Abstract
IntroductionAdvanced glycation end products (AGEs) have been introduced to be involved in the pathogenesis of osteoarthritis (OA). The influence of AGEs on osteoarthritic fibroblast-like synovial cells (FLS) has been incompletely understood as yet. The present study investigates a potential influence of AGE-modified bovine serum albumin (AGE-BSA) on cell growth, and on the expression of proinflammatory and osteoclastogenic markers in cultured FLS.MethodsFLS were established from OA joints and stimulated with AGE-BSA. The mRNA expression of p27Kip1, RAGE (receptor for AGEs), nuclear factor kappa B subunit p65 (NFκB p65), tumor necrosis factor alpha (TNF-α, interleukin-6 (IL-6), receptor activator of NFκB ligand (RANKL) and osteoprotegerin was measured by real-time PCR. The respective protein expression was evaluated by western blot analysis or ELISA. NFκB activation was investigated by luciferase assay and electrophoretic mobility shift assay (EMSA). Cell cycle analysis, cell proliferation and markers of necrosis and early apoptosis were assessed. The specificity of the response was tested in the presence of an anti-RAGE antibody.ResultsAGE-BSA was actively taken up into the cells as determined by immunohistochemistry and western blots. AGE-induced p27Kip1 mRNA and protein expression was associated with cell cycle arrest and an increase in necrotic, but not apoptotic cells. NFκB activation was confirmed by EMSAs including supershift experiments. Anti-RAGE antibodies attenuated all AGE-BSA induced responses. The increased expression of RAGE, IL-6 and TNF-α together with NFκB activation indicates AGE-mediated inflammation. The decreased expression of RANKL and osteoprotegerin may reflect a diminished osteoclastogenic potential.ConclusionsThe present study demonstrates that AGEs modulate growth and expression of genes involved in the pathophysiological process of OA. This may lead to functional and structural impairment of the joints.
Highlights
Advanced glycation end products (AGEs) have been introduced to be involved in the pathogenesis of osteoarthritis (OA)
The present study demonstrates that AGEs modulate growth and expression of genes involved in the pathophysiological process of OA
Characterisation of fibroblast-like synovial cells (FLS) and AGE uptake For characterisation of FLS cultured from synovial tissues, the presence of the fibroblastic marker protein CD90 (Thy-1) was demonstrated in Co-BSA as well as in AGE-modified bovine serum albumin (AGE-BSA) treated cells (Figure 1a)
Summary
Advanced glycation end products (AGEs) have been introduced to be involved in the pathogenesis of osteoarthritis (OA). The influence of AGEs on osteoarthritic fibroblast-like synovial cells (FLS) has been incompletely understood as yet. The present study investigates a potential influence of AGE-modified bovine serum albumin (AGE-BSA) on cell growth, and on the expression of proinflammatory and osteoclastogenic markers in cultured FLS. Osteoarthritis (OA) is the most common joint disease of middle aged and older people across the world. OA is caused by joint degeneration, a process that includes progressive loss of articular cartilage accompanied by remodelling and sclerosis of subchondral bone, and osteophyte formation. Multiple factors for OA initiation and progression have been identified. These factors can be segregated into categories that include hereditary factors, mechanical factors and effects of ageing [2].
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