Table 3. . Key bone regeneration factors mediated by protein or cytokine carried by exosomes.

Bone regeneration factor	Function	Study	Ref.
RUNX2	Key transcription factor for the differentiation of stem cells into osteoblast and inhibition of osteoblast maturation by suppression of OPN, BSP, OSX and OCN expression	Wang et al.; Deng et al.	[77,78]
PI3K-AKT	Key transcription factor with phosphatidylinositol 3-kinase (PI3K) and Akt/protein kinase B proteins involved. This signal transduction pathway promotes metabolism, proliferation, cell survival, growth and angiogenesis in response to extracellular signals	Xu et al.; Zhao et al.	[79,80]
Wnt	Key transcription factor for signaling pathway related to bone remodeling and repair. Wnt signaling system is also known to be a key factor to maintain bone mass	Komiya and Habbas; Issack et al.; Grigorie et al.; De Santis et al.	[81–84]
RANKL-RANK	Key signaling pathway responsible for homeostasis of bone metabolism determined by dynamic balance between osteoblast and osteoclast	Theoleyre et al.; Wada et al.; Leibbrandt et al.; Huynh et al.	[85–88]
BMP2	It is multi-functional growth factors which belong to superfamily TGF-β. The BMPs play critical roles in cartilage development, and specifically has been utilized for the therapeutics of bone defects, bone fractures, osteoporosis, spinal fusion and root canal surgery	Chen et al.	[89]
BMP9	BMP9 is known to have highest osteogenic potentials compared with other BMPs family. However, it is also revealed that BMP9 exerts broad range biological functions such as adipogenesis, angiogenesis, neurogenesis, oncogenesis and/or tumorigenesis and metabolism	Mostafa et al.; Bharadwaz and Jayasuriya	[90,91]
SPP1 (OPN)	SPP1 is also known as BSP1 or OPN. Among its diverse biological functions, OPN is known to regulate biomineralization because its calcium binding sites. As a member of SIBLING (Small Integrin-Binding Ligand, N-linked Glycoprotein) family, it can interact directly with extracellular matrix including fibronectin	Chen et al.; Mukherjee et al.; Fisher et al.; White et al.; Lund et al.; Singh et al.; Si et al.	[92–98]
OCN	Produced by osteoblast, OCN is the most abundant non-collagenous protein in bone. It regulates bone mineralization and coordinates mineral ions homeostasis. Bone quality is regulated by OCN because it aligns biological apatite parallel to the collagen fibrils	Wei and Karsenty; Komori	[99,100]
COL1	Type I collagen is the most abundant collagen and a key structural composition of bone tissue that is also expressed in almost all connective tissue as predominant component of interstitial tissue membrane	Henriksen and Karsdal	[101]
TGFβ1	TGFβ1 is abundant in bone, responsible for bone formation and resorption. It stimulates matrix protein synthesis and at the same time inhibits both osteoclast formation and activity	Bonewald and Mundy; Mundy	[102,103]
VEGF	This growth factor, VEGF belongs to PDGF super family. It regulates angiogenesis and vascular permeability	Risau; Shibuya	[104,105]
PDGF	When being activated, PDGF stimulates cell growth, changes cell shape by reorganization of actin filament and affects chemotaxis which directs cells motility. Its role is important during embryonic development and wound healing	Heldin and Westermark	[106]

The table is summarized from a chapter written by Yang et al. [76].

BMP: Bone morphogenetic protein; BSP: Bone sialoprotein; COL1: Type I collagen; OCN: Osteocalcin; OPN: Osteopontin; OSX: Osterix; SPP1: Secreted phosphoprotein 1