Signal transduction pathways mediating parathyroid hormone regulation of osteoblastic gene expression

Parathyroid hormone (PTH) plays a central role in regulation of calcium metabolism. For example, excessive or inappropriate production of PTH or the related hormone, parathyroid hormone related protein (PTHrP), accounts for the majority of the causes of hypercalcemia. Both hormones act through the same receptor on the osteoblast to elicit enhanced bone resorption by the osteoclast. Thus, the osteoblast mediates the effect of PTH in the resorption process. In this process, PTH causes a change in the function and phenotype of the osteoblast from a cell involved in bone formation to one directing the process of bone resorption. In response to PTH, the osteoblast decreases collagen, alkaline phosphatase, and osteopntin expression and increases production of osteocalcin, cytokines, and neutral proteases. Many of these changes have been shown to be due to effects on mRNA abundance through either transcriptional or post‐transcriptional mechanisms. However, the signal transduction pathway for the hormone to cause these changes is not completely elucidated in any case. Binding of PTH and PTHrP to their common receptor has been shown to result in activation of protein kinases A and C and increases in intracellular calcium. The latter has not been implicated in any changes in mRNA of osteoblastic genes. On the other hand activation of PKA can mimic all the effects of PTH; protein kinase C may be involved in some responses. We will discuss possible mechanisms linking PKA and PKC activation to changes in gene expression, particularly at the nuclear level. © 1994 Wiley‐Liss, Inc.

[1]  H. Donahue,et al.  Regulation of cytokine expression in osteoblasts by parathyroid hormone: Rapid stimulation of interleukin‐6 and leukemia inhibitory factor mRNA , 1993, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[2]  D. Rowe,et al.  Parathyroid hormone represses alpha 1(I) collagen promoter activity in cultured calvariae from neonatal transgenic mice. , 1993, Molecular endocrinology.

[3]  E. Wagner,et al.  Bone and haematopoietic defects in mice lacking c-fos , 1992, Nature.

[4]  J. Clohisy,et al.  Parathyroid hormone induces transcription of collagenase in rat osteoblastic cells by a mechanism using cyclic adenosine 3',5'-monophosphate and requiring protein synthesis. , 1992, Molecular endocrinology.

[5]  S Bord,et al.  Human osteoblasts in culture synthesize collagenase and other matrix metalloproteinases in response to osteotropic hormones and cytokines. , 1992, Journal of cell science.

[6]  J. Roberts,et al.  Beta-adrenergic stimulation of cFOS via protein kinase A is mediated by cAMP regulatory element binding protein (CREB)-dependent and tissue-specific CREB-independent mechanisms in corticotrope cells. , 1992, The Journal of biological chemistry.

[7]  B. Spiegelman,et al.  Pleiotropic effects of a null mutation in the c-fos proto-oncogene , 1992, Cell.

[8]  J. Clohisy,et al.  Parathyroid hormone induces c-fos and c-jun messenger RNA in rat osteoblastic cells. , 1992, Molecular endocrinology.

[9]  D. Kujubu,et al.  The effects of prostaglandin E2, parathyroid hormone, and epidermal growth factor on mitogenesis, signaling, and primary response genes in UMR 106-01 osteoblast-like cells. , 1992, Endocrinology.

[10]  W. R. Weaver,et al.  Regulation of an H-ras-related transcript by parathyroid hormone in rat osteosarcoma cells. , 1992, Molecular endocrinology.

[11]  P. Sassone-Corsi,et al.  Developmental switch of CREM function during spermatogenesis: from antagonist to activator , 1992, Nature.

[12]  M. Karin,et al.  The role of Jun, Fos and the AP-1 complex in cell-proliferation and transformation. , 1991, Biochimica et biophysica acta.

[13]  R. St-Arnaud,et al.  Differential stimulation of fos and jun family members by calcitriol in osteoblastic cells. , 1991, Molecular endocrinology.

[14]  M. Freeman,et al.  A G protein-linked receptor for parathyroid hormone and parathyroid hormone-related peptide. , 1991, Science.

[15]  Jones Nc,et al.  Differential regulation of three members of the ATF/CREB family of DNA-binding proteins. , 1991 .

[16]  N. Jones,et al.  Identification and functional characterisation of the cellular activating transcription factor 43 (ATF-43) protein. , 1991, Nucleic acids research.

[17]  E. Borrelli,et al.  CREM gene: Use of alternative DNA-binding domains generates multiple antagonists of cAMP-induced transcription , 1991, Cell.

[18]  M. Gilman,et al.  Distinct protein targets for signals acting at the c-fos serum response element. , 1991, Science.

[19]  B. A. Hocevar,et al.  Selective translocation of beta II-protein kinase C to the nucleus of human promyelocytic (HL60) leukemia cells. , 1991, The Journal of biological chemistry.

[20]  L. Matrisian,et al.  Rat collagenase. Cloning, amino acid sequence comparison, and parathyroid hormone regulation in osteoblastic cells. , 1990, The Journal of biological chemistry.

[21]  K. Wright,et al.  Coordinate occupancy of AP-1 sites in the vitamin D-responsive and CCAAT box elements by Fos-Jun in the osteocalcin gene: model for phenotype suppression of transcription. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[22]  J. Habener.  Cyclic AMP response element binding proteins: a cornucopia of transcription factors. , 1990, Molecular endocrinology.

[23]  R. Ziegler,et al.  Differential regulation of plasminogen activator and plasminogen activator inhibitor by osteotropic factors in primary cultures of mature osteoblasts and osteoblast precursors. , 1990, Endocrinology.

