ADAM8: A Novel Osteoclast Stimulating Factor

Choi, Sun Jin; Han, Je Ho; Roodman, G. David

doi:10.1359/jbmr.2001.16.5.814

Cited by 94 publications

(107 citation statements)

References 23 publications

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“…In agreement with these earlier studies, the novel D14 0 isoform identified in this report showed a marked increase in the induction of TRAP þ cells. Previous studies have described a 65 kDa human soluble isoform and a 70 kDa truncated murine isoform of ADAM8, structurally similar to the D14 0 isoform (Choi et al, 2001, Mandelin et al, 2003. This soluble murine ADAM8 isoform induced the formation of boneresorbing osteoclasts and acted at later stages of osteoclast differentiation and precursor fusion (Choi et al, 2001).…”

Section: Discussionmentioning

confidence: 90%

“…Previous studies have described a 65 kDa human soluble isoform and a 70 kDa truncated murine isoform of ADAM8, structurally similar to the D14 0 isoform (Choi et al, 2001, Mandelin et al, 2003. This soluble murine ADAM8 isoform induced the formation of boneresorbing osteoclasts and acted at later stages of osteoclast differentiation and precursor fusion (Choi et al, 2001). The fact that this murine form was structurally and functionally related to the D14 0 isoform, which also exhibited a similar pro-osteoclastogenic effect, emphasizes the relevance of ADAM8 in osteoclastogenesis (Choi et al, 2001, Mandelin et al, 2003, Rao et al, 2006, Verrier et al, 2004.…”

Section: Discussionmentioning

confidence: 90%

“…This soluble murine ADAM8 isoform induced the formation of boneresorbing osteoclasts and acted at later stages of osteoclast differentiation and precursor fusion (Choi et al, 2001). The fact that this murine form was structurally and functionally related to the D14 0 isoform, which also exhibited a similar pro-osteoclastogenic effect, emphasizes the relevance of ADAM8 in osteoclastogenesis (Choi et al, 2001, Mandelin et al, 2003, Rao et al, 2006, Verrier et al, 2004. This effect on osteoclast formation was mediated by the interactions between the disintegrin domain and a9b1 integrin (Rao et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

“…A soluble isoform of murine ADAM8 has been previously implicated in osteoclastogenesis (Choi et al, 2001). To examine the role of ADAM8 isoforms in osteoclastogenesis, conditioned media from cells overexpressing native ADAM8, D18a or D14 0 isoforms, were added to mouse bone marrow macrophages to study their ability to induce osteoclast formation.…”

Section: Effects Of Adam8 and Its Isoforms On Osteoclastogenesismentioning

confidence: 99%

“…Recently, it has been suggested that the expression of ADAM8 may be an early prognostic marker for lung adenocarcinomas (Ishikawa et al, 2004). It has also been shown that ADAM8 stimulates osteoclast differentiation (Choi et al, 2001). Thus, we sought to investigate the involvement of lung tumor-derived ADAM8 in the mechanisms of osteolysis and bone destruction during lung cancer metastasis to bone.…”

Section: Introductionmentioning

confidence: 99%

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Novel alternatively spliced ADAM8 isoforms contribute to the aggressive bone metastatic phenotype of lung cancer

et al. 2010

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ADAMs (a disintegrin and metalloprotease) are transmembrane proteins involved in a variety of physiological processes and tumorigenesis. Recently, ADAM8 has been associated with poor prognosis of lung cancer. However, its contribution to tumorigenesis in the context of lung cancer metastasis remains unknown. Native ADAM8 expression levels were lower in lung cancer cell lines. In contrast, we identified and characterized two novel spliced isoforms encoding truncated proteins, D18a and D14 0 , which were present in several tumor cell lines and not in normal cells. Overexpression of D18a protein resulted in enhanced invasive activity in vitro. ADAM8 and its D14 0 isoform expression levels were markedly increased in lung cancer cells, in conditions mimicking tumor microenvironment. Moreover, addition of supernatants from D14 0 -overexpressing cells resulted in a significant increase in tartrate-resistant acid phosphatase þ cells in osteoclast cultures in vitro. These findings were associated with increased pro-osteoclastogenic cytokines interleukin (IL)-8 and IL-6 protein levels. Furthermore, lung cancer cells overexpressing D14 0 increased prometastatic activity with a high tumor burden and increased osteolysis in a murine model of bone metastasis. Thus, the expression of truncated forms of ADAM8 by the lung cancer cells may result in the specific upregulation of their invasive and osteoclastogenic activities in the bone microenvironment. These findings suggest a novel mechanism of tumor-induced osteolysis in metastatic bone colonization.

