Abstract
Several recent papers have shown that both familial primary pulmonary hypertension (FPPH) and sporadic primary pulmonary hypertension (PPH) may have a common etiology that is associated with the inheritance and/or spontaneous development of germline mutations in the bone morphogenetic protein receptor (BMPR) type II gene. Because BMPR-II is a ubiquitously expressed receptor for a family of secreted growth factors known as the bone morphogenetic proteins (BMPs), these findings suggest that BMPs play an important role in the maintenance of normal pulmonary vascular physiology. In the present commentary we discuss the implications of these findings in the context of BMP receptor biology, and relate these data to the genetics and pulmonary pathophysiology of patients with PPH.
Abbreviations
- ActR:
-
activin receptor
- Alk:
-
activin receptor-like kinase
- BMP:
-
bone morphogenetic protein
- BMPR:
-
bone morphogenetic protein receptor
- FPPH:
-
familial primary pulmonary hypertension
- PPH:
-
primary pulmonary hypertension
- TGF:
-
transforming growth factor.
References
Rich S, Dantzker DR, Ayres SM, Bergofsky EH, Brundage BH, Detre KM, Fishman AP, Goldring RM, Groves BM, Koerner SK, et al: Primary pulmonary hypertension. A national prospective study. Ann Intern Med. 1987, 107: 216-223.
Lane KB, Machado RD, Pauciulo MW, Thomson JR, Phillips JA, Loyd JE, Nichols WC, Trembath RC: Heterozygous germline mutations in BMPR2, encoding a TGF-beta receptor, cause familial primary pulmonary hypertension. The International PPH Consortium. Nat Genet. 2000, 26: 81-84. 10.1038/79226.
Thomson JR, Machado RD, Pauciulo MW, Morgan NV, Humbert M, Elliott GC, Ward K, Yacoub M, Mikhail G, Rogers P, Newman J, Wheeler L, Higenbottam T, Gibbs JS, Egan J, Crozier A, Peacock A, Allcock R, Corris P, Loyd JE, Trembath RC, Nichols WC: Sporadic primary pulmonary hypertension is associated with germline mutations of the gene encoding BMPR-II, a receptor member of the TGF-beta family. J Med Genet. 2000, 37: 741-745. 10.1136/jmg.37.10.741.
Machado RD, Pauciulo MW, Thomson JR, Lane KB, Morgan NV, Wheeler L, Phillips JA, Newman J, Williams D, Galie N, Manes A, McNeil K, Yacoub M, Mikhail G, Rogers P, Corris P, Humbert M, Donnai D, Martensson G, Tranebjaerg L, Loyd JE, Trembath RC, Nichols WC: BMPR2 haploinsufficiency as the inherited molecular mechanism for primary pulmonary hypertension. Am J Hum Genet. 2001, 68: 92-102. 10.1086/316947.
Deng Z, Morse JH, Slager SL, Cuervo N, Moore KJ, Venetos G, Kalachikov S, Cayanis E, Fischer SG, Barst RJ, Hodge SE, Knowles JA: Familial primary pulmonary hypertension (gene PPH1) is caused by mutations in the bone morphogenetic protein receptor-II gene. Am J Hum Genet. 2000, 67: 737-744. 10.1086/303059.
Nichols WC, Koller DL, Slovis B, Foroud T, Terry VH, Arnold ND, Siemieniak DR, Wheeler L, Phillips JA, Newman JH, Conneally PM, Ginsburg D, Loyd JE: Localization of the gene for familial primary pulmonary hypertension to chromosome 2q31-32. Nat Genet. 1997, 15: 277-280.
Piek E, Heldin CH, Ten Dijke P: Specificity, diversity, and regulation in TGF-beta superfamily signaling. FASEB J. 1999, 13: 2105-2124.
Kawabata M, Miyazono K: Skeletal Growth Factors. Philadelphia: Lippincott Williams & Wilkins,. 2000
Reddi AH: Interplay between bone morphogenetic proteins and cognate binding proteins in bone and cartilage development: noggin, chordin and DAN. Arthritis Res. 2001, 3: 1-5. 10.1186/ar133.
Wozney JM, Rosen V, Celeste AJ, Mitsock LM, Whitters MJ, Kriz RW, Hewick RM, Wang EA: Novel regulators of bone formation: molecular clones and activities. Science. 1988, 242: 1528-1534.
Hogan BL: Bone morphogenetic proteins: multifunctional regulators of vertebrate development. Genes Dev. 1996, 10: 1580-1594.
Bellusci S, Henderson R, Winnier G, Oikawa T, Hogan BL: Evidence from normal expression and targeted misexpression that bone morphogenetic protein (Bmp-4) plays a role in mouse embryonic lung morphogenesis. Development. 1996, 122: 1693-1702.
Nohno T, Ishikawa T, Saito T, Hosokawa K, Noji S, Wolsing DH, Rosenbaum JS: Identification of a human type II receptor for bone morphogenetic protein-4 that forms differential heteromeric complexes with bone morphogenetic protein type I receptors. J Biol Chem. 1995, 270: 22522-22526. 10.1074/jbc.270.38.22522.
Rosenzweig BL, Imamura T, Okadome T, Cox GN, Yamashita H, Ten Dijke P, Heldin CH, Miyazono K: Cloning and characterization of a human type II receptor for bone morphogenetic proteins. Proc Natl Acad Sci USA. 1995, 92: 7632-7636.
