Activation of hedgehog signaling by loss of GNAS causes heterotopic ossification

Nature Medicine

Volumn 19, Issue 11, 2013, Pages 1505-1512

  Regard, Jean B ^a   Malhotra, Deepti ^a   Gvozdenovic Jeremic, Jelena ^a   Josey, Michelle ^a   Chen, Min ^b   Weinstein, Lee S ^b   Lu, Jianming ^c   Shore, Eileen M ^d   Kaplan, Frederick S ^d,e   Yang, Yingzi ^a  

^a NATIONAL HUMAN GENOME RESEARCH INSTITUTE   (United States)

^b NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES   (United States)

^c University of Pennsylvania ^*  (United States)

^d UNIVERSITY OF PENNSYLVANIA   (United States)

^e UNIVERSITY OF PENNSYLVANIA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ALKALINE PHOSPHATASE; BETA CATENIN; BONE SIALOPROTEIN; COLLAGEN TYPE 1; COLLAGEN TYPE 1A1; GUANINE NUCLEOTIDE BINDING PROTEIN ALPHA SUBUNIT; MESSENGER RNA; OSTEOCALCIN; SONIC HEDGEHOG PROTEIN; TRANSCRIPTION FACTOR OSTERIX; UNCLASSIFIED DRUG; WNT PROTEIN;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; BONE MARROW; CELL DIFFERENTIATION; CONTROLLED STUDY; FIBROUS DYSPLASIA; GAIN OF FUNCTION MUTATION; GENE DELETION; GENE EXPRESSION; GENE MUTATION; GENOTYPE; HETEROTOPIC OSSIFICATION; HUMAN; IMMUNOHISTOCHEMISTRY; MESENCHYMAL STEM CELL; MESENCHYMAL STROMA CELL; MOUSE; NONHUMAN; OSSIFICATION; OSTEOBLAST; PHENOTYPE; PRIORITY JOURNAL; PROGRESSIVE OSSEOUS HETEROPLASIA; SIGNAL TRANSDUCTION; SKELETON MALFORMATION; STEM CELL; UPREGULATION;

ANIMALS; BETA CATENIN; BONE DISEASES, METABOLIC; CELL DIFFERENTIATION; FEMALE; GTP-BINDING PROTEIN ALPHA SUBUNITS, GS; HEDGEHOG PROTEINS; HUMANS; MALE; MICE; MICE, KNOCKOUT; MUTATION; OSSIFICATION, HETEROTOPIC; OSTEOBLASTS; SIGNAL TRANSDUCTION; SKIN DISEASES, GENETIC; WNT SIGNALING PATHWAY;

ANIMALIA; ERINACEIDAE;

EID: 84887420723     PISSN: 10788956     EISSN: 1546170X     Source Type: Journal    
DOI: 10.1038/nm.3314     Document Type: Article

References (75)

