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HMGB1 is a bone‐active cytokine

High mobility group box 1 (HMGB1) is a chromatin protein that acts as an immunomodulatory cytokine upon active release from myeloid cells. HMGB1 is also an alarmin, an endogenous molecule released by dying cells that acts to initiate tissue repair. We have previously reported that osteoclasts and osteoblasts release HMGB1 and release by the latter is regulated by parathyroid hormone (PTH), an agent of bone remodeling. A recent study suggests that HMGB1 acts as a chemotactic agent to osteoclasts and osteoblasts during endochondral ossification. To explore the potential impact of HMGB1 in the bone microenvironment and its mechanism of release by osseous cells, we characterized the effects of recombinant protein (rHMGB1) on multiple murine bone cell preparations that together exhibit the various cell phenotypes present in bone. We also inquired whether apoptotic bone cells release HMGB1. rHMGB1 enhanced the RANKL/OPG steady state mRNA ratio and dramatically augmented the release of tumor necrosis factor‐alpha (TNFα) and interleukin‐6 (IL6) in osteoblastogenic bone marrow stromal cell (BMSC) cultures but not in the calvarial‐derived MC3T3‐E1 cells. Interestingly, rHMGB1 promoted GSK‐3beta phosphorylation in MC3T3‐E1 cells but not in BMSCs. Apoptotic bone cells released HMGB1, including MLO‐Y4 osteocyte‐like cells. MLO‐Y4 release of HMGB1 was coincident with caspase‐3 cleavage. Furthermore, the anti‐apoptotic action of PTH on MC3T3‐E1 cells correlated with the observed decrease in HMGB1 release. Our data suggest that apoptotic bone cells release HMGB1, that within the marrow HMGB1 is a bone resorption signal, and that intramembraneous and endochondral osteoblasts exhibit differential responses to this cytokine. J. Cell. Physiol. 214: 730–739, 2008. © 2007 Wiley‐Liss, Inc.