OSTEOCLASTS CONSTITUTIVELY EXPRESS REGULATORS OF BONE-RESORPTION - ANIMMUNOHISTOCHEMICAL AND IN-SITU HYBRIDIZATION STUDY

Bone resorption is controlled by the local production of soluble regul atory molecules within the marrow microenvironment that mediate osteoc last recruitment, differentiation, and activation. Under normal condit ions osteoclasts are rarely seen; in many pathologic states, however, the number of osteoclasts is dramatically increased, resulting in a ne t-loss of bone mass. The role of the osteoclasts as autocrine regulato rs of bone resorption in either normal or pathologic conditions has no t been extensively investigated. The expression of IL-1 beta, IL-6, an d TNF-alpha was examined in osteoclasts by immunohistochemistry under conditions of normal, reactive, and pathologic bone resorption, includ ing growth plate (3 cases), fracture callus (5 cases), osteomyelitis ( 3 cases), Paget's disease (6 cases), giant-cell tumor of bone (14 case s), and brown tumor of hyperparathyroidism (2 cases). In each case, os teoclasts demonstrated immunoreactivity for IL-1 beta, IL-6, and TNF-a lpha. In areas of active bone resorption, the intensity and uniformity of staining among the various conditions were similar, suggesting con stitutive expression of these cytokines by activated osteoclasts. Gian t-cell tumors of bone showed cytokine reactivity in over half of the g iant cells, whereas stromal cells showed scattered staining. In acute osteomyelitis, inflammatory cells (mainly macrophages) and osteoclasts were intensely positive for all three cytokines. The immunohistochemi cal findings were confirmed by in situ hybridization using probes spec ific 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 ost eoclasts. Because overproduction of these cytokines may enhance bone r esorption through the stimulation of osteoclast progenitor cells as we ll as mature osteoclasts, pathologic bone lesions with a large increas e in the number of osteoclasts may be self-perpetuating. Alteration in the synthesis, secretion, or activity of these important regulatory m olecules may in turn alter bone remodeling and loss.