Notch and the regulation of osteoclast differentiation and function

Yu, Jungeun<sup>1,3</sup>; Canalis, Ernesto<sup>1,2,3</sup>

Affiliations

¹Departments of Orthopaedic Surgery, UConn Musculoskeletal Institute, Farmington, CT 06030, USA

²UConn Musculoskeletal Institute, UConn Health, Farmington, CT 06030, USA

³Medicine, UConn Musculoskeletal Institute, Farmington, CT 06030, USA

Abstract and keywords

Notch 1 through 4 are transmembrane receptors that play a pivotal role in cell differentiation and function; this review addresses the role of Notch signaling in osteoclastogenesis and bone resorption. Notch receptors are activated following interactions with their ligands of the Jagged and Delta-like families. In the skeleton, Notch signaling controls osteoclast differentiation and bone-resorbing activity either directly acting on osteoclast precursors, or indirectly acting on cells of the osteoblast lineage and cells of the immune system. NOTCH1 inhibits osteoclastogenesis, whereas NOTCH2 enhances osteoclast differentiation and function by direct and indirect mechanisms. NOTCH3 induces the expression of RANKL in osteoblasts and osteocytes and as a result induces osteoclast differentiation. There is limited expression of NOTCH4 in skeletal cells. Selected congenital disorders and skeletal malignancies are associated with dysregulated Notch signaling and enhanced bone resorption. In conclusion, Notch signaling is a critical pathway that controls osteoblast and osteoclast differentiation and function and regulates skeletal homeostasis in health and disease.

Keywords: Notch; Jagged; Tumor necrosis factor α; Bone remodeling; Inflammation; Osteoclast; Bone resorption

Links

DOI: 10.1016/j.bone.2020.115474

PubMed: 32526405

WoS: 000557876000019

History

Received: 2020-05-26

Revised: 2020-06-5

Accepted: 2020-06-5

Online: 2020-06-8

Cited Works (3)

Year	Entry
1997	Simonet WS, Lacey DL, Dunstan CR, Kelley M, Chang M-S, Lüthy R, Nguyen HQ, Wooden S, Bennett L, Boone T, Shimamoto G, DeRose M, Elliott R, Colombero A, Tan H-L, Trail G, Sullivan J, Davy E, Bucay N, Renshaw-Gegg L, Hughes TM, Hill D, Pattison W, Campbell P, Sander S, Van G, Tarpley J, Derby P, Lee R, Boyle WJ; Amgen EST Program. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell. April 18, 1997;89(2):309-319.
2002	Takayanagi H, Kim S, Koga T, Nishina H, Isshiki M, Yoshida H, Saiura A, Isobe M, Yokochi T, Inoue J-i, Wagner EF, Mak TW, Kodama T, Taniguchi T. Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts. Dev Cell. December 1, 2002;3(6):889-901.
2007	Asagiri M, Takayanagi H. The molecular understanding of osteoclast differentiation. Bone. February 2007;40(2):251-264.

Cited By (1)

Year	Entry
2022	Canalis E, Yee SP, Economides AN, Schilling L, Yu J. Induction of a NOTCH3 Lehman syndrome mutation in osteocytes causes osteopenia in male C57BL/6J mice. Bone. September 2022;162:116476.