HES1 (Hairy and Enhancer of Split 1) Is a Determinant of Bone Mass

HES1 (hairy and enhancer of split) is a transcription factor that regulates osteoblastogenesis in vitro. The skeletal effects of HES1 misexpression were studied. Transgenic mice where a 3.6-kilobase fragment of the collagen type 1 α1 promoter directs HES1 overexpression were created. Transgenics were osteopenic due to decreased osteoblast function in female and increased bone resorption in male mice. HES1 impaired osteoblastogenesis in vitro, and transgenic osteoblasts enhanced the resorptive activity of co-cultured osteoclast precursors. Mice homozygous for a Hes1 loxP-targeted allele were bred to transgenics, where the paired-related homeobox gene enhancer or the osteocalcin promoter direct Cre recombinase expression to inactivate Hes1 in the limb bud or in osteoblasts. To avoid genetic compensation, Hes1 was inactivated in the context of the global deletion of Hes3 and Hes5. Hes3 and Hes5 null mice had no skeletal phenotype. Hes1 inactivation in the limb bud increased femoral length and trabecular number. Hes1 inactivation in osteoblasts increased trabecular bone volume, number, and connectivity due to increased mineral apposition rate and suppressed bone resorption. Hes1 inactivation in vitro increased alkaline phosphatase expression and suppressed the resorptive activity of co-cultured osteoclast precursors. In conclusion, by inhibiting osteoblast function and inducing bone resorption, HES1 is an intracellular determinant of bone mass and structure.