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

Departments of Medicine (K.Y., A.B., R.B., K.I., A.A., R.M., R.Y., E.A.) and Genetics and Genomic Sciences (G.D., R.W.), Mount Sinai School of Medicine, New York, New York 10029; and Department of Pharmacology (H.A.), School of Dentistry, Showa University, Tokyo, Japan 142

Address all correspondence and requests for reprints to: Etsuko Abe, Ph.D., Division of Endocrinology, Department of Medicine, Mount Sinai School of Medicine, One Gustave Levy Place, Box 1055, New York, New York 10029. E-mail: etsuko.abe{at}mssm.edu.

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 TNF suggests that TNF overexpression in osteoclast progenitors (macrophages) may be involved. It is unknown how TNF expression is regulated in osteoclastogenesis. Here, we describe a receptor activator for nuclear factor-B ligand (RANKL)-responsive sequence (CCG AGA CAG AGG TGT AGG GCC), spanning from –157 to –137 bp of the 5'-flanking region of the TNF 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 TNF transcription. Exogenous HMGB elicits the expression of cytokines, including TNF, as well as osteoclast formation. Conversely, TSH inhibits the expression of HMGB and TNF 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 TNF and osteoclast formation in TSHR-null mice and TNF-null mice. Taken together, we conclude that HMGB and TNF play critical roles in the regulation of osteoclastogenesis and the remodeling of bone.