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Development Hedgehog and PTH signaling pathways in bone and cartilage development

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Development Hedgehog and PTH signaling pathways in bone and cartilage development

Hedgehog and PTH signaling pathways in bone and cartilage development

Both the Hedgehog and the Parathyroid hormone receptor ( PTHR ) signalingpathways take part in bone and cartilage development (12082161): Parathyroid hormone-likehormone ( PTHrP ) stimulates osteogenic cell proliferation [1]; Sonichedgehog homolog ( SHH ) and Indian hedgehog homolog ( IHH ) protein familymembers cause chondrocyte differentiation; IHH induces differentiation of adjacentperichondrial cells into bone-forming osteoblasts [2]. Hedgehog andPTHR signaling pathways closely interact [3].

The Hedgehog protein family members bind their cognate receptor - patched homolog (Ptc ), a 12-transmembrane (TM) protein that otherwise interacts with, andinhibits, 7-TM receptor protein Smoothened homolog ( Smo ). The ligand-inducedrelease of Smo from its interaction with Ptc results in an intracellularsignal transduction cascade [3]. Glioma-associated oncogene homolog (Gli ) family of transcription factors mediates gene expression in response toHedgehog [3], [2]. The details of the Gli activation arenot known [4]. Hedgehog receptor Ptc itself is one of transcriptionaltargets of Hedgehog -signaling [2], [3], [5].

The Hedgehog pathway regulates expression of the genes involved both in bone andcartilage development via transcription factors Gli such as Secretedphosphoprotein 1 ( Osteopontin ) [6], Collagen, type II, alpha 1 ( Collagen 2A1 ) [6] and via PTHRP signaling cascade, inducing PTH/PTHRP receptorexpression [3].

The PTH/PTHRP receptor is a GPCR which binds to both Parathyroid hormone (PTH ) and PTHrP with almost equal affinity [7]. PTH/PTHRPreceptor is associated with at least two signal transduction systems, thecAMP-dependent protein kinase ( PKA ) pathway and the Phospholipase C ( PLCbeta )/ Protein kinase C ( PKC ) activation of v-Ha-ras Harvey rat sarcomaviral oncogene homolog ( H-Ras )/ ERK signaling pathway [1].Both systems take part in regulation of a number of target proteins involved in bone andcartilage development.

Activation of transcription factors cAMP responsive element binding protein 1 (CREB1 ) and Runt-related transcription factor 2 ( Runx2 ) via PKA inresponse to PTH in osteoblasts was clearly shown [8]. TheRunx2 is an important transcription factor necessary for osteoblastdifferentiation and bone formation [9]. PTH stimulates Matrixmetallopeptidase 13 ( MMP-13 ) promoter via a PKA -dependent pathway thatphosphorylates Runx2 and up-regulates v-fos FBJ murine osteosarcoma viral oncogenehomolog ( c-Fos ) and Jun oncogene ( c-Jun ) via phosphorylation ofCREB1 [9]. PTH directly stimulates expression of Tumornecrosis factor superfamily, member 11 ( RANKL ) [8], [10] via a PKA/ CREB1 pathway in osteoblastic cells. CREB1 isproposed to be the central regulator of RANKL expression [10].Cyclin D1 and Cyclin A genes are also targets of the activated PTH/PTHrPreceptor Activation of their both promoters requires functional CREB1 [11].

PTHrP signaling modulates Hedgehog pathway via PKA, which regulatesexpression of Gli factors. PKA may differentially phosphorylatetranscription factors Gli, consequently converting them to repressors and causingdownregulation of some Hedgehog target genes [3].