Aging is one of the major pathologic factors associated with osteoarthritis (OA). Recently, numerous reports have demonstrated the impact of sirtuin-1 (Sirt1), which is the NAD-dependent deacetylase, on human aging. It has been demonstrated that Sirt1 induces osteogenic and chondrogenic differentiation of mesenchymal stem cells. However, the role of Sirt1 in the OA chondrocytes still remains unknown. We postulated that Sirt1 regulates a hypertrophic chondrocyte lineage and degeneration of articular cartilage through the activation of osteogenic transcriptional activator Runx2 and matrix metalloproteinase (MMP)-13 in OA chondrocytes. To verify whether sirtuin-1 (Sirt1) regulates chondrocyte activity in OA, we studied expressions of Sirt1, Runx2 and production of MMP-13, and their associations in human OA chondrocytes. The expression of Sirt1 was ubiquitously observed in osteoarthritic chondrocytes; in contrast, Runx2 expressed in the osteophyte region in patients with OA and OA model mice. OA relating catabolic factor IL-1βincreased the expression of Runx2 in OA chondrocytes. OA chondrocytes, which were pretreated with Sirt1 inhibitor, inhibited the IL-1β-induced expression of Runx2 compared to the control. Since the Runx2 is a promotor of MMP-13 expression, Sirt1 inactivation may inhibit the Runx2 expression and the resultant down-regulation of MMP-13 production in chondrocytes. Our findings suggest thatSirt1 may regulate the expression of Runx2, which is the osteogenic transcription factor, and the production of MMP-13 from chondrocytes in OA. Since Sirt1 activity is known to be affected by several stresses, including inflammation and oxidative stress, as well as aging, SIRT may be involved in the development of OA.
To clarify how the osteoarthritis (OA)-induced catabolic factor interleukin (IL)-1β affects chondrocyte energy metabolism, and especially to define the downstream pathway linking nicotinamide adenine dinucleotide (NAD)-dependent deacetylase Sirtuin-1 (Sirt-1) to energy metabolism in OA chondrocytes. Human chondrocytes were isolated from articular cartilage samples of patients with OA. The level of energy metabolism of OA chondrocytes was evaluated by monitoring the activity of the energy metabolic sensor, adenosine monophosphate-activated protein kinase (AMPK) and the level of production of adenosine triphosphate (ATP) in chondrocytes in the presence or absence of t IL-1β (10 ng/mL). Effects of IL-1β on anabolic and catabolic activities of chondrocytes were analyzed by the levels of production of proteoglycan and matrix metalloproteinase (MMP)-13, respectively. Experiments involving pre-treatment with Sirt-1 inhibitor were also performed to investigate the underlying regulatory mechanism linking Sirt-1 to chondrocyte energy metabolism. IL-1β significantly inhibited the activity of AMPK and production of ATP in OA chondrocytes. The energy metabolism disruption mediated by IL-1β was further decreased by pretreatment with Sirt-1 inhibitor in OA chondrocytes. Treatment with IL-1β significantly decreased the level of proteoglycan production and significantly increased the level of MMP-13 secretion by chondrocytes. These chondrocyte activities were also reduced by pre-treatment with the Sirt-1 inhibitor in OA chondrocytes. IL-1β inhibits the AMPK -ATP energy metabolic pathway in OA chondrocytes. Our findings also suggest that Sirt-1 activity is involved in anabolic and catabolic cellular activities and that Sirt-1 modulates ATP production through functional regulation of the energy sensor AMPK in chondrocytes.
