High-Mobility Group Box Proteins Modulate Tumor Necrosis Factor-α Expression in Osteoclastogenesis via a Novel Deoxyribonucleic Acid Sequence

Abstract

We have previously shown that mice lacking the TSH receptor (TSHR) exhibit osteoporosis due to enhanced osteoclast formation. The fact that this enhancement is not observed in double-null mice of TSHR and TNFalpha suggests that TNFalpha overexpression in osteoclast progenitors (macrophages) may be involved. It is unknown how TNFalpha expression is regulated in osteoclastogenesis. Here, we describe a receptor activator for nuclear factor-kappaB ligand (RANKL)-responsive sequence (CCG AGA CAG AGG TGT AGG GCC), spanning from -157 to -137 bp of the 5'-flanking region of the TNFalpha gene, which functions as a cis-acting regulatory element. We further show how RANKL treatment stimulates the high-mobility group box proteins (HMGB) HMGB1 and HMGB2 to bind the RANKL-responsive sequence and up-regulates TNFalpha transcription. Exogenous HMGB elicits the expression of cytokines, including TNFalpha, as well as osteoclast formation. Conversely, TSH inhibits the expression of HMGB and TNFalpha and the formation of osteoclasts. These results suggest that HMGB play a pivotal role in osteoclastogenesis. We also show a direct correlation between the expression of HMGB and TNFalpha and osteoclast formation in TSHR-null mice and TNFalpha-null mice. Taken together, we conclude that HMGB and TNFalpha play critical roles in the regulation of osteoclastogenesis and the remodeling of bone.

The Coffee Diterpene Kahweol Prevents Osteoclastogenesis via Impairment of NFATc1 Expression and Blocking of Erk Phosphorylation

“…Recently, we have shown that suppression of HO-1 by pharmacological and genetic inhibition causes enhanced HMGB1 release during osteoclastogenesis (7). Extracellular HMGB1, which acts as a proinflammatory cytokine, can bind to cell-surface receptors such as the receptor for advanced glycation end products and Toll-like receptors 2 and 4 and modulates differentiation of OCL precursors in the presence of RANKL in vitro and in vivo (23,29,30). In this study, kahweol induced up-regulation of HO-1 and inhibited extracellular release of HMGB1 during osteoclastogenesis.…”

Role of HMGB1 in proliferation and migration of human gingival and periodontal ligament fibroblasts

“…Another important issue is that periodontium also contains hard tissues: cementum and alveolar bone. Yamoah et al (32) have reported an interrelationship between HMGB1, TNF-α expression and osteoclast formation. A thorough understanding of the molecular mechanism of HMGB1 and its effects on various local cells is essential before this molecule can be applied clinically.…”

Pituitary-bone connection in skeletal regulation

“…The effect of TSH on TNFα synthesis is mediated transcriptionally by binding of two high mobility group box proteins, HMGB1 and HMGB2, to TNFα gene promoter [75]. TNFα production is expectedly upregulated in osteoporotic TSHR -/-mice [37], and the genetic deletion of TNFα in these mice reverses the osteoporosis, as well as the bone formation and resorption defects, proving that the TSHR -/-phenotype is mediated by TNFα, at least in part [64,76].…”