Table 1.
Cytokines involved in bone healing process.
| Cytokine | Phase | Expression | Main source/location | Function |
|---|---|---|---|---|
| TNF-α | Inflammatory phase | Increase and reach peak in 24h (Mouse) [128] | M1 type macrophages; Recruited immune cells | Induced by platelet hyperreactivity, recruit megakaryocytes and induce inflammation [129]; Recruit MSCs and enhance its proliferation and differentiation, but inhibit bone matrix synthesis at the injury site [[130], [131], [132]] |
| Bone formation phase | Decrease [128] | M1 type macrophages; Recruited immune cells | Promote angiogenesis, and MMPs production in endochondral bone [133] | |
| Remodeling phase | Increase again on day 24 and 28 (Mouse) [128] | Macrophages | Promote osteoclast migration and differentiation [134,135] | |
| IL-1 | Inflammatory phase | Increase and reach peak in 24h (Mouse) [128] | M1 type macrophages; Recruited immune cells | Promote catabolism and the degradation of proteoglycan [136] Enhance the chemotactic effect of immune cells migration and is a central role in responses to infections [137,138] |
| Remodeling phase | Increase again on day 24 and 28 (Mouse) [128] | M1 type macrophages; Recruited immune cells |
Promote osteoclast differentiation via RANKL and M-CSF [139,140] | |
| IL-4 | Inflammatory phase | Increase | M2 type macrophages | Inhibit inflammation and bone resorption [141]; Recruit and activate osteoblasts [142]; Inhibit osteogenic differentiation [143] |
| Remodeling phase | Increase | M2 type macrophages | Inhibit osteoclast differentiation and bone resorption via the RANKL/RANK/OPG system [144] | |
| IL-6 | Inflammatory phase; Remodeling phase |
Increase in 72h (Rat) [145] | M1 type macrophages; Monocytes; Other recruited immune cells |
Promote osteoblast differentiation [146,147]; Enhance the production of VEGF to promote angiogenesis [143]; Induce osteoclast formation via gp130 [148,149] |
| IL-10 | Bone formation phase | Increase | M2 type macrophages; B-cell | Suppress the expression of TNF-α and IFN-γ to inhibit inflammation and facilitate bone formation [150] |
| INF-γ | Inflammatory phase; Remodeling phase |
Increase | T lymphocyte; NK cell | Present positive or negative effect in bone formation depending on the experimental model and conditions used: Mediate macrophage polarization to M1 releasing pro-inflammatory cytokine [151]; Inhibit osteogenesis and bone formation [[152], [153], [154]]; Inhibit osteoclastogenesis and bone resorption [[155], [156], [157]] |
| BMPs | Inflammatory phase | Increase and BMP-2 reach peak in 24h (Mouse) [118] | Osteoprogenitor cells; Osteoblasts | BMP-2 initiate the repair cascade [118]; BMP-2, 6, and 9 induce MSCs differentiation to osteoblasts [158]; Promotes differentiation of MSCs into chondrocytes and osteoblasts; |
| Bone formation phase | BMP-3, 4, 5,6,7 and 8 increase (Mouse) [118] | Osteoprogenitor cells; Chondrocytes; Osteoblasts | BMP-3, 4, 7, and 8 specifically participate in osteogenic stage, while BMP-5 and 6 engage in intramembranous and endochondral ossification [118,159]; | |
| Remodeling phase | BMP-3, BMP-4, BMP-7, and BMP-8 Increase |
Osteoblasts; Osteoclast |
BMP-2 and 4 are observed in osteoclast-like cells, as well as prerequisites for osteoclast development [[160], [161], [162]]; BMP2 enhances osteoclast differentiation [163,164] |
|
| TGF-β | Inflammatory phase; | Increase | Platelets; Bone extracellular matrix |
Recruit inflammatory cells and MSCs [165,166]; Repress the differentiation of MSCs and chondrocyte, as well as relieve catabolism [[167], [168], [169], [170]] |
