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Table 1 Main signaling pathways in bone regeneration

From: The role of the immune microenvironment in bone, cartilage, and soft tissue regeneration: from mechanism to therapeutic opportunity

Signaling pathways

Major characteristics and functions

Applications in bone regeneration

BMP-2

BMP-2 initially binds to type II receptors on the cell membrane and then binds to type I receptors to form a dimer. The activated type I receptors rapidly phosphorylate the serine residues of SMAD-1, SMAD-5, and SMAD-8, and the activated SMADs are transferred into the nucleus and exert biological effects [35, 36]

The osteoporotic phenotype was reversed in mice with systematic injections of rhBMP-2 [35]

MSCs infected with a recombinant adenoviral vector encoding human BMP-2 were capable of repairing bone defects in ectopic sites through engrafting and forming bone and cartilage in mice [36, 37]

3D bioprinted implants containing a VEGF gradient, paired with spatially defined BMP-2 localization and release kinetics, expedited the healing of defects in large bone with the minuscule formation of heterotopic bone [38]

mRNA-based BMP-2 therapy was used to facilitate bone regeneration in mice [39,40,41]

NGF-p75 signaling

Cranial bone injuries stimulate NGF expression and its signals via p75 in resident osteogenic precursors that affect their migration into the damaged tissue and promote bone regeneration [42]

NGF-p75 signaling pathway coordinates skeletal cell migration during early bone repair [42]

FAK

Mechanotransduction via the FAK signaling pathway in skeletal stem cells promotes stem-cell-mediated regeneration of adult skeletal tissue [43, 44]

Inhibiting FAK abolishes bone regeneration in distraction osteogenesis [44]

NF-κB

Activation of NF-κB signaling in osteoclasts is crucial for their differentiation and activation, whereas the activation in osteoblasts inhibits bone formation. These unique characteristics imply the great potential of NF-κB as a therapeutic target for bone disorders and regeneration [45]

The activating NF-κB signaling may be one of the extrinsic mechanisms by which skeletal stem cell function decline during human skeletal aging [45,46,47,48,49]

  1. BMP-2 bone morphogenetic protein-2, FAK focal adhesion kinase, NF-κB nuclear factor-κB, NGF nerve growth factor, VEGF vascular endothelial growth factor, rhBMP-2 recombinant human bone morphogenetic protein-2, MSCs mesenchymal stem cells