RANK ligand signaling modulates the matrix metalloproteinase-9 gene expression during osteoclast differentiation

Sundaram, Kumaran; Nishimura, Riko; Senn, Joseph J.; Youssef, Rimon F.; London, Steven D.; Reddy, Sakamuri V.

doi:10.1016/j.yexcr.2006.10.001

Cited by 192 publications

(152 citation statements)

References 49 publications

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“…NMP Suppresses RANKL-induced MMP-9 and Cathepsin KThe bone resorption-related enzymes MMP-9 and cathepsin K are highly expressed in osteoclastic cells and play an important role in skeletal remodeling (22,23). Therefore, we investigated the effect of NMP on the expression of MMP-9 and cathepsin K expression (Fig.…”

Section: Resultsmentioning

confidence: 99%

Inhibition of Osteoclast Differentiation and Bone Resorption by N-Methylpyrrolidone

Ghayor

Correro

Lange

et al. 2011

Journal of Biological Chemistry

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Regulation of RANKL (receptor activator of nuclear factor B ligand)-induced osteoclast differentiation is of current interest in the development of antiresorptive agents. Osteoclasts are multinucleated cells that play a crucial role in bone resorption. In this study, we investigated the effects of N-methylpyrrolidone (NMP) on the regulation of RANKL-induced osteoclastogenesis. NMP inhibited RANKL-induced tartrate-resistant acid phosphatase activity and the formation of tartrate-resistant acid phosphatase-positive multinucleated cells. The RANKL-induced expression of NFATc1 (nuclear factor of activated T cells, cytoplasmic 1) and c-Fos, which are key transcription factors for osteoclastogenesis, was also reduced by treatment with NMP. Furthermore, NMP induced disruption of the actin rings and decreased the mRNAs of cathepsin K and MMP-9 (matrix metalloproteinase-9), both involved in bone resorption. Taken together, these results suggest that NMP inhibits osteoclast differentiation and attenuates bone resorption. Therefore, NMP could prove useful for the treatment of osteoporosis or other bone diseases associated with excessive bone resorption.Bone remodeling is a physiological process that involves the resorption and synthesis of bone by osteoclasts and osteoblasts, respectively (1, 2). Osteoclasts are known to be formed by the fusion of hematopoietic cells of the monocyte-macrophage lineage during the early stage of the differentiation process (3). This process consists of multiple steps, including differentiation of osteoclast precursors into mononuclear osteoclasts, fusion of mononuclear preosteoclasts into mature multinucleated osteoclasts, and activation of osteoclasts to resorb bone (4 -7). The terminal differentiation in this lineage is characterized by acquisition of mature phenotypic markers such as expression of tartrate-resistant acid phosphatase (TRAP), 2 the calcitonin receptor, MMP-9, and cathepsin K, as well as morphological conversion into large multinucleated cells and the ability to form resorption lacunae on bone (8 -10). The essential signaling molecules for osteoclast differentiation include RANKL and M-CSF (macrophage colony-stimulating factor) in bone marrow-derived macrophage precursor cells (11,12).RANKL is a member of the TNF superfamily that is expressed in osteoblasts. It interacts with the osteoclast cell surface receptor RANK, which in turn recruits TNF receptor-associated factors and plays a crucial role in the osteoclast differentiation axis (13,14). The downstream intracellular signaling mediated by RANK in osteoclast progenitor cells includes TRAF6 (TNF receptor-associated factor 6)-dependent activation of NF-B via the IB kinase complex and MAPKs such as ERK, p38 MAPK, and JNK (7,11,15). In addition, RANKL induces the key transcription factors for osteoclastogenesis, NFATc1 and c-Fos (9, 16, 17). Therefore, chemical or natural compounds that specifically inhibit these steps could be developed as antiresorptive drugs for the treatment of metabolic bone disorders characterized by e...

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Section: Resultsmentioning

confidence: 99%

Inhibition of Osteoclast Differentiation and Bone Resorption by N-Methylpyrrolidone

Ghayor

Correro

Lange

et al. 2011

Journal of Biological Chemistry

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“…RANKL and CXCR5 mRNA expression levels were measured by real-time RT-PCR as described earlier (12). Briefly, total RNA was isolated from FREV (human B lymphocyte cell line), SCC1, SCC12, and SCC14a cells treated with or without different concentrations of CXCL13 (0-25 ng/mL) for 48 h using RNAzol reagent (Biotecx Laboratories).…”

Section: Quantitative Real-time Rt-pcrmentioning

confidence: 99%

“…NFAT proteins autoregulate and cooperate with the activator protein (c-Jun/Fos) transcription factors at the cellular level (11). Several genes associated with osteoclast development/bone resorbing activity such as tartrate-resistant acid phosphatase, matrix metalloproteinase 9, OSCAR, calcitonin receptor, and cathepsin K have been shown to be modulated by NFATc1 (10,12). Recently, NFATc1 and NFATc3 were reported to increase osterix transcription activity upon coexpression with PIASxβ in osteoblast cells (13).…”

