MIP-1[delta] Activates NFATc1 and Enhances Osteoclastogenesis: Involvement of Both PLC[gamma]2 and NF[kappa]B Signaling

Pathological bone resorption is a source of significant morbidity in diseases affecting the skeleton such as rheumatoid arthritis, periodontitis, and cancer metastasis to bone. Evidence indicates that elevated levels of inflammatory mediators such as IL-1, IL-6, and TNF-[alpha] play a role in this p...

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Bibliographic Details
Published in:PloS one 2012-07, Vol.7 (7), p.e40799
Main Authors: Weber, Kristy L, Doucet, Michele, Shaner, Adam, Hsu, Nigel, Huang, David, Fogel, Jenna, Kominsky, Scott L
Format: Article
Language:English
Subjects:
Arthritis
Cancer metastasis
Macrophages
Medical schools
Rheumatoid factor
Tumor necrosis factor
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Summary:Pathological bone resorption is a source of significant morbidity in diseases affecting the skeleton such as rheumatoid arthritis, periodontitis, and cancer metastasis to bone. Evidence indicates that elevated levels of inflammatory mediators such as IL-1, IL-6, and TNF-[alpha] play a role in this process by promoting the formation of bone-resorbing osteoclasts. Additionally, current studies have identified inflammatory chemokines of the macrophage inflammatory protein (MIP) family as potential mediators of pathological bone resorption, where both MIP-1[alpha] and -3[alpha] have been shown to enhance osteoclast (OCL) development. In this study we provide evidence that MIP-1[delta], whose expression is associated with renal cell carcinoma bone metastasis and rheumatoid arthritis, enhances OCL formation in vitro via a direct effect on OCL precursors. Consistent with this ability, exposure of OCL precursors to MIP-1[delta] resulted in the activation of PLC[gamma]2 and NF-[kappa]B, two signaling pathways known to regulate OCL differentiation. Moreover, MIP-1[delta] induced expression and nuclear translocation of NFATc1, a master regulator of osteoclastogenesis, which was dependent on activation of both the PLC[gamma]2 and NF[kappa]B signaling pathways. Lastly, consistent with in vitro studies, in vivo administration of MIP-1[delta] significantly increased OCL number and resorption area as determined using a murine calvarial bone resorption model. Taken together, these data highlight the potential of MIP-1[delta] as a mediator of pathological bone resorption and provide insight into the molecular mechanism through which MIP-1[delta] enhances osteoclastogenesis.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0040799