HUMAN OSTEOCLASTS AND OSTEOCLAST-LIKE CELLS SYNTHESIZE AND RELEASE HIGH BASAL AND INFLAMMATORY STIMULATED LEVELS OF THE POTENT CHEMOKINE INTERLEUKIN-8

Chemokines, including interleukin-8 (IL-8), function as hey mediators in diverse inflammatory disorders via promoting the recruitment, proli feration, and activation of vascular and immune cells. IL-8 levels are elevated in inflammatory diseases, such as rheumatoid arthritis, oste oarthritis, osteomyelitis, and periodontal disease, that also exhibit progressive bone lass. Therefore, it is possible that IL-8 contributes to the osteopenia associated with these pathological conditions. Alth ough macrophages, neutrophils, and endothelial cells are considered th e primary sources of inflammation-induced IL-8 in creases, we report h ere for the first time that human bone marrow-derived osteoclast-like cells (hOCL) as well as authentic bone-resorbing human osteoclasts (hO C) isolated from osteoporotic femoral heads express messenger RNA (mRN A) for IL-8 and secrete high levels of IL-8 during culture. Basal IL-8 release by cultured hOC or hOCL was orders of magnitude greater than the release of the proinflammatory cytokines IL-1 beta, IL-6, and tumo r necrosis factor-cu. At a cellular level, in situ hybridization analy sis revealed that IL-8 mRNA was expressed in resorbing hOC of rheumato id arthritic pannus and was substantially greater than that expressed in hOC of noninflammatory giant cell tumor of bone tissue. Therefore, the potential inflammation-mediated induction of IL-8 was directly ass essed using cultured hOCL. IL-8 release was stimulated by proinflammat ory signals (IL-1 alpha, tumor necrosis factor-cu, lipopolysaccharide, or phorbol la-myristate 13-acetate), unaffected by various other oste otropic modulators (transforming growth factor-beta 1 and -beta 3, IL- 6, 17 beta-estradiol, or calcitonin) and was decreased by interferon-g amma, vitamin D-3, and the antiinflammatory glucocorticoid dexamethaso ne. Changes in IL-8 secretion were paralleled by corresponding changes in IL-8 mRNA steady state levels. We conclude that hOC and hOCL synth esize and secrete high constitutive and inflammation-stimulated levels of the chemokine IL-8. Consequently, hOC-derived IL-8 could act as an important regulatory signal for bone, vascular, and immune cell recru itment and activation during normal and pathological bone remodeling.