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Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Effects Of Adam8 and Its Isoforms On Osteoclastogenesismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Novel alternatively spliced ADAM8 isoforms contribute to the aggressive bone metastatic phenotype of lung cancer

et al. 2010

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Glucocorticoid excess in mice results in early activation of osteoclastogenesis and adipogenesis and prolonged suppression of osteogenesis: A longitudinal study of gene expression in bone tissue from glucocorticoid‐treated mice

Yao¹,

Cheng²,

Busse³

et al. 2008

Arthritis & Rheumatism

219

181

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Objective. Glucocorticoid (GC) excess induces alterations in bone metabolism that weaken bone structure and increase fracture risk. The aim of this study was to identify genes associated with bone metabolism in GC-treated mice, by performing a microarray analysis.Methods. Long bones from mice exposed to GC excess were collected after 0, 7, 28, and 56 days of treatment, to measure bone microarchitecture and extract RNA for microarray analyses.Results. Bone loss in this animal model was confirmed by changes in bone turnover markers as well as bone architecture, as measured by microfocal computed tomography. GC excess induced an early upregulation of genes involved in osteoclast activation, function, and adipogenesis, which peaked on day 7. The expression of genes associated with osteoclast cytoskeletal reorganization and genes associated with matrix degradation peaked on day 28. On day 28 and day 56, the expression of genes associated with osteoblast activation and maturation was decreased from baseline, while the expression of Wnt antagonists was increased. In addition, the expression of genes expressed in osteocytes associated with bone mineralization was significantly higher at the later time points, day 28 and day 56. Reverse transcription-polymerase chain reaction confirmed the results of microarray analysis in selected genes.Conclusion. GC excess is associated with early activation of genes associated with osteoclastogenesis and adipogenesis and a later suppression of genes associated with osteogenesis and mineralization. Novel interventions with agents that modulate either Wnt signaling or mineralization may be effective in GCinduced osteoporosis.Glucocorticoids (GCs) are frequently prescribed for the treatment of many chronic noninfectious inflammatory disorders, including arthritis, pulmonary diseases, and skin diseases. Although GCs are potent antiinflammatory agents, long-term use results in several adverse side effects, the most common of which is bone loss, which increases the risk of fracture throughout the skeleton (1). Patients treated with GCs have been reported to have an early, rapid increase in bone resorption accompanied by a prolonged reduction in bone formation (2).The influence of GCs on bone resorption was thought to be indirect and related in part to reduced calcium absorption and increased renal calcium excretion (3). However, recent studies have shown that GCs act directly on osteoclasts to decrease apoptosis of

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Ablation of the Ccr2 gene exacerbates polyarthritis in interleukin‐1 receptor antagonist–deficient mice

Fujii¹,

Baba²,

Ishida³

et al. 2010

Arthritis & Rheumatism

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Objective. The pathogenesis of rheumatoid arthritis (RA) involves cytokines and chemokines. Given the role of intraarticular macrophage infiltration in RA, this study was undertaken to address the pathogenic role of CCR2, a chemokine receptor that is abundantly expressed by macrophages, in Il1rn-deficient mice, a mouse model of RA.Methods. Il1rn-deficient and Il1rn and Ccr2-double-deficient mice were subjected to clinical assessment of arthritis and histologic examination. Bone mineral density was measured with computed tomography. The types of cells infiltrating joints were determined by immunohistochemical analysis and flow cytometric analysis. Osteoclasts in joints were quantified after tartrate-resistant acid phosphatase staining. Cytokine and chemokine levels were measured by enzymelinked immunosorbent assay and multiplex suspension array assay. The expression patterns of chemokines and osteoclastogenic factors were determined by doublecolor immunofluorescence analysis. Anti-mouse CXCR2 antibody was injected into Il1rn and Ccr2-doubledeficient mice for blocking experiments.Results. Ablation of the Ccr2 gene actually exacerbated arthritis and intraarticular osteoclastogenesis, while it enhanced intraarticular neutrophil but not macrophage accumulation in Il1rn-deficient mice. Infiltrated neutrophils expressed the osteoclastogenic factors RANKL and ADAM-8, thereby augmenting intraarticular osteoclastogenesis in Il1rn and Ccr2-doubledeficient mice. Moreover, the double-deficient mice exhibited enhanced expression of the neutrophilic chemokines keratinocyte chemoattractant and macrophage inflammatory protein 2 (MIP-2), compared with Il1rn-deficient mice. Finally, neutralizing antibodies to CXCR2, the receptor for keratinocyte chemoattractant and MIP-2, dramatically attenuated arthritis in Il1rn and Ccr2-double-deficient mice.Conclusion. Our findings indicate that CCR2-mediated signals can modulate arthritis in Il1rn-deficient mice by negatively regulating neutrophil infiltration.

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ADAM8: A Novel Osteoclast Stimulating Factor

Cited by 94 publications

References 23 publications

Novel alternatively spliced ADAM8 isoforms contribute to the aggressive bone metastatic phenotype of lung cancer

Novel alternatively spliced ADAM8 isoforms contribute to the aggressive bone metastatic phenotype of lung cancer

Glucocorticoid excess in mice results in early activation of osteoclastogenesis and adipogenesis and prolonged suppression of osteogenesis: A longitudinal study of gene expression in bone tissue from glucocorticoid‐treated mice

Ablation of the Ccr2 gene exacerbates polyarthritis in interleukin‐1 receptor antagonist–deficient mice

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