Objective: Cold therapy, so-called icing, is often used immediately after muscle injuries as first aid for the suppression of inflammation and pain relief. Recent evidences show icing retards the regeneration of injured skeletal muscle. On the other hand, microcurrent electrical neuromuscular stimulation (MENS) promotes the regeneration of injured skeletal muscle. In this study, we investigated the effects of the MENS with or without icing on the regeneration of injured skeletal muscle. Methods: Eight-week-old male mice (C57BL/6J) were divided into 4 groups: control (C), cardiotoxin (CTX) injected (X), CTX injected with MENS (XM), and CTX injected with combined treatments with icing and MENS (XIM) groups. Necrosis-regeneration cycle was induced by an intramuscular injection of CTX into tibialis anterior (TA) muscles except for C group. After CTX-injection, the hindlimbs of the mice were soaked in ice-cold water (4ºC) for 20 minutes under anesthesia (XIM). After the treatments, both right and left hindlimbs of the mice in XIM and XM groups were treated with MENS (10 µA, 0.3 Hz, 250 msec) for 60 min a day and 3 days per week for 1 or 3 weeks. One and three weeks after CTX injection, TA muscles were dissected. Results: MENS with or without icing facilitated the recovery of muscle protein content and muscle fiber morphology including mean fiber cross-sectional areas of injured TA muscle, compared with non-treated condition. These facilitating effects of MENS with or without icing were accompanied with the increase in the relative number of Pax7-positive nuclei, namely satellite cells. Judging from fiber morphology, MENS with icing had enhanced stimulating effects on the regeneration of injured skeletal muscle, compared with MENS-treated condition. Conclusion: Evidence suggested that MENS with or without icing facilitated the regeneration of injured TA muscle. A combination treatment of MENS with icing might be a useful therapy for sports-related skeletal muscle injuries.
LXR or RXR activation on transcriptional regulation in chondrocytes and on overall cartilage health. Immature murine articular chondrocytes were isolated from post-natal day 5 mice and treated with vehicle control, GW3965, or SR11237. Affymetrix microarray analyses were performed, analyzed through Partek and validated through real-time PCR. Quantitative analysis of cellular lipids was conducted by determining cellular total cholesterol, free cholesterol, cholesteryl-ester and triglyceride mass. As GW3965-treated cartilage explants have been previously shown to experience decreased aggrecanolysis, the dimethylmethylene blue (DMMB) dye-binding assay was conducted on femoral head cartilage treated with vehicle control, SR11237, or Bexarotene for 48 and 96 hours. Results: In the microarray study, both LXR and RXR activation induced a strong lipocentric effect, with differential expression seen primarily in genes implicated in lipid metabolic processes. Co-regulatory effects between LXR and RXR activation include up-regulation of lipogenic genes (Srebf1, Insig1, Scd1 and Scd2) and cholesterol transporters (Abca1), with LXR activation exerting a stronger induction. This upregulation is seen functionally with a significantly increase in cellular triglyceride mass with both LXR and RXR activation, with a higher increase observed for the former. Cellular total cholesterol, free cholesterol, and cholesteryl-ester mass was not significantly different upon LXR or RXR activation compared to control cells. DMMB dye-binding assay demonstrated an increase in the amount of glycosaminoglycans released into the medium in SR11237 or Bexarotene treated femoral heads compared to control. Conclusions: Our findings demonstrate that LXR and RXR activation in articular chondrocytes results in similar induction of lipid metabolic genes, with LXR eliciting a stronger lipogenic effect. This may be the underlying reason behind LXR and RXR's differing effects on glycosaminoglycan breakdown in articular cartilage explants. Transgenic invivo studies are in progress to help understand the role of RXR in cartilage in the hopes of providing further insight into the genetic regulation underlying OA disease onset and progression. SOX9 ACETYLATION REDUCES AGGRECAN EXPRESSION IN ADULT HUMAN CHONDROCYTES
Effects of neuroticism on partial and whole body reaction times were investigated under stress, or choking conditions in student participants (N = 127). We measured simple and choice reaction times of parts of the body and choice reaction times of the whole body in the participants with high and low neuroticism such as depression, cyclic tendency, inferiority feelings, and nervousness under the controlled stress scenario of being in front of people. Results indicated significant differences in reaction times of partial body, discriminative decisions and choice reaction times of participants in the high neuroticism group. Results of whole body reaction times were opposite to that of partial body reactions. However, a two-way factorial analysis of variance indicated neither a significant main effect, nor interactions between reaction times and personality traits. Whole body reactions suggest that the effects of stimulus transduction process from motor commands to motor outputs via motor neurons has a greater effect in the central nervous system than recognition and decision-making. However, it is possible that changes in the intracortical mechanisms related to cognitions and emotions could be correlated in partial body movements with nearly no muscular activity. Our findings suggested that delays indiscrimination, decision-making, and choice times could affect the performance of individuals.
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