[24]  J. Auwerx,et al.  Coupled and uncoupled induction of fos and jun transcription by different second messengers in cells of hematopoietic origin. , 1990, Nucleic acids research.

[25]  T. Hahn,et al.  Protein kinase C activity in UMR‐106‐01 cells: Effects of parathyroid hormone and insulin , 1989, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[26]  K. Riabowol,et al.  Multiple sequence elements of a single functional class are required for cyclic AMP responsiveness of the mouse c-fos promoter , 1989, Molecular and cellular biology.

[27]  L. Aarden,et al.  Parathyroid hormone (PTH) and PTH-like protein (PLP) stimulate interleukin-6 production by osteogenic cells: a possible role of interleukin-6 in osteoclastogenesis. , 1989, Biochemical and biophysical research communications.

[28]  F. D. Di Padova,et al.  Interleukin‐6 is produced by bone and modulated by parathyroid hormone , 1989, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[29]  K. Hruska,et al.  Second messenger signaling in the regulation of collagenase production by osteogenic sarcoma cells. , 1989, Endocrinology.

[30]  S. Teitelbaum,et al.  Parathyroid hormone inhibits collagen synthesis at both ribonucleic acid and protein levels in rat osteogenic sarcoma cells. , 1989, Molecular endocrinology.

[31]  G. Rodan,et al.  Transcriptional regulation of osteopontin production in rat osteoblast- like cells by parathyroid hormone , 1989, The Journal of cell biology.

[32]  G. Rodan,et al.  Cyclic AMP-mediated stabilization of osteocalcin mRNA in rat osteoblast-like cells treated with parathyroid hormone. , 1988, The Journal of biological chemistry.

[33]  Michael E. Greenberg,et al.  c-Jun dimerizes with itself and with c-Fos, forming complexes of different DNA binding affinities , 1988, Cell.

[34]  M. Montminy,et al.  Phosphorylation-induced binding and transcriptional efficacy of nuclear factor CREB , 1988, Nature.

[35]  A. Schönthal,et al.  Requirement for fos gene expression in the transcriptional activation of collagenase by other oncogenes and phorbol esters , 1988, Cell.

[36]  J. Delaisse,et al.  Bone-resorbing agents affect the production and distribution of procollagenase as well as the activity of collagenase in bone tissue. , 1988, Endocrinology.

[37]  E. Chen,et al.  A parathyroid hormone-related protein implicated in malignant hypercalcemia: cloning and expression. , 1987, Science.

[38]  P. Gruss,et al.  Proto-oncogene c-fos expression in growth regions of fetal bone and mesodermal web tissue , 1987, Nature.

[39]  M. Karin,et al.  Phorbol ester-inducible genes contain a common cis element recognized by a TPA-modulated trans-acting factor , 1987, Cell.

[40]  S. Muallem,et al.  Parathyroid hormone-activated calcium channels in an osteoblast-like clonal osteosarcoma cell line. cAMP-dependent and cAMP-independent calcium channels. , 1987, The Journal of biological chemistry.

[41]  P. Herrlich,et al.  12-O-tetradecanoyl-phorbol-13-acetate induction of the human collagenase gene is mediated by an inducible enhancer element located in the 5'-flanking region , 1987, Molecular and cellular biology.

[42]  S. Teitelbaum,et al.  Hormonal regulation of the production of collagenase and a collagenase inhibitor activity by rat osteogenic sarcoma cells. , 1987, Endocrinology.

[43]  Erwin F. Wagner,et al.  Deregulated c-fos expression interferes with normal bone development in transgenic mice , 1987, Nature.

[44]  D. Rowe,et al.  Hormonal regulation of collagen synthesis in a clonal rat osteosarcoma cell line. , 1986, Endocrinology.

[45]  P. McSheehy,et al.  Osteoblast-like cells in the presence of parathyroid hormone release soluble factor that stimulates osteoclastic bone resorption. , 1986, Endocrinology.

[46]  Richard Treisman,et al.  Identification of a protein-binding site that mediates transcriptional response of the c-fos gene to serum factors , 1986, Cell.

[47]  E. Nigg,et al.  Rapid and reversible translocation of the catalytic subunit of cAMP‐dependent protein kinase type II from the Golgi complex to the nucleus. , 1985, The EMBO journal.

[48]  T. Martin,et al.  Regulation of plasminogen activator production by bone-resorbing hormones in normal and malignant osteoblasts. , 1985, Endocrinology.

[49]  T. Curran,et al.  FBJ murine osteosarcoma virus: identification and molecular cloning of biologically active proviral DNA , 1982, Journal of virology.

[50]  T. Martin,et al.  Activation of adenosine 3',5'-monophosphate-dependent protein kinase in normal and malignant bone cells by parathyroid hormone, prostaglandin E2, and prostacyclin. , 1981, Endocrinology.

[51]  D. Rowe,et al.  Parathyroid hormone alters collagen synthesis and procollagen mRNA levels in fetal rat calvaria. , 1980, Proceedings of the National Academy of Sciences of the United States of America.

[52]  R. Luben,et al.  Biochemical characterization with parathormone and calcitonin of isolated bone cells: provisional identification of osteoclasts and osteoblasts. , 1976, Endocrinology.

[53]  S. Miller,et al.  Bone cells in culture: morphologic transformation by hormones. , 1976, Science.

[54]  E. Canalis,et al.  Hormonal control of bone collagen synthesis in vitro: effects of parathyroid hormone and calcitonin. , 1976, Endocrinology.

[55]  G. Aurbach,et al.  The effect of parathyroid hormone on the concentration of adenosine 3',5'-monophosphate in skeletal tissue in vitro. , 1970, The Journal of biological chemistry.