Notch signaling enhances bone regeneration in the zebrafish mandible

Abstract

Loss or damage to the mandible due to trauma, treatment of oral malignancies, and other diseases is treated using bone grafting techniques that suffer from numerous shortcomings and contraindications. Zebrafish naturally heal large injuries to mandibular bone, offering an opportunity to understand how to boost intrinsic healing potential. Using a novel her6:mCherry Notch reporter, we show that canonical Notch signaling is induced during the initial stages of cartilage callus formation in both mesenchymal cells and chondrocytes following surgical mandibulectomy. We also show that modulation of Notch signaling dose during the initial postoperative period results in lasting changes to regenerate bone quantity one month later. Pharmacological inhibition of Notch signaling reduces the size of the cartilage callus and delays its conversion into bone, resulting in non-union. Conversely, conditional transgenic activation of Notch signaling accelerates conversion of the cartilage callus into bone, improving bone healing. Given conserved functions of this pathway in bone repair across vertebrates, we propose that targeted activation of Notch signaling during the early phases of bone healing in mammals may both augment the size of the initial callus and boost its ossification into reparative bone.

Silencing of NOTCH3 Signaling in Meniscus Smooth Muscle Cells Inhibits Fibrosis and Exacerbates Degeneration in a HEYL‐Dependent Manner

“…HEYL, HEY1, and HES1 are effectors of the Notch pathway in fibrosis promotion [ 17 , 18 ] and are up‐regulated upon Notch signaling ligands binding to NOTCH receptors. [ 19 , 20 ] Here, we studied the expression of these genes during meniscus development. HEYL was only expressed in smooth muscle cells and pericytes during embryonic stages (E24 and E35 weeks) and hardly expressed at other stages or in other cell populations ( Figure 7 A,B ), suggesting that HEYL may play pivotal role in the critical stage of meniscus fibrosis.…”

Limb Mesoderm and Head Ectomesenchyme Both Express a Core Transcriptional Program During Chondrocyte Differentiation

“…Importantly, several of these putative novel genes, including Ptn, Tnc, Unc5c, and Fbln7, were also found to be expressed above threshold in mouse limb RNA-seq and scRNA-seq datasets (Ayturk et al, 2020;Duan et al, 2020;Sebastian et al, 2021). In addition, orthologs for most of these novel candidate genes are present in the genome of other vertebrates, including bony fishes, reptiles, amphibians, and cartilaginous fishes, and even some invertebrates, but only a few have been shown to be expressed in chondral bones of nonmammalian vertebrates, such as frog and fish (Nalbant et al, 2005;Geurtzen et al, 2014;Russell et al, 2014;Square et al, 2015;Barske et al, 2020;Kraus et al, 2022). Also, many of these novel putative core cartilage GRN genes have been found to be expressed in OA cartilage, and even to have a role during the progression of this skeletal disease, further supporting the importance of these genes during cartilage development (Mentlein 2007;Johnson et al, 2015;Sun et al, 2018;Zhang et al, 2018;Bhattaram and Jones 2019;Rice et al, 2019;Chakraborty et al, 2020;Hasegawa et al, 2020;Shi et al, 2022).…”

Hydrogel scaffolds in bone regeneration: Their promising roles in angiogenesis

“…The activation of Notch signaling promotes the differentiation of MSCs into osteoblasts and bone mineralization and suppresses osteogenesis via inhibiting the Wnt/β-catenin pathway ( Luo et al, 2019 ). Recently, Kraus et al (2022) showed that Notch signaling activation could accelerate cartilage callus conversion into bone and increase bone repair, whereas the inhibition of the signaling pathway delays the transformation of the cartilage callus into bone. In another study, Goel et al (2019) reported that Notch signaling suppression in osteoclasts improves bone formation rate and healing in mice, characterized by larger bony calluses and increased bone mineral density.…”