Open AccessMIP-1δ Activates NFATc1 and Enhances Osteoclastogenesis: Involvement of Both PLCγ2 and NFκB Signaling
Author(s) -
Kristy Weber,
Michèle Doucet,
Adam C. Shaner,
Nigel Hsu,
David C.S. Huang,
Jenna Fogel,
Scott L. Kominsky
Publication year - 2012
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0040799
Subject(s) - bone resorption , osteoclast , cancer research , nf κb , chemokine , chemistry , arthritis , inflammation , bone metastasis , rankl , signal transduction , mediator , microbiology and biotechnology , immunology , receptor , medicine , biology , metastasis , cancer , biochemistry , activator (genetics)
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-α 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-1α and -3α have been shown to enhance osteoclast (OCL) development. In this study we provide evidence that MIP-1δ, 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-1δ resulted in the activation of PLCγ2 and NF-κB, two signaling pathways known to regulate OCL differentiation. Moreover, MIP-1δ induced expression and nuclear translocation of NFATc1, a master regulator of osteoclastogenesis, which was dependent on activation of both the PLCγ2 and NFκB signaling pathways. Lastly, consistent with in vitro studies, in vivo administration of MIP-1δ 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-1δ as a mediator of pathological bone resorption and provide insight into the molecular mechanism through which MIP-1δ enhances osteoclastogenesis.