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Suppression of Notch Signaling in Osteoclasts Improves Bone Regeneration and Healing
Author(s) -
Goel Peeyush N.,
Moharrer Yasaman,
Hebb John H.,
Egol Alexander J.,
Kaur Gurpreet,
Hankenson Kurt D.,
Ahn Jaimo,
Ashley Jason W.
Publication year - 2019
Publication title -
journal of orthopaedic research®
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.041
H-Index - 155
eISSN - 1554-527X
pISSN - 0736-0266
DOI - 10.1002/jor.24384
Subject(s) - osteoclast , osteoblast , bone resorption , notch signaling pathway , bone remodeling , bone healing , microbiology and biotechnology , resorption , regeneration (biology) , signal transduction , biology , endocrinology , medicine , anatomy , in vitro , receptor , genetics
Owing to the central role of osteoclasts in bone physiology and remodeling, manipulation of their maturation process provides a potential therapeutic strategy for treating bone diseases. To investigate this, we genetically inhibited the Notch signaling pathway in the myeloid lineage, which includes osteoclast precursors, using a dominant negative form of MAML (dnMAML) that inhibits the transcriptional complex required for downstream Notch signaling. Osteoclasts derived from dnMAML mice showed no significant differences in early osteoclastic gene expression compared to the wild type. Further, these demonstrated significantly lowered resorption activity using bone surfaces while retaining their osteoblast stimulating ability using ex vivo techniques. Using in vivo approaches, we detected significantly higher bone formation rates and osteoblast gene expression in dnMAML cohorts. Further, these mice exhibited increased bone/tissue mineral density compared to wild type and larger bony calluses in later stages of fracture healing. These observations suggest that therapeutic suppression of osteoclast Notch signaling could reduce, but not eliminate, osteoclastic resorption without suppression of restorative bone remodeling and, therefore, presents a balanced paradigm for increasing bone formation, regeneration, and healing. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:2089–2103, 2019