1. Shore, E.M. & Kaplan, F.S. Inherited human diseases of heterotopic bone formation. Nat. Rev. Rheumatol. 6, 518-527 (2010).
2. Shore, E.M. et al. A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva. Nat. Genet. 38, 525-527 (2006).
3. Wozney, J.M. et al. Novel regulators of bone formation: molecular clones and activities. Science 242, 1528-1534 (1988).
4. Kaplan, F.S., Hahn, G.V. & Zasloff, M.A. Heterotopic ossification: two rare forms and what they can teach us. J. Am. Acad. Orthop. Surg. 2, 288-296 (1994).
5. Eddy, M.C. et al. Deficiency of the ?-subunit of the stimulatory G protein and severe extraskeletal ossification. J. Bone Miner. Res. 15, 2074-2083 (2000).
6. Trüeb, R.M., Panizzon, R.G. & Burg, G. Cutaneous ossification in Albright's hereditary osteodystrophy. Dermatology 186, 205-209 (1993).
7. Shore, E.M. et al. Paternally inherited inactivating mutations of the GNAS1 gene in progressive osseous heteroplasia. N. Engl. J. Med. 346, 99-106 (2002).
8. Plagge, A., Kelsey, G. & Germain-Lee, E.L. Physiological functions of the imprinted Gnas locus and its protein variants G?s and XL?s in human and mouse. J. Endocrinol. 196, 193-214 (2008).
9. Riminucci, M., Robey, P.G., Saggio, I. & Bianco, P. Skeletal progenitors and the GNAS gene: fibrous dysplasia of bone read through stem cells. J. Mol. Endocrinol. 45, 355-364 (2010).
10. Regard, J.B. et al. Wnt/?-catenin signaling is differentially regulated by G? proteins and contributes to fibrous dysplasia. Proc. Natl. Acad. Sci. USA 108, 20101-20106 (2011).
11. Wu, J.Y. et al. Gs? enhances commitment of mesenchymal progenitors to the osteoblast lineage but restrains osteoblast differentiation in mice. J. Clin. Invest. 121, 3492-3504 (2011).
12. Jiang, J. & Struhl, G. Protein kinase A and hedgehog signaling in Drosophila limb development. Cell 80, 563-572 (1995).
13. Tuson, M., He, M. & Anderson, K.V. Protein kinase A acts at the basal body of the primary cilium to prevent Gli2 activation and ventralization of the mouse neural tube. Development 138, 4921-4930 (2011).
14. Jiang, J. & Hui, C.C. Hedgehog signaling in development and cancer. Dev. Cell 15, 801-812 (2008).
15. St-Jacques, B., Hammerschmidt, M. & McMahon, A.P. Indian hedgehog signaling regulates proliferation and differentiation of chondrocytes and is essential for bone formation. Genes Dev. 13, 2072-2086 (1999).
16. Bastepe, M. et al. Stimulatory G protein directly regulates hypertrophic differentiation of growth plate cartilage in vivo. Proc. Natl. Acad. Sci. USA 101, 14794-14799 (2004).
17. Sakamoto, A., Chen, M., Kobayashi, T., Kronenberg, H.M. & Weinstein, L.S. Chondrocyte-specific knockout of the G protein Gs? leads to epiphyseal and growth plate abnormalities and ectopic chondrocyte formation. J. Bone Miner. Res. 20, 663-671 (2005).
18. Sakamoto, H. et al. A kinetic study of the mechanism of conversion of ?-hydroxyheme to verdoheme while bound to heme oxygenase. Biochem. Biophys. Res. Commun. 338, 578-583 (2005).
19. Ogden, S.K. et al. G protein G?i functions immediately downstream of Smoothened in Hedgehog signalling. Nature 456, 967-970 (2008).
20. Riobo, N.A., Saucy, B., Dilizio, C. & Manning, D.R. Activation of heterotrimeric G proteins by Smoothened. Proc. Natl. Acad. Sci. USA 103, 12607-12612 (2006).
21. Low, W.C. et al. The decoupling of Smoothened from G?i proteins has little effect on Gli3 protein processing and Hedgehog-regulated chick neural tube patterning. Dev. Biol. 321, 188-196 (2008).
22. Vanden Bossche, L. & Vanderstraeten, G. Heterotopic ossification: a review. J. Rehabil. Med. 37, 129-136 (2005).
23. Pignolo, R.J. et al. Heterozygous inactivation of Gnas in adipose-derived mesenchymal progenitor cells enhances osteoblast differentiation and promotes heterotopic ossification. J. Bone Miner. Res. 26, 2647-2655 (2011).
24. Huso, D.L. et al. Heterotopic ossifications in a mouse model of Albright hereditary osteodystrophy. PLoS ONE 6, e21755 (2011).
25. Nakashima, K. et al. The novel zinc finger-containing transcription factor osterix is required for osteoblast differentiation and bone formation. Cell 108, 17-29 (2002).
26. Hill, T.P., Spater, D., Taketo, M.M., Birchmeier, W. & Hartmann, C. Canonical Wnt/?-catenin signaling prevents osteoblasts from differentiating into chondrocytes. Dev. Cell 8, 727-738 (2005).
