Connective tissue growth factor (CTGF) is a secreted, extracellular matrix-associated protein that regulates diverse cellular functions including proliferation, adhesion, migration, differentiation, matrix production and survival. In a study examining differential gene expression in bone from normal and osteopetrotic rats, we discovered that CTGF mRNA was expressed in normal bone. Subsequent studies demonstrated that CTGF is produced and secreted by osteoblasts. Recombinant rat CTGF (rCTGF) was generated and used to examine its effects on osteoblasts in culture. In addition to its effect as a mitogen, rCTGF stimulated functions associated with osteoblast differentiation including alkaline phosphatase activity, osteocalcin gene expression and mineralization. Using a local injection model to test its anabolic effect in vivo, rCTGF induced a potent osteogenic response. The finding that CTGF knockout mice have a skeletal phenotype including severe osteopenia highlights the important role that this growth factor plays in osteoblast development and bone formation. We hypothesize that CTGF is an anabolic bone growth factor. We propose that CTGF is synthesized and secreted by osteoblasts, where it acts as an ECM-associated signaling molecule or a soluble factor to promote osteoblast differentiation and function in an autocrine fashion. Experiments proposed in this application will focus on the association between CTGF and bone with the following aims. Experiments in aim 1 will provide a more comprehensive evaluation of the effects of rCTGF on osteoblast development and function in vitro and bone formation in vivo. Studies in aim 2 will characterize rCTGF binding to osteoblasts and determine whether integrins serve as receptors for CTGF on osteoblasts. The morphological, cytoskeletal and signaling responses of osteoblasts adhered to immobilized rCTGF will also be examined.
In aim 3, studies will examine whether specific effects of TGF-beta1 and BMP-2 on osteoblast proliferation/differentiation are CTGF-dependent, and determine whether selected regulatory elements of the CTGF promoter are necessary for transcriptional activation by TGF-beta1 and/or BMP- 2. Experiments in the first part of aim 4 will characterize the skeletal phenotype in CTGF null (-/-) mice and examine the ability of -/- osteoblasts to differentiate in vitro. In the final part of this aim we propose to generate transgenic mice expressing CTGF under control of the osteocalcin promoter and evaluate whether osteoblast-specific expression has an anabolic effect on bone. The identification of a novel anabolic agent in bone and its mechanisms of action will eventually lead to the development of new therapeutic strategies to selectively stimulate osteogenesis in diseases associated with bone loss and in fracture repair.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
Project #
Application #
Study Section
Oral Biology and Medicine Subcommittee 1 (OBM)
Program Officer
Sharrock, William J
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Temple University
Anatomy/Cell Biology
Schools of Medicine
United States
Zip Code
Hendesi, Honey; Barbe, Mary F; Safadi, Fayez F et al. (2015) Integrin mediated adhesion of osteoblasts to connective tissue growth factor (CTGF/CCN2) induces cytoskeleton reorganization and cell differentiation. PLoS One 10:e0115325
Mundy, Christina; Gannon, Maureen; Popoff, Steven N (2014) Connective tissue growth factor (CTGF/CCN2) negatively regulates BMP-2 induced osteoblast differentiation and signaling. J Cell Physiol 229:672-81
Lambi, Alex G; Pankratz, Talia L; Mundy, Christina et al. (2012) The skeletal site-specific role of connective tissue growth factor in prenatal osteogenesis. Dev Dyn 241:1944-59
Arnott, John A; Lambi, Alex G; Mundy, Christina et al. (2011) The role of connective tissue growth factor (CTGF/CCN2) in skeletogenesis. Crit Rev Eukaryot Gene Expr 21:43-69
Zhang, X; Arnott, J A; Rehman, S et al. (2010) Src is a major signaling component for CTGF induction by TGF-beta1 in osteoblasts. J Cell Physiol 224:691-701
Arnott, J A; Zhang, X; Sanjay, A et al. (2008) Molecular requirements for induction of CTGF expression by TGF-beta1 in primary osteoblasts. Bone 42:871-85
Rico, Mario C; Castaneda, Julian L; Manns, Joanne M et al. (2007) Amelioration of inflammation, angiogenesis and CTGF expression in an arthritis model by a TSP1-derived peptide treatment. J Cell Physiol 211:504-12
Song, Jason J; Aswad, Rulla; Kanaan, Reem A et al. (2007) Connective tissue growth factor (CTGF) acts as a downstream mediator of TGF-beta1 to induce mesenchymal cell condensation. J Cell Physiol 210:398-410
Arnott, J A; Nuglozeh, E; Rico, M C et al. (2007) Connective tissue growth factor (CTGF/CCN2) is a downstream mediator for TGF-beta1-induced extracellular matrix production in osteoblasts. J Cell Physiol 210:843-52
Manns, Joanne M; Uknis, Audrey B; Rico, Mario C et al. (2006) A peptide from thrombospondin 1 modulates experimental erosive arthritis by regulating connective tissue growth factor. Arthritis Rheum 54:2415-22

Showing the most recent 10 out of 11 publications