The Role of Connective Tissue Growth Factor (CTGF/CCN2) in Skeletogenesis

Abstract

Connective tissue growth factor (CTGF) is a 38kDa, cysteine rich, extracellular matrix protein composed of four domains or modules. CTGF has been shown to regulate a diverse array of cellular functions and has been implicated in more complex biological processes such as angiogenesis, chondrogenesis, and osteogenesis. A role for CTGF in the development and maintenance of skeletal tissues first came to light in studies demonstrating its expression in cartilage and bone cells which was dramatically increased during skeletal repair or regeneration. The physiological significance of CTGF in skeletogenesis was confirmed in CTGF-null mice, which exhibited multiple skeletal dysmorphisms as a result of impaired growth plate chondrogenesis, angiogenesis, and bone formation/mineralization. Given the emerging importance of CTGF in osteogenesis and chondrogenesis, this review will focus on its expression in skeletal tissues, its effects on osteoblast and chondrocyte differentiation and function, and the skeletal implications of ablation or over-expression of CTGF in knockout or transgenic mouse models, respectively. In addition, this review will examine the role of integrin-mediated signaling and the regulation of CTGF expression as it relates to skeletogenesis. We will emphasize CTGF studies in bone or bone cells, and will identify opportunities for future investigations concerning CTGF and chondrogenesis/osteogenesis.

Connective Tissue Growth Factor Regulates Retinal Neovascularization through p53 Protein-dependent Transactivation of the Matrix Metalloproteinase (MMP)-2 Gene

“…Genetic modification of CTGF/CCN2 gene expression in mice provided some preliminary but controversial information on the role of CTGF/CCN2 during tissue development and diseases. The traditional knockout of CTGF/CCN2 resulted in perinatal lethality due to skeletal deformity, a phenotype similarly observed in knock-out mice for constitutively expressed ECM proteins, such as the collagens and proteoglycans, suggesting a possible regulatory relationship between CTGF/CCN2 and other ECM proteins (23,24). However, transgenic models of CTGF/CCN2 overproduction in various tissues exhibited various phenotypes, including no fibrotic reaction, mild fibrosis, and clear fibrotic phenotypes depending on the CTGF/CCN2 levels (25).…”

CTGF Mediates Smad-Dependent Transforming Growth Factor β Signaling To Regulate Mesenchymal Cell Proliferation during Palate Development

“…CTGF is a member of the CCN family of matricellular proteins and as such is a contextual modulator of a diverse array of cellular functions (54,55). CTGF has been implicated in complex biological processes such as angiogenesis, chondrogenesis, and osteogenesis, as well as fibrosis and tumorigenesis (22,54).…”

“…CTGF is a member of the CCN family of matricellular proteins and as such is a contextual modulator of a diverse array of cellular functions (54,55). CTGF has been implicated in complex biological processes such as angiogenesis, chondrogenesis, and osteogenesis, as well as fibrosis and tumorigenesis (22,54). Specifically, CTGF induces proliferation in diverse cell types, including chondrocytes (56,57), osteoblasts (51), human bone marrow stromal cells (58), lung fibroblasts (59), and beta cells (60), among others.…”

AML-induced osteogenic differentiation in mesenchymal stromal cells supports leukemia growth

“…CTGF is known to be overexpressed in acute leukemia and has been shown to be a poor prognosis factor in acute lymphoid leukemia (18). It is one of the most highly expressed genes during osteogenic differentiation (26,27), and its expression has been shown to be induced by BMP signaling in MSCs (24). To validate whether AML cells induce CTGF expression in MSCs, we cultured N-MSCs (n = 3) in the presence or absence of OCI-AML3 cells ( Figure 5E) or OCI-AML3-CM ( Figure 5F) for 5 days.…”