

Objectives

This study aimed to examine the effects of SRT1720, a potent SIRT1 activator, on osteoarthritis (OA) progression using an experimental OA model.

Background. Resveratrol is a polyphenolic compound commonly found in the skins of red grapes. Sirtuin 1 (SIRT1) is a human gene that is activated by resveratrol and has been shown to promote longevity and boost mitochondrial metabolism. We examined the effect of resveratrol on normal and osteoarthritic (OA) human chondrocytes. Methods. Normal and OA chondrocytes were incubated with various concentrations of resveratrol (1 µM, 10 µM, 25 µM and 50 µM) and cultured for 24, 48 or 72 hours or for six weeks. Cell proliferation, gene expression, and senescence were evaluated. Results. SIRT1 was significantly upregulated in normal chondrocytes with resveratrol concentrations of 25 µM and 50 µM on both two- (2D) (both p = 0.001) and three-dimensional (3D) cultures (p = 0.008 and 0.001, respectively). It was significantly upregulated in OA chondrocytes treated with 10 µM, 25 µM and 50 µM resveratrol on 2D cultures (p = 0.036, 0.002 and 0.001, respectively) and at 50 µM concentration on 3D cultures (p = 0.001). At 72 hours, the expression of collagen (COL)-10, aggrecan (AGG), and runt-related transcription factor 2 (RUNX2) was significantly greater in both 25 µM (p = 0.011, 0.006 and 0.015, respectively) and 50 µM (p = 0.019, 0.004 and 0.002, respectively) resveratrol-treated normal chondrocyte cultures. In OA chondrocytes, expression of COL10 and RUNX2 was significantly greater in 25 µM (p = 0.004 and 0.024) and 50 µM (p = 0.004 and 0.019) cultures at 72 hours on 3D cultures. Conclusions. At concentrations of 25 µM and/or 50 µM, resveratrol treatment significantly upregulates SIRT1 gene expression in normal and osteoarthritic chondrocytes. Resveratrol induces chondrocytes into a hypertrophic state through upregulation of COL1, COL10, and RUNX2. Cite this article: Bone Joint Res 2014;3:51–9

In animal experiments antioxidants like Resveratrol, Quercetin-dihydrate and Selen-L-Methionine cause a growth rate decrease in synovial tissue and furthermore an inhibition of pro-infiammatory factors. We investigated the effect of these antioxidants on synovial fibroblasts of Osteoarthritis (OA) patients compared to Rheumatoid Arthritis (RA) patients. Random biopsies of synovial membrane were obtained aseptically from joints of OA and RA patients. After in vitro expansion cells were cultivated until passage three, seeded in 96 well microtiterplates and treated with 0μM, 50μM, 100μM and 200μM of Resveratrol, Quercetin-dihydrate and Selen-L-Methionin. After 24 and 48 hours incubation cell proliferation assays and apoptosis FACS analysis were performed. Additionally woundhealing assays and photographic documentation of resettlement of synovial fibroblasts was accomplished. The results of cell proliferation assays showed a highly significant reduction as well in OA and RA cells. In OA synovial fibroblasts 200μM of Resveratrol evoked a decrease of 72,3 ±1,7% (***), 200 μM of Quercetin-dihydrate induced a reduction of 16,11 ±3% (***). 200μM of Selen-L-Methionine evoked a decrease of 27,3 ±3,8% (***). In RA cultures 200 μM of Resveratrol evoked a decrease of 77,7 ±1,8% (***), 200μM of Quercetin-dehydrate induced a reduction of 20,38 ±15,3%(**), 200μM of Seleno-L-Methionine evoked a decrease of 23,3 ±4,8%(***)(n=20). The results of photographic documentation correlated with cell experiments. Analysis with untreated and treated OA and RA synovial fibroblasts for their content of apoptotic and necrotic cells by Annexin/7AAD staining displayed only few apoptotic cells. Caspase 3, a key mediator of apoptosis, was not activated in resveratrol-treated OA and RA synovial fibroblasts. Resveratrol, Quercetin-dihydrate and Selen-L-Methionine showed a significant growth rate decrease in OA and RA synovial fibroblasts. In OA and RA the pharmacologic treatment with these antioxidants may be a therapeutic approach. Different apoptosis assays represented only few apoptotic cells. We therefore conclude that apoptosis is not the major pathway in resveratrol-treated synovial fibroblasts

Despite developing refinements of chemotherapy regimens for osteosarcoma, multi-drug resistant cases are frequently seen and patients with metastatic or recurrent disease continue to have a very poor prognosis. Recently, the expression of the longevity gene Sirt1 was found to be relatively higher expressed in tumors compared with the normal tissues. Association of high level of Sirt1 expression with the development of multi-drug resistance in tumor cells has also been indicated. Thus, it is interesting to study the therapeutic potential of regulating Sirt1 activity for the treatment of osteosarcoma. In the present study, we evaluated the effects of two Sirt1 activators, resveratrol and isonicotinamide, on growth and apoptosis in four human osteosarcoma cell lines, HOS, Saos-2, U-2 OS and MG-63. We found that Sirt1 protein was expressed in all osteosarcoma cell lines. Instead of promoting cell survival, both resveratrol and isonicotinamide decreased cell growth and induced cell apoptosis in a dose-dependent fashion. Furthermore, the pro-apoptotic effect of resveratrol could be enhanced by L-asparaginase-induced nutrition restriction of cultured osteosarcoma cells. Our results demonstrated that Sirt1 activators elicited pro-apoptotic effects in osteosarcomas. Thus, Sirt1 could be a potential target in the treatment of osteosarcoma. However, due to the non-specificity of the Sirt1 activators used further studies, such as knock-down of Sirt1 by siRNA, are needed to confirm the effect of Sirt1 activation on malignant cells