Biology and pathology of Rho GTPase, PI-3 kinase-Akt, and MAP kinase signaling pathways in chondrocytes

Abstract

Chondrocytes provide the framework for the developing skeleton and regulate long-bone growth through the activity of the growth plate. Chondrocytes in the articular cartilage, found at the ends of bones in diarthroidial joints, are responsible for maintenance of the tissue through synthesis and degradation of the extracellular matrix. The processes of growth, differentiation, cell death and matrix remodeling are regulated by a network of cell signaling pathways in response to a variety of extracellular stimuli. These stimuli consist of soluble ligands, including growth factors and cytokines, extracellular matrix proteins, and mechanical factors that act in concert to regulate chondrocyte function through a variety of canonical and non-canonical signaling pathways. Key chondrocyte signaling pathways include, but are not limited to, the p38, JNK and ERK MAP kinases, the PI-3 kinase-Akt pathway, the Jak-STAT pathway, Rho GTPases and Wnt-beta-catenin and Smad pathways. Modulation of the activity of any of these pathways has been associated with various pathological states in cartilage. This review focuses on the Rho GTPases, the PI-3 kinase-Akt pathway, and some selected aspects of MAP kinase signaling. Most studies to date have examined these pathways in isolation but it is becoming clear that there is significant cross-talk among the pathways and that the overall effects on chondrocyte function depend on the balance in activity of multiple signaling proteins.

Fig. 1

Rho GTPase signaling. Numerous cell surface receptors regulate the activity of guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs) which in turn control activity of Rho GTPases. GTP-bound Rho GTPases are the active forms and bind to downstream effectors, including ROCK1/2 and p38 kinases. These in turn control cellular events such as actin and microtubule dynamics, gene expression and cell cycle progression.

Fig. 2

Signaling through the PI-3 Kinase-Akt pathway. Several different types of receptors can activate PI-3 kinase-Akt signaling through upstream mediators including ILK, Src, and IRS1/2. PI-3 kinase can directly activate Akt or indirectly through activation of PDK1 via the conversion of PIP2 to PIP3 which is mediated by PI-3 kinase. Akt phosphorylates numerous downstream signaling proteins resulting in positive regulation of mTOR and negative regulation of GSK-3, FKHR, and Bad among other targets. Inhibition of PI-3 kinase-Akt signaling includes ERK1/2 and JNK1/2 inhibition of IRS-1 as well as Akt inhibition by TRB3. Not shown is the regulation of these pathways by phosphatases which include PTEN, SHP-2, and PP2A, among others.