| Bone formation phase | TGF-β2 and TGF-β3 reach peak on day 7 (Mouse) [118] | Bone extracellular matrix | Promotes osteogenesis and chondrogenesis [119,[171], [172], [173]]; | |
| Remodeling phase | Increase | Bone extracellular matrix | Recruit MSCs to participate in bone remodeling [106,166]; Induce the bone resorption effect of osteoclast [172,174]; Recruit and promote the differentiation of osteoblast precursors [175]. |
|
| PDGF | Inflammatory phase； Bone formation phase |
Increase | Platelets; Macrophages; Osteoblasts | Promotes migration, proliferation, angiogenesis and osteogenic differentiation of MSCs [[176], [177], [178]] |
| FGF | Inflammatory phase； Bone formation phase |
Increase | Macrophages; Mesenchymal cells; Chondrocytes; Osteoblasts | Serve as a mitogen for mesenchymal cells [179]; Promote differentiation of osteoblast and chondrocytes [180,181]; Repress the degradation of cartilage in inflammations [182]; |
| VEGF | Inflammatory phase | Increase | Endothelial progenitor cells; Mesenchymal cells; Chondrocytes; Osteoblasts | Promote macrophage recruitment and angiogenesis [183] |
| Bone formation phase | Increase | Hypertrophic chondrocytes; Osteoblasts | Recruit blood vessels and osteoclasts and promote cartilage resorption [183] Indirectly promote bone formation via BMPs [184,185] |
|
| Remodeling phase | Increase | Osteoblasts | Stimulate osteoclast formation [183] | |
| IGF-1 | Bone formation phase | Increase | Chondrocytes; MSCs |
Enhance the synthesis of cartilage matrix [159,186]; Promote MSCs differentiation into osteoblast and enhance bone formation [187,188] |
| GDF-5/CDMP-1 （Homologues of BMP family） | Bone formation phase | Increase | MSCs; Chondrocytes; Hypertrophic chondrocytes | Stimulates the expression of cartilage anabolic Sox-9 to enhance chondrogenesis [189]; Promote osteogenic differentiation and angiogenic activity of stromal cells [190]; Promote angiogenesis and indirectly enhance osteogenesis [191]; Promotion of mesenchymal cell recruitment and chondrocyte differentiation [121,192] |
| SDF-1 | Bone formation phase | Increase | Stromal cell | Recruit stem cells and encourage osteogenic differentiation and production of bone [[193], [194], [195]] |
| M-CSF | Inflammatory phase | Increase and reach the first peak on day 3 (Mouse) [128] | Immune cells; Stromal cells; Osteoblast lineage | Promote macrophage polarization into M1 type releasing pro-inflammatory cytokines [108]; Promote osteoclast survival, activation and differentiation, as well as induce bone resorption [126,[196], [197], [198]]; |
| Late bone formation phase and remodeling phase | Increase and reach the second peak on day 14 (Mouse) [128] | |||
| RANKL | Inflammatory phase | Increase and reach the first peak on day 3 (Mouse) [128] | Stromal cells; Osteoblast lineage | Promote macrophage polarization into M1 type releasing pro-inflammatory cytokines [107]; Promote osteoclast differentiation and bone resorption [126]; |
| Late bone formation phase and remodeling phase | Increase and reach the second peak on day 14 (Mouse) [128] | Stromal cells; Osteoblast lineage | Promote osteoclast differentiation and bone remodeling [125,126]; | |
| OPG | Inflammatory phase | Increase and reach the first peak in 24h (Mouse) [128] | Stromal cells; Osteoblast lineage | Negatively regulate bone resorption by osteoblast [199] |
| Bone formation phase | Increase and reach the second peak on day 7 (Mouse) [128] | Participate in the long-term anabolism of bone healing [200]; | ||
| Remodeling phase | Increased | Inhibit osteoclastogenesis via competing with RANK for RANKL [201] |