Aims

Osteoarthritis (OA) is a common degenerative disease. PA28γ is a member of the 11S proteasome activator and is involved in the regulation of several important cellular processes, including cell proliferation, apoptosis, and inflammation. This study aimed to explore the role of PA28γ in the occurrence and development of OA and its potential mechanism.

Aims

The role of N,N-dimethylformamide (DMF) in diabetes-induced osteoporosis (DM-OS) progression remains unclear. Here, we aimed to explore the effect of DMF on DM-OS development.

Chondrocyte dysfunction is attributable to the development of osteoarthritis (OA). Deregulation of chondrogenic regulators and deleterious factors, e.g. proteinases, Wnt signalling components, and autophagy repressors lowers chondrogenic activities and ultimately deteriorates cartilage homeostasis. Emerging evidence is that epigenetic pathways, including non-coding microRNAs and histone remodelling switch on/off the expression of joint-deleterious factors. MicroRNAs reduces the expressions of mRNAs through binding to the 3'-untranslation regions of targets. The levels of microRNAs, e.g. miR-29a, miR-128a in serum, synovial fluid, synovium, and cartilage are correlated with the occurrence of OA. Mice overexpressing/deficient microRNAs of interest show minor responses to OA progression. Besides, acetylation and methylation statuses of histones regulate the factors detrimental to chondrocytes through altering the interactions between histones and promoters. Histone deacetylases and demethylases, e.g. HDAC4, SIRT1, and EZH2 contribute to the modification reactions of histones, which modulate cartilage matrix metabolism. An intricate nature is that reciprocal actions between microRNAs and histone deacetylase/demethylase are indispensable in chondrocyte survival and function. Administrations with specific inhibitor/agonists for microRNAs and histone deacetylases/demethylase enable joints to show minor responses to articular injury, which mitigate the pathogenesis of OA. This talk highlights the biological roles and therapeutic advantage of epigenetic microRNAs and histone remodelling in OA

Objectives

The role of mechanical stress and transforming growth factor beta 1 (TGF-β1) is important in the initiation and progression of osteoarthritis (OA). However, the underlying molecular mechanisms are not clearly known.

Objectives. This study aimed to examine the effects of SRT1720, a potent SIRT1 activator, on osteoarthritis (OA) progression using an experimental OA model. Methods. Osteoarthritis was surgically induced by destabilization of the medial meniscus in eight-week-old C57BL/6 male mice. SRT1720 was administered intraperitoneally twice a week after surgery. Osteoarthritis progression was evaluated histologically using the Osteoarthritis Research Society International (OARSI) score at four, eight, 12 and 16 weeks. The expression of SIRT1, matrix metalloproteinase 13 (MMP-13), a disintegrin and metalloproteinase with thrombospondin motifs-5 (ADAMTS-5), cleaved caspase-3, PARP p85, and acetylated nuclear factor (NF)-κB p65 in cartilage was examined by immunohistochemistry. Synovitis was also evaluated histologically. Primary mouse epiphyseal chondrocytes were treated with SRT1720 in the presence or absence of interleukin 1 beta (IL-1β), and gene expression changes were examined by real-time polymerase chain reaction (PCR). Results. The OARSI score was significantly lower in mice treated with SRT1720 than in control mice at eight and 12 weeks associated with the decreased size of osteophytes at four and eight weeks. The delayed OA progression in the mice treated with SRT1720 was also associated with increased SIRT1-positive chondrocytes and decreased MMP-13-, ADAMTS-5-, cleaved caspase-3-, PARP p85-, and acetylated NF-κB p65-positive chondrocytes and decreased synovitis at four and eight weeks. SRT1720 treatment partially rescued the decreases in collagen type II alpha 1 (COL2A1) and aggrecan caused by IL-1β, while also reducing the induction of MMP-13 by IL-1β in vitro. Conclusion. The intraperitoneal injection of SRT1720 attenuated experimental OA progression in mice, indicating that SRT1720 could be a new therapeutic approach for OA. Cite this article: K. Nishida, T. Matsushita, K. Takayama, T. Tanaka, N. Miyaji, K. Ibaraki, D. Araki, N. Kanzaki, T. Matsumoto, R. Kuroda. Intraperitoneal injection of the SIRT1 activator SRT1720 attenuates the progression of experimental osteoarthritis in mice. Bone Joint Res 2018;7:252–262. DOI: 10.1302/2046-3758.73.BJR-2017-0227.R1

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

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