Osteoclasts constitutively express regulators of bone resorption: an immunohistochemical and in situ hybridization study.

Bone resorption is controlled by the local production of soluble regulatory molecules within the marrow microenvironment that mediate osteoclast recruitment, differentiation, and activation. Under normal conditions osteoclasts are rarely seen; in many pathologic states, however, the number of osteoclasts is dramatically increased, resulting in a net-loss of bone mass. The role of the osteoclasts as autocrine regulators of bone resorption in either normal or pathologic conditions has not been extensively investigated. The expression of IL-1 beta, IL-6, and TNF-alpha was examined in osteoclasts by immunohistochemistry under conditions of normal, reactive, and pathologic bone resorption, including growth plate (3 cases), fracture callus (5 cases), osteomyelitis (3 cases), Paget's disease (6 cases), giant-cell tumor of bone (14 cases), and brown tumor of hyperparathyroidism (2 cases). In each case, osteoclasts demonstrated immunoreactivity for IL-1 beta, IL-6, and TNF-alpha. In areas of active bone resorption, the intensity and uniformity of staining among the various conditions were similar, suggesting constitutive expression of these cytokines by activated osteoclasts. Giant-cell tumors of bone showed cytokine reactivity in over half of the giant cells, whereas stromal cells showed scattered staining. In acute osteomyelitis, inflammatory cells (mainly macrophages) and osteoclasts were intensely positive for all three cytokines. The immunohistochemical findings were confirmed by in situ hybridization using probes specific for IL-6 and TNF-alpha, the pattern of mRNA expression paralleled that of immunoreactivity for these cytokines. These findings support the notion of autocrine/paracrine regulation of bone remodeling by osteoclasts. Because overproduction of these cytokines may enhance bone resorption through the stimulation of osteoclast progenitor cells as well as mature osteoclasts, pathologic bone lesions with a large increase in the number of osteoclasts may be self-perpetuating. Alteration in the synthesis, secretion, or activity of these important regulatory molecules may in turn alter bone remodeling and loss.