Mechanical Regulation of Mitogen-activated Protein Kinase Signaling in Articular Cartilage

Abstract

Articular chondrocytes respond to mechanical forces by alterations in gene expression, proliferative status, and metabolic functions. Little is known concerning the cell signaling systems that receive, transduce, and convey mechanical information to the chondrocyte interior. Here, we show that ex vivo cartilage compression stimulates the phosphorylation of ERK1/2, p38 MAPK, and SAPK/ERK kinase-1 (SEK1) of the JNK pathway. Mechanical compression induced a phased phosphorylation of ERK consisting of a rapid induction of ERK1/2 phosphorylation at 10 min, a rapid decay, and a sustained level of ERK2 phosphorylation that persisted for at least 24 h. Mechanical compression also induced the phosphorylation of p38 MAPK in strictly a transient fashion, with maximal phosphorylation occurring at 10 min. Mechanical compression stimulated SEK1 phosphorylation, with a maximum at the relatively delayed time point of 1 h and with a higher amplitude than ERK1/2 and p38 MAPK phosphorylation. These data demonstrate that mechanical compression alone activates MAPK signaling in intact cartilage. In addition, these data demonstrate distinct temporal patterns of MAPK signaling in response to mechanical loading and to the anabolic insulin-like growth factor-I. Finally, the data indicate that compression coactivates distinct signaling pathways that may help define the nature of mechanotransduction in cartilage.

Temporal Expression Patterns and Corresponding Protein Inductions of Early Responsive Genes in Rabbit Bone Marrow–Derived Mesenchymal Stem Cells Under Cyclic Compressive Loading

“…The recent studies found that p38 and ERK MAPK pathways were involved in TGF-ß1-induced chondrogenesis of ATDC5 cells [54,55], whereas Sox9 induction by fibroblast growth factors in chondrocytes and undifferentiated mesenchymal cells was mediated by the ERK MAPK pathway [56]. Moreover, it was recently demonstrated that the MAPK signal pathway was activated in cartilage by static compressive loading with a rapid induction of ERK and p38 MAPK pathways and a delayed stimulation of SAPK/JNK MAPK pathway [57]. Therefore, three major MAPK pathways could be activated in BM-MSCs by dynamic compressive loading.…”

Shear and Compression Differentially Regulate Clusters of Functionally Related Temporal Transcription Patterns in Cartilage Tissue

“…For example, the milder stimulation of c-Fos and c-Jun (Group M3) in response to the dynamic loading compared with static loading may be related to the lower amplitude of the initial deformation applied to the cartilage in dynamic loading. c-Fos and c-Jun are downstream of the mitogen-activated protein kinases (39), which have been identified as mechanically sensitive to static compression (40,41). Extracellular signal-regulated kinases 1 and 2 become maximally phosphorylated within 10 min of application of a 50% static compression, indicating an immediate response to the changing environmental conditions (40).…”

Mechanical Compression of Cartilage Explants Induces Multiple Time-dependent Gene Expression Patterns and Involves Intracellular Calcium and Cyclic AMP

“…Intracellular calcium release, cAMP, and the phospholipase C pathway have been implicated for aggrecan gene up-regulation in response to static compression in cartilage explants (25). Static compression also increased ERK1/2 phosphorylation within minutes of application, with sustained increases during 24 h of compression (26). Although such signaling pathways have been identified in the mechanical regulation of aggrecan gene expression, less is known about chondrocyte gene expression patterns of other ECM-related molecules or whether common upstream signaling pathways are responsible for their regulation.…”