Section: Introductionmentioning

confidence: 99%

A Novel Function of CXCL13 to Stimulate RANK Ligand Expression in Oral Squamous Cell Carcinoma Cells

Sambandam

Griffin

Sundaram

et al. 2009

Molecular Cancer Research

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Oral squamous cell carcinomas (OSCC) are malignant tumors with a potent activity of local bone invasion/ osteolysis. The chemokine ligand, CXCL13, has been identified as a prognostic marker for OSCC development and progression. Here in, we show that recombinant hCXCL13 treatment of OSCC cells stimulates (5-fold) RANK ligand (RANKL), a critical bone resorbing osteoclastogenic factor expression. Anti-CXCR5 chemokine receptor antibody abrogates CXCL13-induced RANKL expression in these cells. Also, CXCL13 stimulated (3.0-fold) hRANKL gene promoter activity in SCC14a cells. SuperArray screening for transcription factors by real-time RT-PCR identified significant increase in the levels of c-Jun and NFATc3 mRNA expression in CXCL13-stimulated OSCC cells. CXCL13 treatment significantly increased (3.5-fold) phospho-c-Jun levels in these cells and a c-Jun-NH 2 -kinase inhibitor abolished CXCL13-stimulated RANKL expression. Furthermore, we show that CXCL13 stimulation induced nuclear translocation of NFATc3 in OSCC cells. Chromatinimmune precipitation assay confirmed NFATc3 binding to the RANKL promoter region. We also show that overexpression of NFATc3 stimulates RANKL expression/ promoter activity and that siRNA suppression of NFATc3 abolished CXCL13-stimulated RANKL expression. Thus, our results suggest that NFATc3 is a downstream target of the CXCL13/CXCR5 axis to stimulate RANKL expression in OSCC cells and implicates CXCL13 as a potential therapeutic target to prevent OSCC bone invasion/

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“…We witnessed a significantly down-regulated expression of DC-STAMP in about threefold in FAtreated cells. Moreover, FA inhibited the RANKLinduced up-regulation of MMP-9 and cathepsin K, both of which are highly expressed in osteoclastic cells and play a crucial role in skeletal remodeling (Costa et al 2011;Sundaram et al 2007). Accumulating lines of evidence suggest that CTSK activity is vital for the initial actin ring formation and activation of osteoclasts (Wilson et al 2009).…”

Section: Discussionmentioning

confidence: 99%

“…Binding of RANKL to its receptor RANK on osteoclast precursor cells induces the activation of multiple intracellular signaling pathways involving MAP kinases and NFkB that are necessary for osteoclast differentiation (Wada et al 2006). When stimulated with RANKL, osteoclast precursor cells express high levels of osteoclast-associated genes such as DC-STAMP, required for osteoclast fusion; and tartrate-resistant acid phosphatase (TRAP) and metalloproteinase-9 (MMP-9), the two key lysosomal proteases that aid osteoclasts in bone matrix resorption (Cappariello et al 2014;Sundaram et al 2007;Yagi et al 2005).…”

Section: Introductionmentioning

confidence: 99%

Ferulic acid impairs osteoclast fusion and exacerbates survival of mature osteoclasts

et al. 2016

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Elevated bone loss induced by osteoclasts is a critical and most commonly observed pathological complication during osteolytic diseases such as osteoporosis. Hence, attenuation of osteoclast formation or function is a classical therapeutic approach to regulate bone loss. In this study, we found that ferulic acid (FA), a natural compound potently inhibited osteoclast formation in human CD14? peripheral blood monocytes ex vivo with an IC 50 of 39 lM. Moreover, due to impaired differentiation of osteoclast progenitors, actin ring formation and bone resorption activity were also perturbed. Investigation of underlying molecular mechanisms revealed that FA inhibited the RANKLinduced expression of dendritic cell-specific transmembrane protein (DC-STAMP), a critical regulator of osteoclast fusion. In addition, expression of matrix metalloproteinase-9 (MMP-9) and cathepsin K, the key osteoclast specific lysosomal proteases involved in bone matrix resorption were severely aggravated by FA. A significant reduction in mature osteoclast numbers was detected in the presence of FA accompanied by increased caspase-3 activity and DNAfragmentation, a characteristic hallmark of apoptosis. Collectively, these results suggested that FA inhibited osteoclast fusion by suppressing the expression of DC-STAMP and induced apoptosis in mature osteoclasts by the caspase-3 pathway.

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RANK ligand signaling modulates the matrix metalloproteinase-9 gene expression during osteoclast differentiation

Cited by 192 publications

References 49 publications

Inhibition of Osteoclast Differentiation and Bone Resorption by N-Methylpyrrolidone

Inhibition of Osteoclast Differentiation and Bone Resorption by N-Methylpyrrolidone

A Novel Function of CXCL13 to Stimulate RANK Ligand Expression in Oral Squamous Cell Carcinoma Cells

Ferulic acid impairs osteoclast fusion and exacerbates survival of mature osteoclasts

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