1,25 (OH)2 Vitamin D3-Stimulated Osteoclast Formation in Spleen-Osteoblast Cocultures Is Mediated in Part by Enhanced IL-1α and Receptor Activator of NF-κB Ligand Production in Osteoblasts

Lee, Sun-Kyeong; Kalinowski, Judy; Jastrzebski, Sandra; Lorenzo, Joseph

doi:10.4049/jimmunol.169.5.2374

Cited by 59 publications

(44 citation statements)

References 66 publications

(34 reference statements)

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“…Thus, CXCL13 may have a paracrine role in regulating RANKL expression in osteoblast and other cell types in the tumor-bone microenvironment. Several osteotropic factors/resorption stimuli including 1,25-(OH) 2 D 3 , parathyroid hormone (PTH), IL-1β, IL-11, and prostaglandin E2 have been shown to up-regulate RANKL expression on marrow stromal/osteoblast cells (23)(24)(25). OSCC showed mRNA expression of osteotropic cytokines such as IL-6, tumor necrosis factor α, and PTHrP (26).…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…A variety of cells in the bone microenvironment, including monocyte/macrophages, osteoblasts, and osteoclasts, can synthesize IL-1 (10,11). Although IL-1 has been known to stimulate osteoclast formation by increasing the production of prostaglandin E 2 (PGE 2 ) and the ratio of RANKL:OPG in osteoblasts and stromal cells (9,12), the relationship of the two factors in IL-1-induced osteoclast formation has not been clearly elucidated.…”

mentioning

confidence: 99%

α-Lipoic Acid Inhibits Inflammatory Bone Resorption by Suppressing Prostaglandin E2 Synthesis

Lee

Kim

et al. 2006

The Journal of Immunology

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α-Lipoic acid (LA) has been intensely investigated as a therapeutic agent for several pathological conditions, including diabetic polyneuropathy. In the present study, we examined the effects of LA on osteoclastic bone loss associated with inflammation. LA significantly inhibited IL-1-induced osteoclast formation in cocultures of mouse osteoblasts and bone marrow cells, but LA had only a marginal effect on osteoclastogenesis from bone marrow macrophages induced by receptor activator of NF-κB ligand (RANKL). LA inhibited both the sustained up-regulation of RANKL expression and the production of PGE2 induced by IL-1 in osteoblasts. In addition, treatment with either prostaglandin E2 (PGE2) or RANKL rescued IL-1-induced osteoclast formation inhibited by LA or NS398, a specific cyclooxygenase-2 (COX-2) inhibitor, in cocultures. LA blocked IL-1-induced PGE2 production even in the presence of arachidonic acid, without affecting the expression of COX-2 and membrane-bound PGE2 synthase. Dihydrolipoic acid (the reduced form of LA), but not LA, attenuated recombinant COX-2 activity in vitro. LA also inhibited osteoclast formation and bone loss induced by IL-1 and LPS in mice. Our results suggest that the reduced form of LA inhibits COX-2 activity, PGE2 production, and sustained RANKL expression, thereby inhibiting osteoclast formation and bone loss in inflammatory conditions.

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“…Several osteotropic factors/resorption stimuli including 1,25-(OH) 2 D 3 , parathyroid hormone (PTH), IL-1b, IL-11 and prostaglandin E2 (PGE2) have been shown to upregulate RANKL expression on marrow stromal/osteoblast cells. 6,7,29 Abnormal OCLs in PDB are characterized by expression of MVNP transcripts and shown to produce high levels of IL-6. 5 However, IL-6 increases RANKL expression in murine systems but does not induce RANKL expression in human marrow stromal cells or osteoblasts.…”