27. Day, T.F., Guo, X., Garrett-Beal, L. & Yang, Y. Wnt/?-catenin signaling in mesenchymal progenitors controls osteoblast and chondrocyte differentiation during vertebrate skeletogenesis. Dev. Cell 8, 739-750 (2005).
28. Hu, H. et al. Sequential roles of Hedgehog and Wnt signaling in osteoblast development. Development 132, 49-60 (2005).
29. Holmen, S.L. et al. Essential role of ?-catenin in postnatal bone acquisition. J. Biol. Chem. 280, 21162-21168 (2005).
30. Logan, C.Y. & Nusse, R. The Wnt signaling pathway in development and disease. Annu. Rev. Cell Dev. Biol. 20, 781-810 (2004).
31. Keely, S.L. Jr., Corbin, J.D. & Park, C.R. On the question of translocation of heart cAMP-dependent protein kinase. Proc. Natl. Acad. Sci. USA 72, 1501-1504 (1975).
32. Seamon, K. & Daly, J.W. Activation of adenylate cyclase by the diterpene forskolin does not require the guanine nucleotide regulatory protein. J. Biol. Chem. 256, 9799-9801 (1981).
33. Goodrich, L.V., Milenkovic, L., Higgins, K.M. & Scott, M.P. Altered neural cell fates and medulloblastoma in mouse patched mutants. Science 277, 1109-1113 (1997).
34. Ribes, V. & Briscoe, J. Establishing and interpreting graded Sonic Hedgehog signaling during vertebrate neural tube patterning: the role of negative feedback. Cold Spring Harb. Perspect. Biol. 1, a002014 (2009).
35. Svärd, J. et al. Genetic elimination of Suppressor of fused reveals an essential repressor function in the mammalian Hedgehog signaling pathway. Dev. Cell 10, 187-197 (2006).
36. Ingham, P.W. & McMahon, A.P. Hedgehog signaling in animal development: paradigms and principles. Genes Dev. 15, 3059-3087 (2001).
37. Wang, B., Fallon, J.F. & Beachy, P.A. Hedgehog-regulated processing of Gli3 produces an anterior/posterior repressor gradient in the developing vertebrate limb. Cell 100, 423-434 (2000).
38. Zhang, Q. et al. Multiple Ser/Thr-rich degrons mediate the degradation of Ci/Gli by the Cul3-HIB/SPOP E3 ubiquitin ligase. Proc. Natl. Acad. Sci. USA 106, 21191-21196 (2009).
39. Pan, Y., Wang, C. & Wang, B. Phosphorylation of Gli2 by protein kinase A is required for Gli2 processing and degradation and the Sonic Hedgehog-regulated mouse development. Dev. Biol. 326, 177-189 (2009).
40. te Welscher, P. et al. Progression of vertebrate limb development through SHH-mediated counteraction of GLI3. Science 298, 827-830 (2002).
41. Matise, M.P., Epstein, D.J., Park, H.L., Platt, K.A. & Joyner, A.L. Gli2 is required for induction of floor plate and adjacent cells, but not most ventral neurons in the mouse central nervous system. Development 125, 2759-2770 (1998).
42. Taipale, J. et al. Effects of oncogenic mutations in Smoothened and Patched can be reversed by cyclopamine. Nature 406, 1005-1009 (2000).
43. Kim, J., Lee, J.J., Gardner, D. & Beachy, P.A. Arsenic antagonizes the Hedgehog pathway by preventing ciliary accumulation and reducing stability of the Gli2 transcriptional effector. Proc. Natl. Acad. Sci. USA 107, 13432-13437 (2010).
44. Lauth, M., Bergstrom, A., Shimokawa, T. & Toftgard, R. Inhibition of GLI-mediated transcription and tumor cell growth by small-molecule antagonists. Proc. Natl. Acad. Sci. USA 104, 8455-8460 (2007).
45. Bai, C.B. & Joyner, A.L. Gli1 can rescue the in vivo function of Gli2. Development 128, 5161-5172 (2001).
46. Joeng, K.S. & Long, F. The Gli2 transcriptional activator is a crucial effector for Ihh signaling in osteoblast development and cartilage vascularization. Development 136, 4177-4185 (2009).
47. Mao, J. et al. A novel somatic mouse model to survey tumorigenic potential applied to the Hedgehog pathway. Cancer Res. 66, 10171-10178 (2006).
48. Mukhopadhyay, S. et al. The ciliary G-protein-coupled receptor Gpr161 negatively regulates the Sonic Hedgehog pathway via cAMP signaling. Cell 152, 210-223 (2013).
49. Day, T.F. & Yang, Y. Wnt and hedgehog signaling pathways in bone development. J. Bone Joint Surg. Am. 90 (suppl. 1), 19-24 (2008).
50. Joeng, K.S., Schumacher, C.A., Zylstra-Diegel, C.R., Long, F. & Williams, B.O. Lrp5 and Lrp6 redundantly control skeletal development in the mouse embryo. Dev. Biol. 359, 222-229 (2011).
