Development - Hedgehog and PTH signaling pathways in bone and cartilage development

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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 [1]; 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 [2]. Hedgehog and PTHR 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, 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 [3]. Glioma-associated oncogene homolog (Gli) family of transcription factors mediates gene expression in response to Hedgehog [2], [3]. The details of the Gli activation are not known [4]. Hedgehog receptor Ptc itself is one of transcriptional targets of Hedgehog -signaling [2], [3], [5].

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) [6], and via parathyroid hormone signaling, inducing Parathyroid hormone 1 receptor (PTHR1) expression [3].

The PTHR1 is a GPCR which binds to both Parathyroid hormone (PTH) and PTHrP with almost equal affinity [7]. 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 [1]. 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 [8]. The Runx2 is an important transcription factor necessary for osteoblast differentiation and bone formation [9]. 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 [9]. PTH directly stimulates expression of Tumor necrosis factor superfamily, member 11 (RANKL) [8], [10] via a PKA/ CREB1 pathway in osteoblastic cells. CREB1 is proposed to be the central regulator of RANKL expression [10]. Cyclin D1 and Cyclin A genes are also targets of the activated PTHR1. Activation of their both promoters requires functional CREB1 [11].

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 [3].

References:

  1. Miao D, Tong XK, Chan GK, Panda D, McPherson PS, Goltzman D
    Parathyroid hormone-related peptide stimulates osteogenic cell proliferation through protein kinase C activation of the Ras/mitogen-activated protein kinase signaling pathway. The Journal of biological chemistry 2001 Aug 24;276(34):32204-13
  2. Yamaguchi A, Komori T, Suda T
    Regulation of osteoblast differentiation mediated by bone morphogenetic proteins, hedgehogs, and Cbfa1. Endocrine reviews 2000 Aug;21(4):393-411
  3. Deckelbaum RA, Chan G, Miao D, Goltzman D, Karaplis AC
    Ihh enhances differentiation of CFK-2 chondrocytic cells and antagonizes PTHrP-mediated activation of PKA. Journal of cell science 2002 Jul 15;115(Pt 14):3015-25
  4. Sushchenko OV, Evdokimov EV
    [Selection in the context of provocation in artificial populations of Drosophila melanogaster]. Genetika 1992 Sep;28(9):75-81
  5. Eichberger T, Regl G, Ikram MS, Neill GW, Philpott MP, Aberger F, Frischauf AM
    FOXE1, a new transcriptional target of GLI2 is expressed in human epidermis and basal cell carcinoma. The Journal of investigative dermatology 2004 May;122(5):1180-7
  6. Yoon JW, Kita Y, Frank DJ, Majewski RR, Konicek BA, Nobrega MA, Jacob H, Walterhouse D, Iannaccone P
    Gene expression profiling leads to identification of GLI1-binding elements in target genes and a role for multiple downstream pathways in GLI1-induced cell transformation. The Journal of biological chemistry 2002 Feb 15;277(7):5548-55
  7. Mannstadt M, Juppner H, Gardella TJ
    Receptors for PTH and PTHrP: their biological importance and functional properties. The American journal of physiology 1999 Nov;277(5 Pt 2):F665-75
  8. Bellido T, Ali AA, Plotkin LI, Fu Q, Gubrij I, Roberson PK, Weinstein RS, O'Brien CA, Manolagas SC, Jilka RL
    Proteasomal degradation of Runx2 shortens parathyroid hormone-induced anti-apoptotic signaling in osteoblasts. A putative explanation for why intermittent administration is needed for bone anabolism. The Journal of biological chemistry 2003 Dec 12;278(50):50259-72
  9. Franceschi RT, Xiao G
    Regulation of the osteoblast-specific transcription factor, Runx2: responsiveness to multiple signal transduction pathways. Journal of cellular biochemistry 2003 Feb 15;88(3):446-54
  10. Fu Q, Jilka RL, Manolagas SC, O'Brien CA
    Parathyroid hormone stimulates receptor activator of NFkappa B ligand and inhibits osteoprotegerin expression via protein kinase A activation of cAMP-response element-binding protein. The Journal of biological chemistry 2002 Dec 13;277(50):48868-75
  11. Beier F, LuValle P
    The cyclin D1 and cyclin A genes are targets of activated PTH/PTHrP receptors in Jansen's metaphyseal chondrodysplasia. Molecular endocrinology (Baltimore, Md.) 2002 Sep;16(9):2163-73

  1. Miao D, Tong XK, Chan GK, Panda D, McPherson PS, Goltzman D
    Parathyroid hormone-related peptide stimulates osteogenic cell proliferation through protein kinase C activation of the Ras/mitogen-activated protein kinase signaling pathway. The Journal of biological chemistry 2001 Aug 24;276(34):32204-13
  2. Yamaguchi A, Komori T, Suda T
    Regulation of osteoblast differentiation mediated by bone morphogenetic proteins, hedgehogs, and Cbfa1. Endocrine reviews 2000 Aug;21(4):393-411
  3. Deckelbaum RA, Chan G, Miao D, Goltzman D, Karaplis AC
    Ihh enhances differentiation of CFK-2 chondrocytic cells and antagonizes PTHrP-mediated activation of PKA. Journal of cell science 2002 Jul 15;115(Pt 14):3015-25
  4. Sushchenko OV, Evdokimov EV
    [Selection in the context of provocation in artificial populations of Drosophila melanogaster]. Genetika 1992 Sep;28(9):75-81
  5. Eichberger T, Regl G, Ikram MS, Neill GW, Philpott MP, Aberger F, Frischauf AM
    FOXE1, a new transcriptional target of GLI2 is expressed in human epidermis and basal cell carcinoma. The Journal of investigative dermatology 2004 May;122(5):1180-7
  6. Yoon JW, Kita Y, Frank DJ, Majewski RR, Konicek BA, Nobrega MA, Jacob H, Walterhouse D, Iannaccone P
    Gene expression profiling leads to identification of GLI1-binding elements in target genes and a role for multiple downstream pathways in GLI1-induced cell transformation. The Journal of biological chemistry 2002 Feb 15;277(7):5548-55
  7. Mannstadt M, Juppner H, Gardella TJ
    Receptors for PTH and PTHrP: their biological importance and functional properties. The American journal of physiology 1999 Nov;277(5 Pt 2):F665-75
  8. Bellido T, Ali AA, Plotkin LI, Fu Q, Gubrij I, Roberson PK, Weinstein RS, O'Brien CA, Manolagas SC, Jilka RL
    Proteasomal degradation of Runx2 shortens parathyroid hormone-induced anti-apoptotic signaling in osteoblasts. A putative explanation for why intermittent administration is needed for bone anabolism. The Journal of biological chemistry 2003 Dec 12;278(50):50259-72
  9. Franceschi RT, Xiao G
    Regulation of the osteoblast-specific transcription factor, Runx2: responsiveness to multiple signal transduction pathways. Journal of cellular biochemistry 2003 Feb 15;88(3):446-54
  10. Fu Q, Jilka RL, Manolagas SC, O'Brien CA
    Parathyroid hormone stimulates receptor activator of NFkappa B ligand and inhibits osteoprotegerin expression via protein kinase A activation of cAMP-response element-binding protein. The Journal of biological chemistry 2002 Dec 13;277(50):48868-75
  11. Beier F, LuValle P
    The cyclin D1 and cyclin A genes are targets of activated PTH/PTHrP receptors in Jansen's metaphyseal chondrodysplasia. Molecular endocrinology (Baltimore, Md.) 2002 Sep;16(9):2163-73

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