Willis SA, Zimmerman CM, Li LI, Mathews LS: Formation and activation by phosphorylation of activin receptor complexes. Mol Endocrinol. 1996, 10: 367-379.
Shibuya H, Iwata H, Masuyama N, Gotoh Y, Yamaguchi K, Irie K, Matsumoto K, Nishida E, Ueno N: Role of TAK1 and TAB1 in BMP signaling in early Xenopus development. EMBO J. 1998, 17: 1019-1028. 10.1093/emboj/17.4.1019.
Monzen K, Shiojima I, Hiroi Y, Kudoh S, Oka T, Takimoto E, Hayashi D, Hosoda T, Habara-Ohkubo A, Nakaoka T, Fujita T, Yazaki Y, Komuro I: Bone morphogenetic proteins induce car-diomyocyte differentiation through the mitogen-activated protein kinase kinase kinase TAK1 and cardiac transcription factors Csx/Nkx-2.5 and GATA-4. Mol Cell Biol. 1999, 19: 7096-7105.
Gupta IR, Piscione TD, Grisaru S, Phan T, Macias-Silva M, Zhou X, Whiteside C, Wrana JL, Rosenblum ND: Protein kinase A is a negative regulator of renal branching morphogenesis and modulates inhibitory and stimulatory bone morphogenetic proteins. J Biol Chem. 1999, 274: 26305-26314. 10.1074/jbc.274.37.26305.
Massague J, Wotton D: Transcriptional control by the TGF-beta/Smad signaling system. EMBO J. 2000, 19: 1745-1754. 10.1093/emboj/19.8.1745.
Aridor M, Balch WE: Integration of endoplasmic reticulum signaling in health and disease. Nat Med. 1999, 5: 745-751. 10.1038/10466.
Hentze MW, Kulozik AE: A perfect message: RNA surveillance and nonsense-mediated decay. Cell. 1999, 96: 307-310.
Liu F, Ventura F, Doody J, Massague J: Human type II receptor for bone morphogenic proteins (BMPs): extension of the two-kinase receptor model to the BMPs. Mol Cell Biol. 1995, 15: 3479-3486.
Frisch A, Wright CV: XBMPRII, a novel Xenopus type II receptor mediating BMP signaling in embryonic tissues. Development. 1998, 125: 431-442.
Ishikawa T, Yoshioka H, Ohuchi H, Noji S, Nohno T: Truncated type II receptor for BMP-4 induces secondary axial structures in Xenopus embryos. Biochem Biophys Res Commun. 1995, 216: 26-33. 10.1006/bbrc.1995.2587.
Newman JH, Wheller L, Lane KB, Loyd E, Ghaddipatti R, Phillips JA, Loyd JE: Mutations in the gene for bone morphogenetic protein receptor II as a cause of primary pulmonary hypertension in a large kindred. N Engl J Med. 2001,
Loyd JE, Butler MG, Foroud TM, Conneally PM, Phillips JA, Newman JH: Genetic anticipation and abnormal gender ratio at birth in familial primary pulmonary hypertension. Am J Respir Crit Care Med. 1995, 152: 93-97.
Lanska DJ: George Huntington (1850-1916) and hereditary chorea. J Hist Neurosci. 2000, 9: 76-89. 10.1076/0964-704X(200004)9:1;1-2;FT076.
Beppu H, Kawabata M, Hamamoto T, Chytil A, Minowa O, Noda T, Miyazono K: BMP type II receptor is required for gastrulation and early development of mouse embryos. Dev Biol. 2000, 221: 249-258. 10.1006/dbio.2000.9670.
Willette RN, Gu JL, Lysko PG, Anderson KM, Minehart H, Yue T: BMP-2 gene expression and effects on human vascular smooth muscle cells. J Vasc Res. 1999, 36: 120-125. 10.1159/000025634.
Nakaoka T, Gonda K, Ogita T, Otawara-Hamamoto Y, Okabe F, Kira Y, Harii K, Miyazono K, Takuwa Y, Fujita T: Inhibition of rat vascular smooth muscle proliferation in vitro and in vivo by bone morphogenetic protein-2. J Clin Invest. 1997, 100: 2824-2832.
Lee SD, Shroyer KR, Markham NE, Cool CD, Voelkel NF, Tuder RM: Monoclonal endothelial cell proliferation is present in primary but not secondary pulmonary hypertension. J Clin Invest. 1998, 101: 927-934.
Yeager ME, Halley GR, Golpon HA, Voelkel NF, Tuder RM: Microsatellite instability of endothelial cell growth and apoptosis genes within plexiform lesions in primary pulmonary hypertension. Circ Res. 2001, 88: E2-E11.
Chazova I, Loyd JE, Zhdanov VS, Newman JH, Belenkov Y, Meyrick B: Pulmonary artery adventitial changes and venous involvement in primary pulmonary hypertension. Am J Pathol. 1995, 146: 389-397.
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Caestecker, M.D., Meyrick, B. Bone morphogenetic proteins, genetics and the pathophysiology of primary pulmonary hypertension. Respir Res 2, 193 (2001). https://doi.org/10.1186/rr57
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DOI: https://doi.org/10.1186/rr57