51. Holmen, S.L. et al. Decreased BMD and limb deformities in mice carrying mutations in both Lrp5 and Lrp6. J. Bone Miner. Res. 19, 2033-2040 (2004).
52. de Boer, J. et al. Wnt signaling inhibits osteogenic differentiation of human mesenchymal stem cells. Bone 34, 818-826 (2004).
53. Cho, H.H. et al. Endogenous Wnt signaling promotes proliferation and suppresses osteogenic differentiation in human adipose derived stromal cells. Tissue Eng. 12, 111-121 (2006).
54. Boland, G.M., Perkins, G., Hall, D.J. & Tuan, R.S. Wnt 3a promotes proliferation and suppresses osteogenic differentiation of adult human mesenchymal stem cells. J. Cell. Biochem. 93, 1210-1230 (2004).
55. Chen, Y. ?-catenin signaling plays a disparate role in different phases of fracture repair: implications for therapy to improve bone healing. PLoS Med. 4, e249 (2007).
56. Kim, J.B. et al. Bone regeneration is regulated by Wnt signaling. J. Bone Miner. Res. 22, 1913-1923 (2007).
57. Cooper, K.L. et al. Initiation of proximal-distal patterning in the vertebrate limb by signals and growth. Science 332, 1083-1086 (2011).
58. Roselló-Diez, A., Ros, M.A. & Torres, M. Diffusible signals, not autonomous mechanisms, determine the main proximodistal limb subdivision. Science 332, 1086-1088 (2011).
59. Zhang, D. et al. ALK2 functions as a BMP type I receptor and induces Indian hedgehog in chondrocytes during skeletal development. J. Bone Miner. Res. 18, 1593-1604 (2003).
60. Shimono, K. et al. Potent inhibition of heterotopic ossification by nuclear retinoic acid receptor-? agonists. Nat. Med. 17, 454-460 (2011).
61. Chen, M. et al. Increased glucose tolerance and reduced adiposity in the absence of fasting hypoglycemia in mice with liver-specific Gs? deficiency. J. Clin. Invest. 115, 3217-3227 (2005).
62. Logan, M. et al. Expression of Cre Recombinase in the developing mouse limb bud driven by a Prrx1 enhancer. Genesis 33, 77-80 (2002).
63. Yu, K. et al. Conditional inactivation of FGF receptor 2 reveals an essential role for FGF signaling in the regulation of osteoblast function and bone growth. Development 130, 3063-3074 (2003).
64. Nelson, D.K. & Williams, T. Frontonasal process-specific disruption of AP-2? results in postnatal midfacial hypoplasia, vascular anomalies, and nasal cavity defects. Dev. Biol. 267, 72-92 (2004).
65. Mak, K.K., Chen, M.H., Day, T.F., Chuang, P.T. & Yang, Y. Wnt-?-catenin signaling interacts differentially with Ihh signaling in controlling endochondral bone and synovial joint formation. Development 133, 3695-3707 (2006).
66. Bai, C.B. & Joyner, A.L. Gli1 can rescue the in vivo function of Gli2. Development 128, 5161-5172 (2001).
67. Corrales, J.D., Blaess, S., Mahoney, E.M. & Joyner, A.L. The level of sonic hedgehog signaling regulates the complexity of cerebellar foliation. Development 133, 1811-1821 (2006).
68. Long, F., Zhang, X.M., Karp, S., Yang, Y. & McMahon, A.P. Genetic manipulation of hedgehog signaling in the endochondral skeleton reveals a direct role in the regulation of chondrocyte proliferation. Development 128, 5099-5108 (2001).
69. Mao, J. et al. A novel somatic mouse model to survey tumorigenic potential applied to the Hedgehog pathway. Cancer Res. 66, 10171-10178 (2006).
70. Regard, J.B. et al. Probing cell type-specific functions of Gi in vivo identifies GPCR regulators of insulin secretion. J. Clin. Invest. 117, 4034-4043 (2007).
71. Yang, J. et al. Loss of signaling through the G protein, Gz, results in abnormal platelet activation and altered responses to psychoactive drugs. Proc. Natl. Acad. Sci. USA 97, 9984-9989 (2000).
72. Livak, K.J. & Schmittgen, T.D. Analysis of relative gene expression data using real-time quantitative PCR and the 2'CT method. Methods 25, 402-408 (2001).
73. Yang, Y., Topol, L., Lee, H. & Wu, J. Wnt5a and Wnt5b exhibit distinct activities in coordinating chondrocyte proliferation and differentiation. Development 130, 1003-1015 (2003).
74. Storm, E.E. & Kingsley, D.M. GDF5 coordinates bone and joint formation during digit development. Dev. Biol. 209, 11-27 (1999).
75. Bai, C.B., Stephen, D. & Joyner, A.L. All mouse ventral spinal cord patterning by hedgehog is Gli dependent and involves an activator function of Gli3. Dev. Cell 6, 103-115 (2004)