ABSTRACT
Osteoarthritis (OA) is a prevalent disease among elderly people and is often characterized by chronic joint pain and dysfunction. Recently, growing evidence of chondrocyte senescence in the pathogenesis of OA has been found, and targeting senescence has started to be recognized as a therapeutic approach for OA. Piezo1, a mechanosensitive Ca2+ channel, has been reported to be harmful in sensing abnormal mechanical overloading and leading to chondrocyte apoptosis. However, whether Piezo1 can transform mechanical signals into senescence signals has rarely been reported. In this study, we found that severe OA cartilage expressed more Piezo1 and the senescence markers p16 and p21. 24 h of periodic mechanical stress induced chondrocyte senescence in vitro. In addition, we demonstrated the pivotal role of Piezo1 in OA chondrocyte senescence induced by mechanical stress. Piezo1 sensed mechanical stress and promoted chondrocyte senescence via its Ca2+ channel ability. Moreover, Piezo1 promoted SASP factors production under mechanical stress, particularly in IL-6 and IL-1ß. p38MAPK and NF-κB activation were two key pathways that responded to Piezo1 activation and promoted IL-6 and IL-1ß production, respectively. Collectively, our study revealed a connection between abnormal mechanical stress and chondrocyte senescence, which was mediated by Piezo1.
Subject(s)
Interleukin-6 , Osteoarthritis , Humans , Aged , Stress, Mechanical , Interleukin-6/metabolism , Osteoarthritis/metabolism , Signal Transduction , Gene Expression Regulation , Interleukin-1beta/metabolism , Chondrocytes/metabolism , Cellular Senescence/physiologyABSTRACT
Osteoporosis-related bone fracture and falls have a severe impact on patients' daily lives. Osteoblasts are bone-building cells that play a vital role in bone formation and remodeling. Imbalanced osteoblast differentiation could lead to osteoporosis. GPR39 is an orphan G protein-coupled receptor that mediates metabolic pathways. In this study, we show that GPR39 is expressed in MC3T3-E1 cells. Osteoblast differentiation culture media induces GPR39, suggesting that GPR39 is a differentiation-responsive factor. Activation of GPR39 using its selective agonist TC-G 1008 induces alkaline phosphatase (ALP), osteocalcin (OCN), and type I collagen (Col-I) expression, and increases cellular ALP activity and calcium deposition, implying that GPR activation promotes cells toward osteoblast differentiation. Treatment with TC-G 1008 also increases Runx-2 expression and AMPK activation. However, the inhibition of AMPK by Compound C abolished TC-G 1008-mediated ALP, OCN, and Col-I induction, and reduces ALP activity and cellular calcium deposition as well as Runx-2 induction. These data indicate that TC-G 1008-mediated GPR39 activation involves AMPK-mediated Runx-2 induction. In summary, our study uncovers a new role of GPR39 activation in osteoblast differentiation, implying that GPR39 could be a promising therapeutic target for osteoporosis.
Subject(s)
Cell Differentiation/drug effects , Minerals/metabolism , Osteoblasts/cytology , Osteoblasts/drug effects , Pyrimidines/pharmacology , Receptors, G-Protein-Coupled/agonists , Sulfonamides/pharmacology , 3T3 Cells , AMP-Activated Protein Kinases/metabolism , Animals , Cell Line , Core Binding Factor Alpha 1 Subunit/genetics , Core Binding Factor Alpha 1 Subunit/metabolism , Enzyme Activation/drug effects , Gene Expression Regulation/drug effects , Mice , Nitric Oxide/biosynthesis , Nitric Oxide Synthase Type III/metabolism , Osteoblasts/metabolism , Osteogenesis/drug effects , Phosphorylation/drug effectsABSTRACT
OBJECTIVE: To explore the therapeutic effect of debridement and vacuum sealing drainage (VSD) of cavitas medullaris for the treatment of chronic osteomyelitis of tibia. METHODS: From March 2006 to May 2009, 19 patients with chronic osteomyelitis of tibia were treated by debridment and VSD, then the second operation were performed to close the wound. Among them, 12 patients were male and 7 patients were female, the average age was 39 years (ranged from 25 to 68 years). The course of disease were from 10 months to 5 years. The main clinical symptoms were red swelling, tenderness and fluid of local soft tissue. There were prolonged unhealed sinus and pus; the X-ray showed osteosclerosis, increased bone mineral, and sequestrum and dead space was formed. The result of bacterial culture showed 3 cases were aeruginosus bacillus, 13 cases staphylococcus aureus, 1 case bacillus aerogenes and 2 cases beta streptococcus. Among them, 3 cases were methicillin resistant staphylococcus (MRS). RESULTS: After debridement and VSD of cavitas medullaris 18-22 days later, the granulation tissue grow well and the wounds of the 19 patients all healed primarily with direct suturing of 17 cases, loco-regional flap of 2 cases. The standard of wound healing was the dryness, cleanness and no drainage. The X-ray revealed the bone tissue grew well and no relapse and fracture occurred during followed-up 6-12 months. CONCLUSION: The debridement and VSD of cavitas medullaris is a very effective and safe treatment for chronic osteomyelitis of tibia.
