Effect of interleukin‐1β on osteogenic protein 1–induced signaling in adult human articular chondrocytes

Abstract

Objectives To investigate the effect of interleukin-1β (IL-1β) on osteogenic protein-1 (OP-1) signaling in human adult articular chondrocytes. We examined two major receptor-activated Smad (R-Smad) signaling pathways, the BMP and MAPK, in the model of IL-1β-induced cartilage degeneration. Methods Ankle chondrocytes from 26 normal human donors were cultured in high density monolayers in a serum-free media. Effect of IL-1β on BMP receptors was studied by RT-PCR and flow cytometry. Phosphorylation of R-Smads was tested in cells treated with IL-1β (10ng/ml), OP-1 (100ng/ml) or combined IL-1β and OP-1. Cell lysates were analyzed by Western blots with polyclonal antibodies against two R-Smads phosphorylated sites (BMP and MAPK) or total, non-phosphorylated R-Smad as a control. To identify through which MAPK IL-1β activates linker region, chondrocytes were pre-incubated with specific MAPK inhibitors (PD98059 for MAP/ERK; SP600125 for JNK; and SB203580 for p38). Results We found that IL-1β reduced the number of ALK-2 and ALK-3 receptors, inhibited Smad1 and Smad6 expression, delayed and prematurely terminated the onset of OP-1 mediated R-Smad phosphorylation and affected nuclear translocation of R-Smad/Smad4 complexes. We discovered that the alternative phosphorylation of R-Smad in the linker region via the MAPK pathway (primarily p38 and JNK) could be a possible mechanism through which IL-1β offsets OP-1 signaling and responses to OP-1. Conversely, OP-1 was found to directly inhibit phosphorylation of p38. Conclusions Our findings describe new mechanisms of the cross-talk between OP-1 and IL-1β in chondrocytes. The study also identifies potential targets for therapeutic interventions in the treatment of cartilage degenerative processes.

BMP-7 inhibits cartilage degeneration through suppression of inflammation in rat zymosan-induced arthritis

“…In spite of the difference of cell sources, this result might provide a clue to clarifying our own question. In addition, Chubinskaya et al (2007a) have pointed out the mechanism by which BMP-7 counteracts IL-1β signaling (Elshaier et al 2009) and suggest that BMP-7 has a potential to reverse mitogen-activated protein kinase signaling via the inhibition of IL-1β-induced P38 phosphorylation Zymosan was injected into both sides of the knee of rats. PBS or BMP-7 at 100-1000 ng per joint was injected into both knees 30 min before and 2 days after induction of ZIA.…”

“…BMP-7 also suppresses the secretion of IL-1β, a major pro-inflammatory cytokine, and promotes the secretion of IL-10, an anti-inflammatory cytokine in the synovium. Consequently, BMP-7 inhibits cartilage degeneration (Chubinskaya et al 2007a;Elshaier et al 2009). These findings support one of the expected mechanisms of antiinflammatory effects of BMP-7 in several inflammatory models.…”

Anti‐catabolic effect of OP‐1 in chronically compressed intervertebral discs

“…13,14,17 Interestingly, anabolic and anti-catabolic activities of OP-1 have also been documented in different models of human and animal cartilage degeneration. 18,19,21,[30][31][32][33][34] As our numerous studies indicate, OP-1 is able not only act as a potent cartilage anabolic factor, but also as an anti-catabolic agent.…”

“…At the same time, OP-1 is also capable of inhibiting endogenous IL-1b and TNF-a production induced by injurious compression, thus enhancing the net result of the anti-catabolic activity of OP-1. [18][19][20][21]34 Along with the inhibition of proinflammatory cytokines and various matrix metalloproteinases, OP-1 stimulates gene expression of the tissue inhibitor of matrix metalloproteinases. 40 There is an increased number of publications that suggest the involvement of certain neuropeptides in mechanotransduction of nonneuronal tissues and cells, such as cells of the immune system (T cells, monocytes, macrophages), osteoclasts, human mucosal mononuclear cells, and most surprisingly, chondrocytes.…”

Activin A and bone metastasis

“…1d). In addition to the canonical Smaddependent pathway, Act A also interacts with other important intracellular pathways such as p38MAPK, ERK1/2 and JNK mitogen-activated kinase pathways (Bao et al, 2005;Chen et al, 2006;Leivonen and Kähäri, 2007;Elshaier et al, 2009) which cooperate with Smads in modulating several important biological functions (Moustakas and Heldin, 2005;Chen et al, 2006;Fig. 1e).…”