Adipokines regulate mesenchymal stem cell osteogenic differentiation

Table 1 Key activities of factors released by adipose tissue

Classification	Appellation	Mechanism	Ref.
Cytokine and cytokine-like proteins	Interleukin	IL-6 induces osteogenic differentiation in human bone marrow-derived MSCs via MAPK signaling. IL-10 inhibits osteogenic differentiation of MSCs prior to ALP expression. IL-17 promoting the transformation of MSC into bone progenitor cells or osteoblasts	[24,26,28]
	TNF-α	High dose of TNF could stimulate the upregulation of some osteogenic factors in MSCs, including VEGF and insulin-like growth factor. Low-dose TNF-α inhibited the mineralization and activation of ALP and OPN in cultured MSCs	[22,30]
	MCP-1	Influencing monocyte migration and subsequent macrophage polarization	[31]
	TGF-β	Through the precise matching of ligands, receptors, and cell signaling molecules, TGF-β is involved in the lineage transformation process of the differentiation of various stem cells, such as lipid, osteoblast, chondrogenic, and myogenic	[34]
	Chemerin	Chemerin promotes lipogenesis and inhibits osteogenic differentiation of MSCs	[42]
Proteins of the fibrinolytic system	PAI-1	Loss of PAI-1 significantly weakened the expression of bone marrow-derived MSC osteogenic genes, such as BMP-2 and ALP	[45]
	Tissue factor	Tissue factor silencing could effectively induce higher differentiation of MSCs in osteogenic and lipid-forming media	[48]
Complement and complement-related proteins	Adipsin	Adipsin initiates adipogenesis from bone marrow MSCs by activating Wnt signaling	[53]
Adipokines	Leptin	Leptin has been shown to cross-regulate BMP-9 signaling through the JAK/STAT signaling pathway in MSCs, thereby enhancing BMP-9-induced osteogenesis	[60]
	Adiponectin	adiponectin regulates BMSC osteogenic differentiation and osteogenesis through the Wnt/β-catenin pathway	[63]
	Visfatin	Promoting the proliferation and mineralization activity of osteoblasts	[68]
	Nicotinamide	Nampt is a speed-limit enzyme and participates in the all-around MC3T3-E1. Osteogenesis prior to the cell differentiation process of NAD salvage pathways	[67]
	Visceral	Attenuating the osteogenic differentiation of preosteoblast cell line MC3T3-E1	[73]
	Bone morphogenetic proteins	BMP-7 induced increased expression of ALP, a marker of osteoblast differentiation, and accelerated calcification. The absence of BMP-2 and BMP-4 resulted in severely impaired osteogenic function. BMP-3 regulates adult bone mass by limiting the differentiation of bone progenitor cells into mature osteoblasts	[78-80]
	Nesfatin-1	Promoting the expression of osteogenic genes such as ALP and RUNX2 in rats’ newly derived stem cells	[89]
	Cathepsins	Knockout or inhibition of cathepsin K could promote the regeneration of bone marrow MSCs of jaw bone through glycolysis. Cathepsin S deficiency alters the balance between adipocyte and osteoblast differentiation, increases bone turnover, and alters bone microstructure	[94,95]
	Apelin	Promoting postpositional MSC osteoblast differentiation by activating the Wnt/β-catenin signaling pathway	[98]
	Omentin-1	Increasing the expression of BMP2, RUNX2, OPN, and osteocalcin	[102]
	Lipocalin 2	Disrupting osteoclast formation in bone tissue by negatively regulating the proliferation and differentiation of osteoclast precursors	[105]
	Melatonin	Differentiating bone marrow progenitors from adipocytes to osteoblasts	[111]
	Gremlin-1	BMP protein inhibitor	[112]
Lipid transport	ApoE	Enhancing osteogenic differentiation of the mouse mesenchymal progenitor cell line	[120]
Enzymes	DPP-4	Restricting the induction of osteogenic differentiation of heart artery flap-derived mesenchymal cells by the autocrine insulin-like growth factor-1 signaling pathway	[122]
	Tissue inhibitors of metalloproteinases	Inhibition of endogenous TIMP-1 can inhibit the proliferation, metabolic activity, and osteogenic differentiation ability of MSCs by activating the Wnt/β-catenin signal	[127]

ALP: Alkaline phosphatase; ApoE: Apolipoprotein E; BMP-2: Bone morphogenetic protein 2; DPP-4: Dipeptidyl peptidase 4; IL: Interleukin; JAK: Janus kinase; MAPK: Mitogen-activated protein kinase; MCP-1: Monocyte chemotactic protein 1; MSC: Mesenchymal stem cell; Nampt: Nicotinamide phosphoribosyltransferase; OPN: Osteopontin; PAI-1: Plasminogen activator inhibitor-1; RUNX2: Runt-related transcription factor 2; TIMP-1: Tissue inhibitors of metalloproteinase; TGF-β: Transforming growth factor beta; TNF: Tumor necrosis factor; VEGF: Vascular endothelial growth factor.