HMGB1 Regulates RANKL-Induced Osteoclastogenesis in a Manner Dependent on RAGE

Abstract

High-mobility group box 1 (HMGB1), a nonhistone nuclear protein, is released by macrophages into the extracellular milieu consequent to cellular activation. Extracellular HMGB1 has properties of a pro-inflammatory cytokine through its interaction with receptor for advanced glycation endproducts (RAGE) and/or toll-like receptors (TLR2 and TLR4). Although HMGB1 is highly expressed in macrophages and differentiating osteoclasts, its role in osteoclastogenesis remains largely unknown. In this report, we present evidence for a function of HMGB1 in this event. HMGB1 is released from macrophages in response to RANKL stimulation and is required for RANKL-induced osteoclastogenesis in vitro and in vivo. In addition, HMGB1, like other osteoclastogenic cytokines (e.g., TNF␣), enhances RANKL-induced osteoclastogenesis in vivo and in vitro at subthreshold concentrations of RANKL, which alone would be insufficient. The role of HMGB1 in osteoclastogenesis is mediated, in large part, by its interaction with RAGE, an immunoglobin domain containing family receptor that plays an important role in osteoclast terminal differentiation and activation. HMGB1-RAGE signaling seems to be important in regulating actin cytoskeleton reorganization, thereby participating in RANKL-induced and integrin-dependent osteoclastogenesis. Taken together, these observations show a novel function of HMGB1 in osteoclastogenesis and provide a new link between inflammatory mechanisms and bone resorption.

Disruption of the Cx43/miR21 pathway leads to osteocyte apoptosis and increased osteoclastogenesis with aging

“…This is consistent with previous work showing that apoptotic MLO‐Y4 osteocytic cells release HMGB1 (Charoonpatrapong et al ., 2006; Klune et al ., 2008). Further, HMGB1 is chemotactic for osteoclasts and triggers osteoclastogenesis by activating RAGE (Taniguchi et al ., 2007; Zhou et al ., 2008; Yang et al ., 2013). Consistently, inhibition of apoptosis prevents RANKL and HMGB1 release and attenuates the enhanced osteoclastogenesis and osteoclast marker expression induced by conditioned media from Cx43‐deficient osteocytes.…”

“…In osteocytes and other cells, apoptotic cell death results in the release of the pro‐inflammatory cytokine high‐mobility group box‐1 (HMGB1), a nonhistone nuclear DNA‐binding protein responsible for stabilization of nucleosomal structures facilitating gene transcription (Charoonpatrapong et al ., 2006; Yang et al ., 2008). HMGB1 released from the cells activates the receptor for advanced glycation end products (RAGE) and Toll‐like receptor 4 (TLR4) and can regulate recruitment and differentiation of osteoclast precursors (Zhou et al ., 2008; Yang et al ., 2013). However, whether HMGB1 is involved in osteoclast recruitment and differentiation induced by apoptotic osteocytes is not known.…”

Immunogene Zelltodmarker HMGB1 und sRAGE als neue prädiktive und prognostische Serum Biomarker bei Tumorerkrankungen/Immunogenic cell death markers HMGB1 and sRAGE as new predictive and prognostic serum biomarkers in cancer disease

“…Extrazellul ä res HMGB1 regt bei RA offenbar Makrophagen zur Aussch ü ttung proinflammatorischer Zytokine an und induziert RANKL-abh ä ngig die Bildung von Osteoklasten, die dann zu Gelenkdestruktionen f ü hren [79,80] .…”

Acute Coronary Syndrome: Pathological Findings by Means of Electron Microscopy, Advance Imaging in Cardiology

“…Un-sequestrated calcium leads to loss of function of membrane pumps and consequently cell death [Ewence et al, 2008]. VSMC death potentiates calcification by providing a nidus for further nucleation and activation of various downstream inflammatory pathways as release of cytokines [Proudfoot et al, 2000, Park et al, 2006, Zhou et al, 2008, Porto et al, 2006. In addition to size, crystal composition is also of paramount importance.…”