Chondrocyte Reponse to Growth Factors
Chondrocyte Reponse to Growth Factors
Inhibitors of p38 mitogen-activated protein kinase (MAPK) diminish inflammatory arthritis in experimental animals. This may be effected by diminishing the production of inflammatory mediators, but this kinase is also part of the IL-1 signal pathway in articular chondrocytes. We determined the effect of p38 MAPK inhibition on proliferative and synthetic responses of lapine chondrocytes, cartilage, and synovial fibroblasts under basal and IL-1-activated conditions.
Basal and growth factor-stimulated proliferation and proteoglycan synthesis were determined in primary cultures of rabbit articular chondrocytes, first-passage synovial fibroblasts, and cartilage organ cultures. Studies were performed with or without p38 MAPK inhibitors, in IL-1-activated and control cultures. Media nitric oxide and prostaglandin E2 were assayed.
p38 MAPK inhibitors blunt chondrocyte and cartilage proteoglycan synthesis in response to transforming growth factor beta; responses to insulin-like growth factor 1 (IGF-1) and fetal calf serum (FCS) are unaffected. p38 MAPK inhibitors significantly reverse inhibition of cartilage organ culture proteoglycan synthesis by IL-1. p38 MAPK inhibition potentiated basal, IGF-1-stimulated and FCS-stimulated chondrocyte proliferation, and reversed IL-1 inhibition of IGF-1-stimulated and FCS-stimulated DNA synthesis. Decreases in nitric oxide but not prostaglandin E2 synthesis in IL-1-activated chondrocytes treated with p38 MAPK inhibitors are partly responsible for this restoration of response. Synovial fibroblast proliferation is minimally affected by p38 MAPK inhibition.
p38 MAPK activity modulates chondrocyte proliferation under basal and IL-1-activated conditions. Inhibition of p38 MAPK enhances the ability of growth factors to overcome the inhibitory actions of IL-1 on proliferation, and thus could facilitate restoration and repair of diseased and damaged cartilage.
Proinflammatory cytokines are responsible for much of the pathophysiology of both osteoarthritis and rheumatoid arthritis. Activation of p38 mitogen-activated protein kinase (MAPK) has been implicated in the catabolic and anti-anabolic actions of both IL-1 and tumor necrosis factor alpha. These cytokines are also induced in mechanically stressed and damaged cartilage. The signal pathways they activate, including p38 MAPK, may thus influence the course of cartilage repair. It is therefore important to understand the consequences of p38 MAPK inhibition on cartilage/chondrocyte responses to the anabolic effectors, which stimulate the repair processes of proliferation and cartilage matrix protein synthesis.
Members of the pyridinyl imidazole class of compounds that inhibit p38 MAPK have been developed, and their potential as therapeutic agents in inflammation, arthritis, septic shock, and myocardial injury is currently being explored. One of these compounds, SB 203580 (SB), is a potent inhibitor of cytokine production in mice and rats, and decreases paw inflammation in collagen-induced arthritis in mice. A second related compound, SB 242235, decreases adjuvant-induced arthritis in rats. SB also inhibits IL-1 induction of inducible nitric oxide synthase (iNOS) in bovine chondrocytes, and thus blocks nitric oxide (NO) synthesis. This effect may also protect cartilage from the damaging actions of NO.
p38 MAPK was recently identified, however, as part of the signal transduction pathway effecting transforming growth factor beta (TGF-β) stimulation of aggrecan gene expression by the chondrogenic cell line ATDC5. The relationship between TGF-β signaling through p38 MAPK and the Smad family was characterized in C2C12 cells. The conclusion was that the nuclear target of p38, ATF-2, becomes phosphorylated in response to TGF-β and forms a complex with Smad 4. Similar signal synergy studies have not been carried out for chondrocytes. However, given the important anabolic and anticatabolic actions of TGF-β, any maneuver that modifies responses to TGF-β and other anabolic growth factors could have critical consequences for maintenance and repair of cartilage. These studies were thus initiated to determine whether p38 MAPK inhibition affects chondrocyte responses to TGF-β, insulin-like growth factor 1 (IGF-1), and serum, and also whether p38 MAPK inhibition reverses the anti-anabolic actions of IL-1 on proliferative and synthetic responses of rabbit articular chondrocytes, cartilage, and synovial fibroblasts.
