LIPOPOLYSACCHARIDE-STIMULATED OSTEOCLASTOGENESIS IS MEDIATED BY TUMOR-NECROSIS-FACTOR VIA ITS P55 RECEPTOR

Chronic bone infection, as attends periodontitis, is often complicated by severe osteolysis. While LPS is believed to be central to the path ogenesis of the osteolytic lesion, the mechanisms by which this bacter ia-derived molecule promotes bone resorption are unknown. We find that LPS induces bone marrow macrophages (BMMs) to express c-src, a protoo ncogene product that we demonstrate is a specific marker of commitment to the osteoclast phenotype. We next turned to possible soluble media tors of LPS-induced c-src. Of a number of osteoclastogenic cytokines t ested, only TNF-alpha mirrors the c-src-enhancing effect of LPS. Sugge sting that LPS augmentation of c-src is TNF-mediated, endotoxin sequen tially induces BMM expression of TNF, followed by c-src. TNF and c-src expression, by cultured BMMs derived from LPS-injected mice, reflects duration of exposure to circulating endotoxin, intimating that endoto xin's effect in vivo is also mediated by TNF, Consistent with these fi ndings, thalidomide (which antagonizes TNF action) attenuates c-src in duction by LPS, An anti-TNF antibody blacks LPS enhancement of c-src m RNA, validating the cytokine's modulating role in vitro, Using BMMs of TNF receptor-deleted mice, we demonstrate that TNF induction of c-src is transmitted through the cytokine's p55, but not p75, receptor. Mos t importantly, LPS administered to wild-type mice prompts osteoclast p recursor differentiation, manifest by profound osteoclastogenesis in m arrow cultured ex vivo, and by a profusion of marrow-residing cells ex pressing the osteoclast marker tartrate resistant acid phosphatase, in vivo, In contrast, LPS does not substantially enhance osteoclast prol iferation in mice lacking the p55TNF receptor, confirming that LPS-ind uced osteoclastogenesis is mediated by TNF in vivo via this receptor, Thus, therapy targeting TNF and/or its p55 receptor presents itself as a means of preventing the osteolysis of chronic bacterial infection.