Epidermal growth factor signalling pathway in endochondral ossification: an evidence-based narrative review

Abstract

During endochondral bone development, a complex process that leads to the formation of the majority of skeletal elements, mesenchymal cells condense, differentiating into chondrocytes and producing the foetal growth plate. Chondrocytes progressively hypertrophy, induce angiogenesis and are then gradually replaced by bone. Epidermal Growth Factor (EGF), one of many growth factors, is the prototype of the EGF-ligand family, which comprises several proteins involved in cell proliferation, migration and survival. In bone, EGF pathway signalling finely tunes the first steps of chondrogenesis by maintaining mesenchymal cells in an undifferentiated stage, and by promoting hypertrophic cartilage replacement. Moreover, EGF signalling modulates bone homeostasis by stimulating osteoblast and osteoclast proliferation, and by regulating osteoblast differentiation under specific spatial and temporal conditions. This evidence-based narrative review describes the EGF pathway in bone metabolism and endochondral bone development. This comprehensive description may be useful in light of possible clinical applications in orthopaedic practice. A deeper knowledge of the role of EGF in bone may be useful in musculoskeletal conditions which may benefit from the modulation of this signalling pathway. Key messages The EGF pathway is involved in bone metabolism. EGF signalling is essential in the very early stages of limb development by maintaining cells in an undifferentiated stage. EGF pathway positively regulates chondrocyte proliferation, negatively modulates hypertrophy, and favours cartilage replacement by bone. EGF and EGF-like proteins finely tune the proliferation and differentiation of bone tissue cells, and they also regulate the initial phases of endochondral ossification.

CD10-Bound Human Mesenchymal Stem/Stromal Cell-Derived Small Extracellular Vesicles Possess Immunomodulatory Cargo and Maintain Cartilage Homeostasis under Inflammatory Conditions

“…Several studies have associated high NGFR gene and protein expressions in MSC with their increased chondrogenic capacity in vitro and osteochondral cartilage repair in vivo [39][40][41]. Pro-chondrogenic and pro-angiogenic actions can be also attributed to MSC with high expression levels of ALPL, EGF, BMP7, and ITGAX genes [42][43][44]. Of note, the MCAM (CD146) gene higher expressed in CD10High IFP-MSC is directly related to increased immunomodulatory MSC actions in vitro and in vivo [45].…”

Insulin-like growth factor receptor / mTOR signaling elevates global translation to accelerate zebrafish fin regenerative outgrowth

“…We discounted BMP receptors, previously implicated in fin osteoblast differentiation (Stewart et al, 2014), given AB.9 cells autonomously activated BMP signaling without differentiating (Figure Supplement 4-1). We then focused on pathways previously associated with osteoblast maturation (reviewed in Plotkin and Bruzzaniti, 2019, Mangiavini et al, 2022, Hacemi et al, 2018). We assessed the ability of corresponding ligands (IGF-1, FGF, EGF, PDGF), a canonical Wnt agonist (the GSK3 inhibitor CHIR99021), and a glucocorticoid receptor agonist (Dexamethasone (Dex)) to promote AB.9 cell differentiation.…”

Identification of cellular heterogeneity and key signaling pathways associated with vascular remodeling and calcification in young and old primate aortas based on single-cell analysis

“…Besides, we found that EGF signaling pathway was exclusively received by SMCs in aged aortas, which indicates its important role in vascular aging. EGF encodes a member of the epidermal growth factor superfamily that plays an important role in the growth, proliferation and differentiation of numerous cell types [50]. Moreover, EGF signaling has been reported to play an important role in endochondral ossification and bone homeostasis [51], which indicates that EGF signaling pathway may be involved in vascular calcification of aged aortas.…”