Chondrocyte response to growth factors is modulated by p38 mitogen-activated protein kinase inhibition

Abstract

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 E 2 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 E 2 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.

Cissus quadrangularis inhibits IL-1β induced inflammatory responses on chondrocytes and alleviates bone deterioration in osteotomized rats via p38 MAPK signaling

“… 31 , 32 On the other hand, growth factors, such as TGF-β and insulin-like growth factor (IGF) modulate chondrocyte proliferation via inhibition of p38 MAPK and upregulation of ERK signaling. 33 Our study showed similar results where exposure of chondrocytes to IL-1β significantly increased expression of proinflammatory cytokines, NO, and p38 MAPK. However, treatment of cells with herbals, in particularly C. quadrangularis and the combination therapy, considerably alleviated production of catabolic agents by inhibiting activation of p38 MAPK and ERK2 signaling.…”

“…This in turn leads to inflammation, further cytokine production, osteoclast differentiation, and chondrocyte apoptosis 31,32. On the other hand, growth factors, such as TGF-β and insulin-like growth factor (IGF) modulate chondrocyte proliferation via inhibition of p38 MAPK and upregulation of ERK signaling 33. Our study showed similar results where exposure of chondrocytes to IL-1β significantly increased expression of proinflammatory cytokines, NO, and p38 MAPK.…”

Gene Expression Analysis before and after Treatment with Adalimumab in Patients with Ankylosing Spondylitis Identifies Molecular Pathways Associated with Response to Therapy

“…In particular, it has been shown that high serum levels of IL-6 may associate with the development of AS [ 36 ]. The triggering of mitogen-activated kinase (MAPK) signaling cascade leads to activation of downstream JUN N-terminal kinase (JNK) and p38/MAPK14 [ 37 ], which is involved in the proinflammatory activity of interleukin 1 (IL-1) and TNF-alpha [ 38 ]. The transcript for this kinase was 1.8 fold increased in AS samples.…”

Shear- and Compression-induced Chondrocyte Transcription Requires MAPK Activation in Cartilage Explants

“…For example, transforming growth factor-␤-induced aggrecan transcription in ATDC5 chondrogenic cells requires ERK1/2 and p38 activation (42). In addition, p38 signaling contributes toward transforming growth factor-␤-stimulated proteoglycan synthesis and chondrocyte proliferation (36,37), and ERK1/2 is activated by insulin-like growth factor-1, which strongly promotes anabolic chondrocyte behavior (17,35). It was also shown recently that JNK inhibition during cyclic compression of tissue-engineered constructs prevents up-regulation of aggrecan and type II collagen, as well as MMP3 and MMP13 genes (51).…”