Signaling pathway leading to chondrogenesis of mesenchymal cells

다국어 초록 (Multilingual Abstract)

Chondrocytes are differentiated from a mesenchymal cell population. The chick limb bud mesenchymal cells have been widely used as a model system to study chondrogenic differentiation. Dissociated chick limb bud mesenchymal cells spontaneously differentiate into chondrocytes when maintained as micromass culture by plating at high density. Chondrogenic differentiation during in vitro micromass culture requires extensive cell-cell and cell-extracellular matrix interactions to induce precartilage condensation. The precartilage condensation subsequently differentiates into cartilage nodules in which differentiated chondrocytes are located, surrounded by the cartilage-specific ECM components such as type Ⅱ collagen and aggrecan. Several cell adhesion molecules such as N-cadherin, integrins, and matrix components including fibronectin, type Ⅰ collagen, laminin, and tenascin are known to regulate precartilage condensation as well as formation of cartilage nodules.
The induction and regulation of chondrogenesis is exerted by protein kinase signaling cascades which include protein kinase C(PKC), mitogen-activated protein(MAP) kinase subtyes ERK and p38, protein kinase A(PKA), p70 S6 kinase, phosphatidylinositol (PI) 3-kinase, etc. PKC positively regulates chondrogenesis of mesenchymal cells. Among the expressed PKC isoforms, increase in expression and activation of PKCα is essential for chondrogenesis. PKC regulated both cell proliferation and expression of cell adhesion molecules. PKC-dependent regulation of chondrogenesis is exerted by inhibiting ERK-1/2 signaling. Activity of p38 MAP kinase is increased during chondrogenesis in a PKC-independent manner, and inhibition of p38 MAP kinase activity blocked chondrogenesis. p38 and Erk-1/2 MAP kinase subtypes thus acted as positive and negative regulator of chondrogenesis, respectively, by conversely regulating the expression of cell adhesion molecules at post-precartilage condensation stage. Activity of PKCα is positively regulated by PKA signaling. p70 S6 kinase, that is activated by PI 3-kinase and mTOR, also positively regulates PKCα as well as p38 MAP kinase. In contrast, epidermal growth factor signaling that inhibits chondrogenesis negatively regulates PKCα, ERK, and p38 signaling pathways.