Cell communication and relevant signaling pathways in osteogenesis-angiogenesis coupling

Abstract

Osteogenesis is the process of bone formation mediated by the osteoblasts, participating in various bone-related physiological processes including bone development, bone homeostasis and fracture healing. It exhibits temporal and spatial interconnectivity with angiogenesis, constructed by multiple forms of cell communication occurring between bone and vascular endothelial cells. Molecular regulation among different cell types is crucial for coordinating osteogenesis and angiogenesis to facilitate bone remodeling, fracture healing, and other bone-related processes. The transmission of signaling molecules and the activation of their corresponding signal pathways are indispensable for various forms of cell communication. This communication acts as a "bridge" in coupling osteogenesis to angiogenesis. This article reviews the modes and processes of cell communication in osteogenesis-angiogenesis coupling over the past decade, mainly focusing on interactions among bone-related cells and vascular endothelial cells to provide insights into the mechanism of cell communication of osteogenesis-angiogenesis coupling in different bone-related contexts. Moreover, clinical relevance and applications are also introduced in this review.

Fig. 1

Schematic diagram of different cell communication modes. Among these modes, intracrine and autocrine involve signal transmission within the same cell (self-communication), whereas the other modes facilitate communication between different cells (cell-to-cell communication), either directly or indirectly. Direct cell-cell communication (juxtacrine) occurs through physical contact between two cells, either via ligand-receptor interactions on cell membranes or through intercellular structures like gap junctions and membrane nanotubes, which allow the exchange of diffusible signaling molecules. Meanwhile, indirect cell-cell communication involves the transmission of signaling molecules (ligands) over a certain distance from donor cells to recipient cells. For instance, paracrine signaling affects nearby cells over short distances through diffusion, while endocrine signaling uses blood circulation to transport hormones over long distances to their target cells. Synaptic/neurotransmitter communication involves the release of neurotransmitter from synaptic vesicles (SVs) into synapses, and vesicular-cell communication employs extracellular vehicles (EVs) to deliver signaling molecules to target cells

Fig. 2

Key signal pathways involved in communication between bone and vascular cells. a The WNT signaling pathway and its ligands. b The PDGF signaling pathway. c The Notch signaling pathway. d The BMP Signaling pathway and its ligands. e The FGF signaling pathway. f The IGF signaling pathway. g The Hedgehog signaling pathway. h Other potential models of ECs factors regulating OBs. (Reproduced with permission; Copyright 2020, Ivyspring International Publisher)

Fig. 3

Communication between OBs and OCs. a Paracrine signaling molecules in OB-OC communication (Reproduced with permission; Copyright 2018, Nature Portfolio). b Vesicular RANKL and miRNAs in OB-exos (Reproduced with permission; Copyright 2022, Frontiers Media S.A.). c Vesicular RANK and RANK Reverse Pathway in OB-OC communication (Reproduced with permission; Copyright 2019, BMC). d Membrane proteins and miRNAs in osteoclast-derived exosomes (OC-exos) (Reproduced with permission; Copyright 2022, Frontiers Media S.A.). e Gap junctions between OBs, OCs, and Osteocytes (Reproduced with permission; Copyright 2023, MDPI)

Fig. 4

OB-EC communication. a Paracrine communication and soluble factors between OBs and ECs. b GJCs between human osteoprogenitor cells (HOPs) and HUVECs (Fig. 4a and b are reproduced with permission; Copyright 2009, Cell Press). c Paracrine soluble factors and the Notch signaling pathways in direct-contact mode of the cell communication between OPs (i.e., OPCs) and ECs, regulating the differentiation of OPs to OBs (Reproduced with permission; Copyright 2016, Annual Reviews Inc.)

Fig. 5

OC-EC communication. a Different modes of cell communication in the conversation of OCs, OBs, and ECs (Reproduced with permission; Copyright 2018, John Wiley and Sons). b Cell communication of type H ECs with osteoclast and its precursor (Reproduced with permission; Copyright 2020, Ivyspring International Publisher)

Fig. 6

An integrated signaling cascade in OB-OC-EC cross-communication and osteogenesis-angiogenesis coupling