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

Sundaram, Kumaran; Rao, D. Sudhaker; Ries, William L.; Reddy, Sakamuri V.

doi:10.1038/labinvest.2013.5

Cited by 19 publications

(15 citation statements)

References 45 publications

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“…It is possible that other CXCR2 ligands, specifically CXCL8 (IL-8) and CXCL5, could contribute to the adipocyte-induced effects on osteoclasts. Both chemokines have been shown to stimulate osteoclast differentiation and activity [27, 67, 68] and both are reported to be present in the adipose tissue; however their expression is associated primarily with non-adipose (stromal) component of fat tissue [69-71]. This suggests that marrow adipocyte-induced CXCR2 signaling in osteoclasts is likely driven by CXCL1 and CXCL2 chemokines.…”

Section: Discussionmentioning

confidence: 99%

Marrow adipocyte-derived CXCL1 and CXCL2 contribute to osteolysis in metastatic prostate cancer

Hardaway

Herroon

Rajagurubandara

et al. 2015

Clin Exp Metastasis

121

112

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Increased bone marrow adiposity is a common feature of advanced age, obesity and associated metabolic pathologies. Augmented numbers of marrow adipocytes positively correlate with dysregulated bone remodeling, also a well-established complication of metastatic disease. We have shown previously that marrow adiposity accelerates prostate tumor progression in the skeleton and promotes extensive destruction of the bone; however, the factors behind adipocyte-driven osteolysis in the skeletal tumor microenvironment are not currently known. In this study, utilizing in vivo diet-induced models of bone marrow adiposity, we reveal evidence for positive correlation between increased marrow fat content, bone degradation by ARCaP(M) and PC3 prostate tumors, and augmented levels of host-derived CXCL1 and CXCL2, ligands of CXCR2 receptor. We show by in vitro osteoclastogenesis assays that media conditioned by bone marrow adipocytes is a significant source of CXCL1 and CXCL2 proteins. We also demonstrate that both the adipocyte-conditioned media and the recombinant CXCL1 and CXCL2 ligands efficiently accelerate osteoclast maturation, a process that can be blocked by neutralizing antibodies to each of the chemokines. We further confirm the contribution of CXCR2 signaling axis to adiposity-driven osteoclastogenesis by blocking fat cell-induced osteoclast differentiation with CXCR2 antagonist or neutralizing antibodies. Together, our results link CXCL1 and CXCL2 chemokines with bone marrow adiposity and implicate CXCR2 signaling in promoting effects of marrow fat on progression of skeletal tumors in bone.

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Section: Discussionmentioning

confidence: 99%

Marrow adipocyte-derived CXCL1 and CXCL2 contribute to osteolysis in metastatic prostate cancer

Hardaway

Herroon

Rajagurubandara

et al. 2015

Clin Exp Metastasis

121

112

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“…More recently, it has been demonstrated that MVNP induction of IL-6 in OCL cells results in elevated levels of IGF-1 which in turn increases the expression of coupling factors, ephrinB2 on OCLs and EphB4 on osteoblasts, thereby enhancing the OCL driven osteoblast activity in PDB ( Teramachi et al, 2016 ). Earlier, we showed that patients with PDB contain elevated levels of FGF-2 and chemokine CXCL5 which modulates osteoclastogenesis through induction of RANKL expression in osteoblast cells ( Sundaram et al, 2009 , Sundaram et al, 2013 ). Therefore, MVNP regulation of SIRPβ1 signaling in OCL cells could modulate secretory factors which influence OCL/osteoblast activity.…”

Section: Discussionmentioning

confidence: 98%

Measles virus nucleocapsid protein modulates the Signal Regulatory Protein-β1 (SIRPβ1) to enhance osteoclast differentiation in Paget's disease of bone