Section: Discussionmentioning

confidence: 99%

“…5 Receptor activator for nuclear factor-kB ligand (RANKL) is expressed by marrow stromal/osteoblast cells in response to several osteotropic factors such as 1,25 dihydroxy vitamin D 3 , parathyroid hormone (PTH), prostaglandin E 2 and interleukin 1b (IL-1b). [6][7][8] RANKL-RANK signaling is critical for osteoclast differentiation/bone resorption activity. Enhanced levels of RANKL are associated with PDB.…”

mentioning

confidence: 99%

CXCL5 stimulation of RANK ligand expression in Paget's disease of bone

Sundaram¹,

Rao

Ries

et al. 2013

Laboratory Investigation

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Paget's disease of bone (PDB) is a chronic focal skeletal disorder that affects 2-3% of the population over 55 years of age. PDB is marked by highly localized areas of bone turnover with increased osteoclast activity. Evidence suggests a functional role for measles virus nucleocapsid protein (MVNP) in the pathogenesis of PDB. In the present study, we identified elevated levels (B180-fold) of CXCL5 mRNA expression in bone marrow cells from patients with PDB compared with that in normal subjects. In addition, CXCL5 levels are increased (five-fold) in serum samples from patients with PDB. Furthermore, MVNP transduction in human bone marrow monocytes significantly increased CXCL5 mRNA expression. Realtime PCR analysis showed that CXCL5 stimulation increased (6.8-fold) RANKL mRNA expression in normal human bone marrow-derived stromal (SAKA-T) cells. Moreover, CXCL5 increased (5.2-fold) CXCR1 receptor expression in these cells. We further showed that CXCL5 treatment elevated the expression levels of phospho-ERK1/2 and phospho-p38. CXCL5 also significantly increased phosphorylation of CREB (cAMP response element-binding) in bone marrow stromal/preosteoblast cells. Chromatin immuneprecipitation (ChIP) assay confirmed phospho-CREB binding to RANKL gene promoter region. Further, the suppression of p-CREB expression by the inhibitors of ERK1/2, p38 and PKA significantly decreased CXCL5 stimulation of hRANKL gene promoter activity. Thus, our results suggest that CREB is a downstream effector of CXCL5 signaling and that increased levels of CXCL5 contribute to enhanced levels of RANKL expression in PDB. Paget's disease of bone (PDB) is characterized by highly localized areas of bone turnover with increased osteoclast (OCL) activity followed by poor quality new bone formation due to an exaggerated osteoblast response. Approximately 1% of patients with PDB develop osteosarcoma. 1 PDB is inherited as an autosomal dominant trait with genetic heterogeneity and affects 2-3% of the population over the age of 55 years. Both genetic and environmental factors are involved in the pathogenesis of PDB. Mutations in the ubiquitin-associated domain of sequestosome 1 (SQSTM1/p62) have been identified at 40% in familial and 10% in sporadic cases. 2 Environmental factors such as paramyxoviruses are implicated in PDB. 3 We have previously detected the expression of measles virus nucleocapsid (MVNP) transcripts in OCL from patients with PDB. 4 Moreover, the expression of MVNP in OCL precursors develops pagetic OCL in mice. 5 Receptor activator for nuclear factor-kB ligand (RANKL) is expressed by marrow stromal/osteoblast cells in response to several osteotropic factors such as 1,25 dihydroxy vitamin D 3 , parathyroid hormone (PTH), prostaglandin E 2 and interleukin 1b (IL-1b). 6-8 RANKL-RANK signaling is critical for osteoclast differentiation/bone resorption activity. Enhanced levels of RANKL are associated with PDB. 9,10 In addition, elevated levels of IL-6, macrophage colony-stimulating factor (M-CSF) and endothelin-1 have been reported in PD...

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1,25 (OH)2 Vitamin D3-Stimulated Osteoclast Formation in Spleen-Osteoblast Cocultures Is Mediated in Part by Enhanced IL-1α and Receptor Activator of NF-κB Ligand Production in Osteoblasts

Cited by 59 publications

References 66 publications

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

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

α-Lipoic Acid Inhibits Inflammatory Bone Resorption by Suppressing Prostaglandin E2 Synthesis

CXCL5 stimulation of RANK ligand expression in Paget's disease of bone

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