Fibroblast Growth Factors and Cellular Communication Network Factors: Intimate Interplay by the Founding Members in Cartilage

Abstract

Fibroblast growth factors (FGFs) constitute a large family of signaling molecules that act in an autocrine/paracrine, endocrine, or intracrine manner, whereas the cellular communication network factors (CCN) family is composed of six members that manipulate extracellular signaling networks. FGFs and CCNs are structurally and functionally distinct, except for the common characteristics as matricellular proteins. Both play significant roles in the development of a variety of tissues and organs, including the skeletal system. In vertebrates, most of the skeletal parts are formed and grow through a process designated endochondral ossification, in which chondrocytes play the central role. The growth plate cartilage is the place where endochondral ossification occurs, and articular cartilage is left to support the locomotive function of joints. Several FGFs, including FGF-2, one of the founding members of this family, and all of the CCNs represented by CCN2, which is required for proper skeletal development, can be found therein. Research over a decade has revealed direct binding of CCN2 to FGFs and FGF receptors (FGFRs), which occasionally affect the biological outcome via FGF signaling. Moreover, a recent study uncovered an integrated regulation of FGF and CCN genes by FGF signaling. In this review, after a brief introduction of these two families, molecular and genetic interactions between CCN and FGF family members in cartilage, and their biological effects, are summarized. The molecular interplay represents the mutual involvement of the other in their molecular functions, leading to collaboration between CCN2 and FGFs during skeletal development.

Keywords: CCN2; cartilage; cellular communication network factor; fibroblast growth factor; skeletal development.

Figure 1

Two major modes of the ossification that constructs the human skeleton. Clavicle and cranial bones are formed through intramembranous ossification, where osteoblasts create the prototype (left) and grow the bone (shown in pink). Most of the other bones are initially formed by chondrocytes as cartilage anlagen (left, shown in light blue), and chondrocytes grow them at the growth plate inside and develop articular cartilage at the epiphysis. Along with bone growth, ECM is mineralized by osteoblasts. In the growth plate, chondrocytes follow a serial differentiation process from resting (R), proliferation (P), mature (M), and hypertrophic (H) stages towards ossification (bottom).

Figure 2

Molecular structure of CCN2 and its interactions with canonical FGFs and their receptors. Tetra-modular structure of CCN2 with a signal peptide for secretion (black triangle) and a hinge domain (wavy line between V and T) is illustrated at the middle of the top. I, V, T, and C represent insulin-like growth factor binding protein-like (IGFBP), von Willebrand factor type C repeat (VWC), thrombospondin 1 type 1 repeat (TSP1), and C-terminal cystine knot (CT) modules, respectively. Bi-directional arrows denote direct binding between the two. Out of four FGF receptors, FGFR1, -2 and -3 are all known to bind to CCN2.

Figure 3

Multimolecular interactions among FGF-2, FGFR1, CCN2, and its single modular sub fragment. Activated form of FGFR1 is represented by stars in red, whereas silent form is represented by spheres in light blue. Letters indicate the same modules defined in Figure 2, with the exception of F, which denotes FGF-2.

Figure 4

Integrated bidirectional regulation of FGF1 and CCN2 by the FGF signal in chondrocytes. Canonical FGF signaling emitted by FGF-1 induces FOXA1 to activate FGF1 and repress CCN2 simultaneously. Activation of FGF1 results in the formation of a positive feedback loop to amplify the outcome of this bipartite regulation. Synergistic cartilage degeneration would be induced by enhancing the catabolic effects of the FGF signal and repressing the anabolic effects of CCN2. Objects on FGF1 and CCN2 stand for transcriptional co-activator and co-repressor, respectively.