Hedgehog and PTH signaling pathways in bone and cartilage
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) ,
and via parathyroid hormone signaling, inducing Parathyroid hormone 1 receptor
(PTHR1) expression .
The PTHR1 is a GPCR which binds to both Parathyroid
hormone (PTH) and PTHrP with
almost equal affinity . PTHR1 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
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 PTHR1. 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 .
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