Figure 6.

Schematic drawing of the possible signalling pathways regulated by PACAP in bone formation. PAC1 receptor activation leads to the increase of intracellular cAMP, which activates PKA. Downstream targets of PKA can be CREB or Runx2 transcription factors which activations induce the expression of collagen type I, osterix, osteocalcin, ostepontin and ALP. BMP6 and BMP7 binding to BMPR1 triggers the activation of Smad cascade which can induce the expression of collagen type I, osterix, osteocalcin, ostepontin, ALP and IHH. The activation of BMP signalling is fine-tuned by the activation of PACAP signalling. Runx2 phosphorylation can occur via BMPR1 activation, showing a PACAP independent mechanism. IHH and SHH activate Gli1 transcription factor which is inhibited by PACAP signalling. This signalling pathway is also responsible for the activation of collagen type I and ALP expression. Increased ALP expression and activation elevates the Ca²⁺ phosphate production. PACAP signalling keeps a balance between BMP and hedgehog signalling activation via this regulates proper bone formation.