EGR1, Osteocalcin , PKA-cat (cAMP-dependent), Adenylate cyclase type I, Collagen II, PTHrP, SHH, 18.104.22.168, MMP-13, Cyclin D1, ATP, GLI-1, GLI-2, COL1A1, DAG, CREB1, COL1A2, PKA-reg (cAMP-dependent), Osteopontin, VDR, PTCH1, RANKL(TNFSF11), 22.214.171.124, RUNX2, G-protein alpha-s, G-protein alpha-q/11, Cyclin A, Galpha(q)-specific parathyroid hormone GPCRs, Parathyroid hormone, Ihh, IP3, c-Fos, PtdIns(4,5)P2, Bone sialoprotein, PLC-beta, Smoothened, cAMP
Hedgehog and PTH signaling pathways in bone and cartilage development
Both the Hedgehog and the Parathyroid hormone receptor ( PTHR ) signaling pathways take part in bone and cartilage development (12082161): Parathyroid hormone-like hormone ( PTHrP ) stimulates osteogenic cell proliferation ; Sonic hedgehog homolog ( SHH ) and Indian hedgehog homolog ( IHH ) protein family members cause chondrocyte differentiation; IHH induces differentiation of adjacent perichondrial cells into bone-forming osteoblasts . Hedgehog and PTHR signaling pathways closely interact .
The Hedgehog protein family members bind their cognate receptor - patched homolog ( Ptc ), a 12-transmembrane (TM) protein that otherwise interacts with, and inhibits, 7-TM receptor protein Smoothened homolog ( Smo ). The ligand-induced release of Smo from its interaction with Ptc results in an intracellular signal transduction cascade . Glioma-associated oncogene homolog ( Gli ) family of transcription factors mediates gene expression in response to Hedgehog , . The details of the Gli activation are not known . Hedgehog receptor Ptc itself is one of transcriptional targets of Hedgehog -signaling , , .
The Hedgehog pathway regulates expression of the genes involved both in bone and cartilage development via transcription factors Gli such as Secreted phosphoprotein 1 ( Osteopontin ) , Collagen, type II, alpha 1 ( Collagen 2A1 )  and via PTHRP signaling cascade, inducing PTH/PTHRP receptor expression .
The PTH/PTHRP receptor is a GPCR which binds to both Parathyroid hormone ( PTH ) and PTHrP with almost equal affinity . PTH/PTHRP receptor is associated with at least two signal transduction systems, the cAMP-dependent protein kinase ( PKA ) pathway and the Phospholipase C ( PLC beta )/ Protein kinase C ( PKC ) activation of v-Ha-ras Harvey rat sarcoma viral oncogene homolog ( H-Ras )/ ERK signaling pathway . Both systems take part in regulation of a number of target proteins involved in bone and cartilage development.
Activation of transcription factors cAMP responsive element binding protein 1 ( CREB1 ) and Runt-related transcription factor 2 ( Runx2 ) via PKA in response to PTH in osteoblasts was clearly shown . The Runx2 is an important transcription factor necessary for osteoblast differentiation and bone formation . PTH stimulates Matrix metallopeptidase 13 ( MMP-13 ) promoter via a PKA -dependent pathway that phosphorylates Runx2 and up-regulates v-fos FBJ murine osteosarcoma viral oncogene homolog ( c-Fos ) and Jun oncogene ( c-Jun ) via phosphorylation of CREB1 . PTH directly stimulates expression of Tumor necrosis factor superfamily, member 11 ( RANKL ) ,  via a PKA/ CREB1 pathway in osteoblastic cells. CREB1 is proposed to be the central regulator of RANKL expression . Cyclin D1 and Cyclin A genes are also targets of the activated PTH/PTHrP receptor Activation of their both promoters requires functional CREB1 .
PTHrP signaling modulates Hedgehog pathway via PKA, which regulates expression of Gli factors. PKA may differentially phosphorylate transcription factors Gli, consequently converting them to repressors and causing downregulation of some Hedgehog target genes .