Association between Bone Turnover Markers and Fracture Healing in Long Bone Non-Union: A Systematic Review.

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Abstract

Conflict of interest statement: The authors declare no conflicts of interest. 14. J Orthop Res. 2020 Nov;38(11):2350-2361. doi: 10.1002/jor.24650. Epub 2020 Mar 16. Modulation of Notch1 signaling regulates bone fracture healing. Novak S(1), Roeder E(1), Sinder BP(1), Adams DJ(2)(3), Siebel CW(4), Grcevic D(5), Hankenson KD(6), Matthews BG(1)(7), Kalajzic I(1). Author information: (1)Department of Reconstructive Sciences, UConn Health, Farmington, Connecticut. (2)Department of Orthopedic Surgery, UConn Health, Farmington, Connecticut. (3)Department of Orthopedics, University of Colorado - Anschutz Medial Campus, Aurora, Colorado. (4)Department of Discovery Oncology, Genentech, Inc., South San Francisco, California. (5)Department of Physiology and Immunology, University of Zagreb, Zagreb, Croatia. (6)Department of Orthopaedic Surgery, University of Michigan Medical School, Ann Arbor, Michigan. (7)Department of Molecular Medicine and Pathology, University of Auckland, Auckland, New Zealand. Fracture healing involves interactions of different cell types, driven by various growth factors, and signaling cascades. Periosteal mesenchymal progenitor cells give rise to the majority of osteoblasts and chondrocytes in a fracture callus. Notch signaling has emerged as an important regulator of skeletal cell proliferation and differentiation. We investigated the effects of Notch signaling during the fracture healing process. Increased Notch signaling in osteochondroprogenitor cells driven by overexpression of Notch1 intracellular domain (NICD1) (αSMACreERT2 mice crossed with Rosa-NICD1) during fracture resulted in less cartilage, more mineralized callus tissue, and stronger and stiffer bones after 3 weeks. Periosteal cells overexpressing NICD1 showed increased proliferation and migration in vitro. In vivo data confirmed that increased Notch1 signaling caused expansion of alpha-smooth muscle actin (αSMA)-positive cells and their progeny including αSMA-derived osteoblasts in the callus without affecting osteoclast numbers. In contrast, anti-NRR1 antibody treatment to inhibit Notch1 signaling resulted in increased callus cartilage area, reduced callus bone mass, and reduced biomechanical strength. Our study shows a positive effect of induced Notch1 signaling on the fracture healing process, suggesting that stimulating the Notch pathway could be beneficial for fracture repair. © 2020 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. DOI: 10.1002/jor.24650 PMCID: PMC7483882