Identification and Cloning of a Connective Tissue Growth Factor-like cDNA from Human Osteoblasts Encoding a Novel Regulator of Osteoblast Functions

Kumar, Sanjay; Hand, Annalisa T.; Connor, J.T.H.; Dodds, Robert A.; Ryan, P. J.; Trill, John J.; Fisher, Seth; Nuttall, Mark; Lipshutz, David B.; Zou, Cheng; Hwang, Shing Mei; Votta, Bartholomew J.; James, Ian E.; Rieman, David J.; Gowen, Maxine; Lee, John C.

doi:10.1074/jbc.274.24.17123

Cited by 95 publications

(89 citation statements)

References 34 publications

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“…CCN5 has also been described in human fetal bone (Kumar et al 1999); human pancreas (Dhar et al 2007); and breast ductal and lobular epithelium (Banerjee et al 2003). CCN5 protein and mRNA has also been detected in numerous cultured cells and tissue specimens using Western and Northern blots, respectively (summarized in Gray and Castellot 2004).…”

Section: Discussionmentioning

confidence: 99%

“…Studies of CCN5 mRNA expression by Northern blot, in situ hybridization (ISH), and quantitative polymerase chain reaction (Q-PCR) indicate that additional sites of CCN5 mRNA expression might include adult brain, heart, lung, colon, prostate gland, testis, ovary, skeletal muscle, and most cell types in bone (Delmolino et al 2001;Kumar et al 1999;Pennica et al 1998).…”

Section: Introductionmentioning

confidence: 99%

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CCN5 Expression in mammals. II. Adult rodent tissues

Gray

Malmquist

Sullivan

et al. 2007

J. Cell Commun. Signal.

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CCN5 is a secreted heparin-and estrogenregulated matricellular protein that inhibits vertebrate smooth muscle cell proliferation and motility. CCN5 is expressed throughout murine embryonic development in most organs and tissues. However, after embryonic development is complete, we hypothesized that CCN5 distribution would be largely restricted to small set of tissues, including smooth muscle cells of the arteries, uterus, airway, and digestive tract. Because CCN5 inhibits proliferation of smooth muscle cells in vitro, it might function to prevent excessive growth in vivo. In contrast, another member of the CCN family, CCN2, promotes smooth muscle cell proliferation in vitro, and thus it was expected that its expression levels would be low in uninjured normal adult tissues. Frozen sections from adult tissues and organs were analyzed immunohistochemically using anti-CCN5 and anti-CCN2 antibodies. Both proteins were detected in arteries, the uterus, bronchioles, and the digestive tract as expected, and also in many other tissues including the pancreas, spleen, liver, skeletal muscle, ovary, testis, thymus, brain, olfactory epithelium, and kidney. CCN5 and CCN2 protein was found in smooth muscle, endothelial cells, epithelial cells, skeletal muscle, cells of the nervous system, and numerous other cell types. In many cells, both CCN5 and CCN2 was present in the nucleus. Rather than having opposite patterns of localization, CCN5 and CCN2 often had similar sites of expression. The wide distribution of both CCN5 and CCN2 suggests that both proteins have additional biological functions beyond those previously identified in specific cellular and pathological models.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

CCN5 Expression in mammals. II. Adult rodent tissues

Gray

Malmquist

Sullivan

et al. 2007

J. Cell Commun. Signal.

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“…The abbreviation`CCN' stands for the assemblage of the names of the original members ± ctgf, cef10 and nov. Recently in addition to these, several other genes, such as ctgf-3/ctgf-L/wisp-2/ cop1, wisp-1/elm1, and wisp-3, have been discovered, and newly classi®ed as members of this gene family (Hashimoto et al, 1998;Zhang et al, 1998;Kumar et al, 1999). They are characterized by conserved cysteine residues and modular structure with four distinct domains in primary sequences.…”

