Journal
MOLECULAR ENDOCRINOLOGY
Volume 22, Issue 5, Pages 1141-1153Publisher
ENDOCRINE SOC
DOI: 10.1210/me.2007-0460
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Funding
- NCI NIH HHS [R24 CA088325, CA88325] Funding Source: Medline
- NCRR NIH HHS [RR017802, S10 RR017802, RR022415, S10 RR022415] Funding Source: Medline
- NIAMS NIH HHS [AR052258] Funding Source: Medline
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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 alpha suggests that TNF alpha overexpression in osteoclast progenitors ( macrophages) may be involved. It is unknown how TNF alpha expression is regulated in osteoclastogenesis. Here, we describe a receptor activator for nuclear factor-kappa 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 alpha 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 alpha transcription. Exogenous HMGB elicits the expression of cytokines, including TNF alpha, as well as osteoclast formation. Conversely, TSH inhibits the expression of HMGB and TNF alpha 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 alpha and osteoclast formation in TSHR-null mice and TNF alpha-null mice. Taken together, we conclude that HMGB and TNF alpha play critical roles in the regulation of osteoclastogenesis and the remodeling of bone.
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