ECTS Abstracts (2015) 1 P191

IL-8 is an Alternative Pathway for Osteoclastogenesis

Archana Kamalakar, Diarra Williams, Nisreen Akel, Frances Swain, Dana Gaddy & Larry Suva

University of Arkansas for medical Sciences, Little Rock, USA.

Physiologic bone resorption is regulated by macrophage colony stimulating factor (m-CSF), essential for osteoclast survival and receptor activated nuclear factor kB ligand (RANKL). Interestingly, we and others have demonstrated that alternative pathways of osteoclastogenesis are active under a variety of pathophysiologic situations, such as inflammatory arthritis and tumour osteolysis. In breast cancer bone metastasis, osteoclastogenesis is induced by tumour-derived agents such as Interleukin-8 (IL-8). Indeed, serum IL-8 levels are significantly correlated with increased bone resorption in breast cancer bone metastasis patients. Since no differences in osteoclast behaviour are apparent in normal or pathologic conditions, we hypothesised that RANKL and IL-8 signalling converge. First, no additive or apparent synergy was observed when human osteoclast precursors were differentiated with RANKL or IL-8. Next, western blot analysis of lysates from differentiated human osteoclasts treated with IL-8 resulted in phosphorylation of NF-kB, ERK, AKT and P38, all known RANKL-induced mediators of osteoclastogenesis. Furthermore, we determined the bone phenotype of novel IL-8 Tg mice that contain a bacterial artificial chromosome encompassing the entire human IL-8 gene, including all the endogenous regulatory elements. These mice have detectable IL-8 levels in serum and bone marrow supernatants >7.5pg/ml at baseline (uninduced) and up to ~5000pg/ml when stimulated using LPS (5mg/kg) and a low bone mass by microCT. Ex vivo bone marrow cultures from IL-8 Tg mice showed significantly decreased numbers of osteoclasts as well as a significant decrease in osteoblast recruitment and mineralisation, compared with age-matched WT mice. The decreased activity and number of osteoclasts and osteoblasts in ex vivo cultures explains the low bone mass phenotype observed in vivo. In summary, these data suggest that signals responsible for human osteoclastogenesis and bone resorption are shared between IL-8 and RANKL. Understanding the dynamics of pathologic osteoclast differentiation is critical for the development of effective therapeutic strategies.

Disclosure: The authors declared no competing interests. This work was supported by the NIH (grant number R01 CA166060-01A1), UAMS Translational Research Institute (TRI) (CTSA grant award #1 UL1TR000039).

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