Section: Introductionmentioning

confidence: 99%

Identification of an RNA element that confers post-transcriptional repression of connective tissue growth factor/hypertrophic chondrocyte specific 24 (ctgf/hcs24) gene: Similarities to retroviral RNA-protein interactions

et al. 2000

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“…IL-11 stimulates osteoclastic bone resorption by increasing osteoblast production of RANKL. Connective tissue growth factor (CTGF) increases osteoblast proliferation (Kumar et al 1999). The chemokine receptor CXCR4 binds to the osteoblast product, stromalderived factor-1 (SDF-1), to increase tumor homing to bone (Sun et al 2005).…”

Section: Bone Metastasis Genesmentioning

confidence: 99%

Breaking down bone: new insight into site-specific mechanisms of breast cancer osteolysis mediated by metalloproteinases: Figure 1.

Guise

2009

Genes Dev.

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Bone metastases are the most common skeletal complication of malignancy. Tumor cells disrupt normal bone remodeling to promote bone destruction and its associated morbidity. In the August 15, 2009, issue of Genes & Development, Lu and colleagues (pp. 1882-1894) propose a novel molecular mechanism by which tumor-produced metalloproteinases release epidermal growth factor (EGF) ligands to activate the central osteoclastogenic pathway receptor activator of NF-kB ligand (RANKL) to promote breast cancer osteolysis. This work has important therapeutic applications that may quickly translate to more effective treatment for bone metastases.Bone metastases are common in breast, prostate, and lung cancer, and are associated with significant morbidity. Unique aspects of the bone microenvironment-such as mineralized bone matrix, which houses immobilized growth factors, bone-destroying osteoclasts, and boneforming osteoblasts-make it a fertile soil for these cancers to grow. Significant insight into the molecular mechanisms responsible for the proclivity of tumors to metastasize and grow in bone has been gleaned in recent years from mouse models and clinical studies. Bone destruction mediated by solid tumor metastases to bone, particularly in breast cancer, is driven by tumor stimulation of osteoclastic bone resorption. Collective evidence supports the notion that effective therapy for bone metastases should target both the tumor and the bone microenvironment. Indeed, bisphosphonate therapy to block osteoclastic bone resorption, used in conjunction with standard anti-cancer treatments, reduces bone pain, pathologic fracture, and hypercalcemia associated with bone metastases from all tumor types. However, regression and cure of bone metastases have yet to be achieved with the current therapeutic armamentarium. Thus, a better understanding of the molecular mechanisms responsible for this devastating skeletal complication of malignancy is required to develop more effective therapy, with the eventual goal of curing and preventing bone metastases. In the August 15, 2009, issue of Genes & Development, Lu et al. (2009) bring the field closer to this goal. They describe an autocrine/paracrine signaling cascade triggered by metalloproteinases-matrix metalloproteinase-1 (MMP-1) and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS1)-and cleavage of epidermal growth factor (EGF) ligands to reduce the ratio of osteoblast-produced receptor activator of NF-kB ligand (RANKL) to osteoprotegerin (OPG) to favor osteoclastogenesis and promote breast cancer osteolysis. These studies, described herein, have important implications for new applications of standard cancer therapy that could result in more effective treatment for bone metastases. Bone metastases: clinical features and current therapyCertain solid tumors-such as breast, prostate, and lung cancer-have a propensity to metastasize to bone to cause bone pain, fracture, hypercalcemia, and paralysis. This morbidity is great: Up to 75% of advanced breast and prostate c...

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Identification and Cloning of a Connective Tissue Growth Factor-like cDNA from Human Osteoblasts Encoding a Novel Regulator of Osteoblast Functions

Cited by 95 publications

References 34 publications

CCN5 Expression in mammals. II. Adult rodent tissues

CCN5 Expression in mammals. II. Adult rodent tissues

Identification of an RNA element that confers post-transcriptional repression of connective tissue growth factor/hypertrophic chondrocyte specific 24 (ctgf/hcs24) gene: Similarities to retroviral RNA-protein interactions

Breaking down bone: new insight into site-specific mechanisms of breast cancer osteolysis mediated by metalloproteinases: Figure 1.

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