%0 Journal Article
%T Hairy and enhancer of split 1 is a primary effector of NOTCH2 signaling and induces osteoclast differentiation and function.
%A Yu J
%A Schilling L
%A Eller T
%A Canalis E
%J J Biol Chem
%V 297
%N 6
%D Nov 2021 3
%M 34742737
暂无%R 10.1016/j.jbc.2021.101376
%X Notch2tm1.1Ecan mice, which harbor a mutation replicating that found in Hajdu-Cheney syndrome, exhibit marked osteopenia because of increased osteoclast number and bone resorption. Hairy and enhancer of split 1 (HES1) is a Notch target gene and a transcriptional modulator that determines osteoclast cell fate decisions. Transcript levels of Hes1 increase in Notch2tm1.1Ecan bone marrow-derived macrophages (BMMs) as they mature into osteoclasts, suggesting a role in osteoclastogenesis. To determine whether HES1 is responsible for the phenotype of Notch2tm1.1Ecan mice and the skeletal manifestations of Hajdu-Cheney syndrome, Hes1 was inactivated in Ctsk-expressing cells from Notch2tm1.1Ecan mice. Ctsk encodes the protease cathepsin K, which is expressed preferentially by osteoclasts. We found that the osteopenia of Notch2tm1.1Ecan mice was ameliorated, and the enhanced osteoclastogenesis was reversed in the context of the Hes1 inactivation. Microcomputed tomography revealed that the downregulation of Hes1 in Ctsk-expressing cells led to increased bone volume/total volume in female mice. In addition, cultures of BMMs from CtskCre/WT;Hes1Δ/Δ mice displayed a decrease in osteoclast number and size and decreased bone-resorbing capacity. Moreover, activation of HES1 in Ctsk-expressing cells led to osteopenia and enhanced osteoclast number, size, and bone resorptive capacity in BMM cultures. Osteoclast phenotypes and RNA-Seq of cells in which HES1 was activated revealed that HES1 modulates cell-cell fusion and bone-resorbing capacity by supporting sealing zone formation. In conclusion, we demonstrate that HES1 is mechanistically relevant to the skeletal manifestation of Notch2tm1.1Ecan mice and is a novel determinant of osteoclast differentiation and function.