Sundaram¹,

Sambandam²,

Shanmugarajan³

et al. 2017

Bone Reports

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Paget's disease of bone (PDB) is a chronic localized bone disorder in an elderly population. Environmental factors such as paramyxovirus are implicated in PDB and measles virus nucleocapsid protein (MVNP) has been shown to induce pagetic osteoclasts (OCLs). However, the molecular mechanisms underlying MVNP stimulation of OCL differentiation in the PDB are unclear. We therefore determined the MVNP regulated gene expression profiling during OCL differentiation. Agilent microarray analysis of gene expression identified high levels of SIRPβ1 (353-fold) expression in MVNP transduced human bone marrow mononuclear cells stimulated with RANKL. Real-time PCR analysis further confirmed that MVNP alone upregulates SIRPβ1 mRNA expression in these cells. Also, bone marrow mononuclear cells derived from patients with PDB showed high levels of SIRPβ1 mRNA expression compared to normal subjects. We further show that MVNP increases SIRPβ1 interaction with DAP12 adaptor protein in the presence and absence of RANKL stimulation. shRNA knockdown of SIRPβ1 expression in normal human bone marrow monocytes decreased the levels of MVNP enhanced p-Syk and c-Fos expression. In addition, SIRPβ1 knockdown significantly decreased MVNP stimulated dendritic cell–specific transmembrane protein (DC-STAMP) and connective tissue growth factor (CTGF) mRNA expression during OCL differentiation. Furthermore, we demonstrated the contribution of SIRPβ1 in MVNP induced OCL formation and bone resorption. Thus, our results suggest that MVNP modulation of SIRPβ1 provides new insights into the molecular mechanisms which control high bone turnover in PDB.

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“…Earlier, we showed that patients with PDB contain elevated levels of FGF-2 and chemokine CXCL5, which modulate osteoclastogenesis through induction of RANKL expression in osteoblast cells [19,29]. Since the pagetic OCL contain MVNP and shown directly induces osteoclastogenesis, it is important to unravel the underlying molecular mechanisms to determine the pathogenesis of PDB.…”

Section: Discussionmentioning

confidence: 99%

NFAM1 signaling enhances osteoclast formation and bone resorption activity in Paget's disease of bone

Sambandam¹,

Sundaram²,

Saigusa

et al. 2017

Bone

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Paget's disease of bone (PDB) is marked by the focal activity of abnormal osteoclasts (OCLs)with excess bone resorption. We previously detected measles virus nucleocapsid protein (MVNP) transcripts in OCLs from patients with PDB. Also, MVNP stimulates pagetic OCL formation in vitro and in vivo. However, the mechanism by which MVNP induces excess OCLs/bone resorption activity in PDB is unclear. Microarray analysis identified MVNP induction of NFAM1 (NFAT activating protein with ITAM motif 1) expression. Therefore, we hypothesize that MVNP induction of NFAM1 enhances OCL differentiation and bone resorption in PDB.MVNP transduced normal human PBMC showed an increased NFAM1 mRNA expression without RANKL treatment. Further, bone marrow cells from patients with PDB demonstrated elevated levels of NFAM1 mRNA expression. Interestingly, shRNA suppression of NFAM1 inhibits MVNP induced OCL differentiation and bone resorption activity in mouse bone marrow cultures. Live cell widefield fluorescence microscopy analysis revealed that MVNP induced intracellular Ca2+ oscillations and levels were significantly reduced in NFAM1 suppressed preosteoclasts. Further, western blot analysis demonstrates that shRNA against NFAM1 inhibits MVNP stimulated PLCγ, calcineurin, and Syk activation in preosteoclast cells. Furthermore, NFAM1 expression controls NFATc1, a critical transcription factor expression and nuclear translocation in MVNP transuded preosteoclast cells. Thus, our results suggest that MVNP modulation of the NFAM1 signaling axis plays an essential role in pagetic OCL formation and bone resorption activity.

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

Cited by 19 publications

References 45 publications

Marrow adipocyte-derived CXCL1 and CXCL2 contribute to osteolysis in metastatic prostate cancer

Marrow adipocyte-derived CXCL1 and CXCL2 contribute to osteolysis in metastatic prostate cancer

Measles virus nucleocapsid protein modulates the Signal Regulatory Protein-β1 (SIRPβ1) to enhance osteoclast differentiation in Paget's disease of bone

NFAM1 signaling enhances osteoclast formation and bone resorption activity in Paget's disease of bone

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