Cytokines Expressed in Multinucleated Cells: Paget's Disease and Giant Cell Tumors versus Normal Bone

Abstract

Human osteoclasts are well characterized multinucleated cells whose function is the directed resorption of normal bone (NB). Osteoclastic bone destruction accompanies lytic solid tumors and myeloma as well as Paget's disease (PD) of bone and giant cell tumors of bone (GCTB). The mechanism of this stimulation of osteoclastic bone resorption is unknown. This study was designed to detect cytokines present in the multinucleated cells of PD and GCTB in order to determine whether cytokine abnormalities exist to account for bone lysis. Nine cytokines, representing the functions of bone resorption, angiogenesis, tumor necrosis, bone cell proliferation, and osteoblast-osteoclast coupling, were examined by immunohistochemistry using tissue samples from 15 NB, 17 PD, and 19 GCTB patients. Standard nonparametric statistical analysis showed a significant increase (P < 0.01 to 0.05) in immunostaining between osteoclasts of PD and NB for interleukin-6 (Il-6), tumor necrosis factor beta (TNFbeta), epidermal growth factor (EGF), platelet derived growth factor (PDGF), and basic fibroblast growth factor (bFGF). There was a statistically significant decrease in immunostaining of giant cells of GCTB as compared with NB for transforming growth factor beta (TGFbeta), but no other differences from normal osteoclasts. The increase in staining of PD osteoclasts over the giant cells of GCTB was significant (P < 0.01) for Il-6, TNFbeta, PDGF, bFGF and insulin growth factor-1 (IGF-1), and (P < 0. 05) for Il-1 and EGF. It was concluded that marked cytokine differences exist in vivo between osteoclasts of NB and PD lesions consistent with stimulated resorption. Alternatively, "osteoclastoma" cells in the center of the tumor did not overexpress the cytokines associated with bone lysis, suggesting some other mechanism for stimulated resorption.

Functional Role for Heat Shock Factors in the Transcriptional Regulation of Human RANK Ligand Gene Expression in Stromal/Osteoblast Cells

“…Disruption of b-FGF (FGF-2) gene resulted in decreased bone mass and bone formation in mice (49). Pathological conditions such as Paget's disease of bone demonstrated increased levels of b-FGF expression in osteoclasts compared with normal bone (50). Therefore, local concentrations of osteotropic factors including b-FGF may have significant effects on HSP and HSF activation in both physiological and pathological conditions in modulating RANKL gene expression in stromal/osteoblastic cells present in the bone microenvironment.…”

VEGF-C, a Lymphatic Growth Factor, Is a RANKL Target Gene in Osteoclasts That Enhances Osteoclastic Bone Resorption through an Autocrine Mechanism

“…Osteoclasts can be activated to secrete factors that act through autocrine and paracrine mechanisms to contribute to inflammation and autoimmunity (4). For example, osteoclasts from patients with Paget's disease or giant cell tumors of bone produce higher levels of various cytokines and growth factors, including IL-6 and platelet-derived growth factor, than cells from normal bone (5). In co-cultures, myeloma cells and osteoclasts constitutively secrete the proangiogenic factors, VEGF-A (vascular endothelial growth factor-A) and osteopontin (6).…”

Immunolocalization of RANKL is Increased and OPG Decreased During Dietary Magnesium Deficiency in the Rat

“…The quantitative estimate of numbers of cells staining was a = <20%, b = 20–60%, and c = >60%. The mean relative positivity was <1b = 0; 2a and 2b = 1; and 3b and 3c = 2 [24,25]. In this study, in some instances, no clear staining was observed for OPG at 4 and 6 months in animals on the 25% NR Mg diet, therefore, a minimum value of 0.01 was given to allow for calculation of RANKL/OPG ratio.…”

“…No difference in background localization was observed between Mg deficient and control rats. Cells and tissues stained specifically as described for the antigen in the literature [24,25]. Intensity was graded as 0 = no localization, 1 = weak localization, 2 = moderate, and 3 = strong localization.…”