Sirtuin 1 enzymatic activity is required for cartilage homeostasis in vivo in a mouse model
| Autor: | Michael W. McBurney, Xiao Hong He, Kristien J. M. Zaal, Mona Dvir-Ginzberg, Christelle Sanchez, Viktoria Gagarina, Odile Gabay, Yingjie Song |
|---|---|
| Rok vydání: | 2012 |
| Předmět: |
Immunoblotting
Immunology Cell Culture Techniques Type II collagen Osteoarthritis Article Chondrocyte Extracellular matrix Mice Chondrocytes Sirtuin 1 Rheumatology medicine Animals Homeostasis Point Mutation Immunology and Allergy Pharmacology (medical) Aggrecans Collagen Type II Aggrecan Extracellular Matrix Proteins biology Cartilage homeostasis Cartilage medicine.disease Immunohistochemistry Cell biology Disease Models Animal medicine.anatomical_structure biology.protein Female |
| Zdroj: | Arthritis & Rheumatism. 65:159-166 |
| ISSN: | 0004-3591 |
| DOI: | 10.1002/art.37750 |
| Popis: | Osteoarthritis (OA) is a multifactorial and complex degenerative disease of the cartilage. Different mechanisms are involved in cartilage degradation, including inflammation, apoptosis, and breakdown of major extracellular matrix (ECM) components, such as type II collagen and aggrecan (1). Aging is one of the most important risk factors linked to OA susceptibility (2,3). More than 50% of adults ages 65 or older reported an arthritis diagnosis, making OA one of the most common diseases in developed countries (4). Sirtuin 1 (SIRT-1) has been shown to regulate the lifespan and aging in simple eukaryotes (2,5,6). In mammals, SIRT-1 has been reported to play an important role in age-related diseases, such as osteoporosis, diabetes, and cancer (6–8). We have previously shown in vitro that SIRT-1 modulates gene expression in human chondrocytes. SIRT-1 elevates the expression of genes encoding the cartilage ECM in human chondrocytes (9) and enhances the survival of human OA chondrocytes by repressing apoptosis (10,11). Recently, SIRT-1 has been reported to be involved in the pathogenesis of OA by modulating chondrocyte gene expression and hypertrophy (12). Finally, SIRT-1 plays an antiinflammatory role in different tissues by inhibiting the transcription of proinflammatory genes (6). So far, in vitro studies have suggested a protective role of SIRT-1 in cartilage; however, very few studies have demonstrated these roles in vivo. We previously created SIRT-1–null mice (13,14) and found that they were smaller than wild-type (WT) mice, had craniofacial abnormalities, and their long bones mineralized slower than normal (15). These observations were consistent with the notion that SIRT-1 may play a role in cartilage development and homeostasis. Additional analysis of heterozygous SIRT-1 mice (SIRT-1+/−) showed that they have elevated levels of apoptotic chondrocytes and develop more severe OA with age compared to WT mice (16). In this study, we investigated the articular cartilage of mice carrying a SIRT-1 protein lacking enzymatic activity (SIRT-1tm2.1Mcby or SIRT-1y/y) and found that these mutant mice were predisposed to develop OA, especially with age. Our results showed an altered cartilage phenotype and an acceleration of the OA process in these SIRT-1 mutant mice due to a higher level of cartilage breakdown and apoptosis (17). |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Plný text