ERK-1/2 and p38 in the Regulation of Hypertrophic Changes of Normal Articular Cartilage Chondrocytes Induced by Osteoarthritic Subchondral Osteoblasts

Abstract

Objective. Previous studies have shown the influence
of subchondral bone osteoblasts (SBOs) on phenotypical
changes of articular cartilage chondrocytes
(ACCs) during the development of osteoarthritis (OA).
The molecular mechanisms involved during this process
remain elusive, in particular, the signal transduction
pathways. The aim of this study was to investigate the in
vitro effects of OA SBOs on the phenotypical changes in
normal ACCs and to unveil the potential involvement of
MAPK signaling pathways during this process.
Methods. Normal and arthritic cartilage and bone
samples were collected for isolation of ACCs and SBOs.
Direct and indirect coculture models were applied to
study chondrocyte hypertrophy under the influence of
OA SBOs. MAPKs in the regulation of the cell–cell
interactions were monitored by phosphorylated antibodies
and relevant inhibitors.
Results. OA SBOs led to increased hypertrophic
gene expression and matrix calcification in ACCs by
means of both direct and indirect cell–cell interactions.
In this study, we demonstrated for the first time that OA
SBOs suppressed p38 phosphorylation and induced
ERK-1/2 signal phosphorylation in cocultured ACCs.
The ERK-1/2 pathway inhibitor PD98059 significantly
attenuated the hypertrophic changes induced by conditioned
medium from OA SBOs, and the p38 inhibitor
SB203580 resulted in the up-regulation of hypertrophic
genes in ACCs.
Conclusion. The findings of this study suggest
that the pathologic interaction of OA SBOs and ACCs is
mediated via the activation of ERK-1/2 phosphorylation
and deactivation of p38 phosphorylation, resulting in
hypertrophic differentiation of ACCs.