Inhibitors of p38 mitogen-activated protein kinase (MAPK) diminish inflammatory arthritis in experimental animals. This may be effected by diminishing the production of inflammatory mediators, but this kinase is also part of the IL-1 signal pathway in articular chondrocytes. We determined the effect of p38 MAPK inhibition on proliferative and synthetic responses of lapine chondrocytes, cartilage, and synovial fibroblasts under basal and IL-1-activated conditions.
Basal and growth factor-stimulated proliferation and proteoglycan synthesis were determined in primary cultures of rabbit articular chondrocytes, first-passage synovial fibroblasts, and cartilage organ cultures. Studies were performed with or without p38 MAPK inhibitors, in IL-1-activated and control cultures. Media nitric oxide and prostaglandin E2 were assayed.
p38 MAPK inhibitors blunt chondrocyte and cartilage proteoglycan synthesis in response to transforming growth factor beta; responses to insulin-like growth factor 1 (IGF-1) and fetal calf serum (FCS) are unaffected. p38 MAPK inhibitors significantly reverse inhibition of cartilage organ culture proteoglycan synthesis by IL-1. p38 MAPK inhibition potentiated basal, IGF-1-stimulated and FCS-stimulated chondrocyte proliferation, and reversed IL-1 inhibition of IGF-1-stimulated and FCS-stimulated DNA synthesis. Decreases in nitric oxide but not prostaglandin E2 synthesis in IL-1-activated chondrocytes treated with p38 MAPK inhibitors are partly responsible for this restoration of response. Synovial fibroblast proliferation is minimally affected by p38 MAPK inhibition.
p38 MAPK activity modulates chondrocyte proliferation under basal and IL-1-activated conditions. Inhibition of p38 MAPK enhances the ability of growth factors to overcome the inhibitory actions of IL-1 on proliferation, and thus could facilitate restoration and repair of diseased and damaged cartilage.
Proinflammatory cytokines are responsible for much of the pathophysiology of both osteoarthritis and rheumatoid arthritis. Activation of p38 mitogen-activated protein kinase (MAPK) has been implicated in the catabolic and anti-anabolic actions of both IL-1 and tumor necrosis factor alpha. These cytokines are also induced in mechanically stressed and damaged cartilage. The signal pathways they activate, including p38 MAPK, may thus influence the course of cartilage repair. It is therefore important to understand the consequences of p38 MAPK inhibition on cartilage/chondrocyte responses to the anabolic effectors, which stimulate the repair processes of proliferation and cartilage matrix protein synthesis.
Members of the pyridinyl imidazole class of compounds that inhibit p38 MAPK have been developed, and their potential as therapeutic agents in inflammation, arthritis, septic shock, and myocardial injury is currently being explored. One of these compounds, SB 203580 (SB), is a potent inhibitor of cytokine production in mice and rats, and decreases paw inflammation in collagen-induced arthritis in mice. A second related compound, SB 242235, decreases adjuvant-induced arthritis in rats. SB also inhibits IL-1 induction of inducible nitric oxide synthase (iNOS) in bovine chondrocytes, and thus blocks nitric oxide (NO) synthesis. This effect may also protect cartilage from the damaging actions of NO.
p38 MAPK was recently identified, however, as part of the signal transduction pathway effecting transforming growth factor beta (TGF-β) stimulation of aggrecan gene expression by the chondrogenic cell line ATDC5. The relationship between TGF-β signaling through p38 MAPK and the Smad family was characterized in C2C12 cells. The conclusion was that the nuclear target of p38, ATF-2, becomes phosphorylated in response to TGF-β and forms a complex with Smad 4. Similar signal synergy studies have not been carried out for chondrocytes. However, given the important anabolic and anticatabolic actions of TGF-β, any maneuver that modifies responses to TGF-β and other anabolic growth factors could have critical consequences for maintenance and repair of cartilage. These studies were thus initiated to determine whether p38 MAPK inhibition affects chondrocyte responses to TGF-β, insulin-like growth factor 1 (IGF-1), and serum, and also whether p38 MAPK inhibition reverses the anti-anabolic actions of IL-1 on proliferative and synthetic responses of rabbit articular chondrocytes, cartilage, and synovial fibroblasts.