Osteoblast-derived EGFL6 couples angiogenesis to osteogenesis during bone repair

Abstract

Rationale: Angiogenesis and osteogenesis are highly coupled processes which are indispensable to bone repair. However, the underlying mechanism(s) remain elusive. To bridge the gap in understanding the coupling process is crucial to develop corresponding solutions to abnormal bone healing. Epidermal growth factor-like protein 6 (EGFL6) is an angiogenic factor specifically and distinctively up-regulated during osteoblast differentiation. In contrast with most currently known osteoblast-derived coupling factors, EGFL6 is highlighted with little or low expression in other cells and tissues. Methods: In this study, primary bone marrow mesenchymal stem cells (MSCs) and osteoblastic cell line (MC3T3-E1) were transduced with lentiviral silencing or overexpression constructs targeting EGFL6. Cells were induced by osteogenic medium, followed by the evaluation of mineralization as well as related gene and protein expression. Global and conditional knockout mice were established to examine the bone phenotype under physiological condition. Furthermore, bone defect models were created to investigate the outcome of bone repair in mice lacking EGFL6 expression. Results: We show that overexpression of EGFL6 markedly enhances osteogenic capacity in vitro by augmenting bone morphogenic protein (BMP)-Smad and MAPK signaling, whereas downregulation of EGFL6 diminishes osteoblastic mineralization. Interestingly, osteoblast differentiation was not affected by the exogenous addition of EGFL6 protein, thereby indicating that EGFL6 may regulate osteoblastic function in an intracrine manner. Mice with osteoblast-specific and global knockout of EGFL6 surprisingly exhibit a normal bone phenotype under physiological conditions. However, EGFL6-deficiency leads to compromised bone repair in a bone defect model which is characterized by decreased formation of type H vessels as well as osteoblast lineage cells. Conclusions: Together, these data demonstrate that EGFL6 serves as an essential regulator to couple osteogenesis to angiogenesis during bone repair.

Polydopamine-coated 3D-printed β-tricalcium phosphate scaffolds to promote the adhesion and osteogenesis of BMSCs for bone-defect repair: mRNA transcriptomic sequencing analysis

“…47 The TGF-b, MAPK, and PI3K-Akt signaling pathways have been shown to regulate osteogenesis and bone metabolism. [48][49][50] Moreover, the Wnt and BMP signaling pathways are critical for the osteogenic differentiation of BMSCs. [44][45][46] Studies have also shown that suppressing the NF-kappa B signaling pathway can improve the osteogenic differentiation of stem cells.…”

Structural and Functional Adaptive Artificial Bone: Materials, Fabrications, and Properties

“…Reproduced with permission. [ 242 ] Copyright 2021, PubMed Central. C) The addition of exogenous drug dexamethasone in bone regeneration.…”

“…[241] Chen et al studied the function of epidermal growth factor-like protein 6 (EGFL6) in the osteogenic capacity of BMSCs and MC3T3-E1 cells, and the results indicated that EGFL6 enhanced osteogenic capacity and directed angiogenesis during bone repair. [242] Novais et al investigated the effect of FGF-2 in collagen hydrogels on the bone formation in the context of craniofacial bone repair and found that FGF-2 allowed a rapid compact extracellular matrix for favor bone formation. [247] Adv.…”

ROS-scavenging hydrogel as protective carrier to regulate stem cells activity and promote osteointegration of 3D printed porous titanium prosthesis in osteoporosis

“…EDITED BY multiple signals trigger BMSCs in bone marrow or surrounding tissues to migrate to the injured regions and play a paracrine role (Chen et al, 2021;Du et al, 2021;Sheng et al, 2022). In addition, BMSCs also have a hand in the healing stages of inflammation, repair, and remodeling together with stromal cells, progenitor cells, pro-inflammatory (M1 phenotype) macrophages, and anti-inflammatory (M2 phenotype) macrophages (Zou et al, 2021;Arostegui et al, 2022).…”

“…In bone homeostasis, the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) is an important issue in the repair of bone injuries, including fracture healing and osteointegration at the prosthesis interface after joint replacement ( Wang et al, 2021 ). Once bone injuries occur, multiple signals trigger BMSCs in bone marrow or surrounding tissues to migrate to the injured regions and play a paracrine role ( Chen et al, 2021 ; Du et al, 2021 ; Sheng et al, 2022 ). In addition, BMSCs also have a hand in the healing stages of inflammation, repair, and remodeling together with stromal cells, progenitor cells, pro-inflammatory (M1 phenotype) macrophages, and anti-inflammatory (M2 phenotype) macrophages ( Zou et al, 2021 ; Arostegui et al, 2022 ).…”