The biological function of type I receptors of bone morphogenetic protein in bone

Abstract

Bone morphogenetic proteins (BMPs) have multiple roles in skeletal development, homeostasis and regeneration. BMPs signal via type I and type II serine/threonine kinase receptors (BMPRI and BMPRII). In recent decades, genetic studies in humans and mice have demonstrated that perturbations in BMP signaling via BMPRI resulted in various diseases in bone, cartilage, and muscles. In this review, we focus on all three types of BMPRI, which consist of activin-like kinase 2 (ALK2, also called type IA activin receptor), activin-like kinase 3 (ALK3, also called BMPRIA), and activin-like kinase 6 (ALK6, also called BMPRIB). The research areas covered include the current progress regarding the roles of these receptors during myogenesis, chondrogenesis, and osteogenesis. Understanding the physiological and pathological functions of these receptors at the cellular and molecular levels will advance drug development and tissue regeneration for treating musculoskeletal diseases and bone defects in the future.

Molecular biology: Signaling receptors tied to bone disease

Understanding how a group of receptors activate growth factors called bone morphogenetic proteins (BMPs) could lead to new drug targets. BMPs are essential for proper development, and diseases of the bone, cartilage, and muscles have all been linked to aberrant BMP signaling. In a review article, a team led by Xinquan Jiang from Shanghai Jiao Tong University in China and Jian Feng from Texas A&M Baylor College of Dentistry in the USA discuss the essential roles of cell-surface BMP “type I” receptors in bone formation. Animal models have revealed the molecular ways in which all three kinds of type I receptors have distinct biological functions in a variety of cells. The authors note that modulating BMP signaling through these receptors could one day help patients with bone and muscle defects.

References

[1] Wozney JM. Bone morphogenetic proteins. Prog Growth Factor Res, 1989, 1: 267-280

[2] Urist MR. Bone: formation by autoinduction. Science, 1965, 150: 893-899

[3] Chen D, Zhao M, Mundy GR. Bone morphogenetic proteins. Growth Factors, 2004, 22: 233-241

[4] Kang Q, Sun MH, Cheng H et al Characterization of the distinct orthotopic bone-forming activity of 14 BMPs using recombinant adenovirus-mediated gene delivery. Gene Ther, 2004, 11: 1312-1320

[5] Gautschi OP, Frey SP, Zellweger R. Bone morphogenetic proteins in clinical applications. ANZ J Surg, 2007, 77: 626-631

[6] Koenig BB, Cook JS, Wolsing DH et al Characterization and cloning of a receptor for BMP-2 and BMP-4 from NIH 3T3 cells. Mol Cell Biol, 1994, 14: 5961-5974

[7] Hoodless PA, Haerry T, Abdollah S et al MADR1, a MAD-related protein that functions in BMP2 signaling pathways. Cell, 1996, 85: 489-500

[8] Chen Y, Bhushan A, Vale W. Smad8 mediates the signaling of the ALK-2 [corrected] receptor serine kinase. Proc Natl Acad Sci USA, 1997, 94: 12938-12943

[9] Nishimura R, Kato Y, Chen D et al Smad5 and DPC4 are key molecules in mediating BMP-2-induced osteoblastic differentiation of the pluripotent mesenchymal precursor cell line C2C12. J Biol Chem, 1998, 273: 1872-1879

[10] Hauburger A, von Einem S, Schwaerzer GK et al The pro-form of BMP-2 interferes with BMP-2 signalling by competing with BMP-2 for IA receptor binding. FEBS J, 2009, 276: 6386-6398

[11] ten Dijke P, Yamashita H, Sampath TK et al Identification of type I receptors for osteogenic protein-1 and bone morphogenetic protein-4. J Biol Chem, 1994, 269: 16985-16988

[12] Cheifetz S. BMP receptors in limb and tooth formation. Crit Rev Oral Biol Med, 1999, 10: 182-198

[13] Kamiya N, Kaartinen VM, Mishina Y. Loss-of-function of ACVR1 in osteoblasts increases bone mass and activates canonical Wnt signaling through suppression of Wnt inhibitors SOST and DKK1. Biochem Biophys Res Commun, 2011, 414: 326-330

[14] Lavery K, Swain P, Falb D, Alaoui-Ismaili MH. BMP-2/4 and BMP-6/7 differentially utilize cell surface receptors to induce osteoblastic differentiation of human bone marrow-derived mesenchymal stem cells. J Biol Chem, 2008, 283: 20948-20958

[15] Shore EM, Xu M, Feldman GJ et al A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva. Nat Genet, 2006, 38: 525-527

[16] Huning I, Gillessen-Kaesbach G. Fibrodysplasia ossificans progressiva: clinical course, genetic mutations and genotype-phenotype correlation. Mol Syndromol, 2014, 5: 201-211

[17] Zhang W, Zhang K, Song L et al The phenotype and genotype of fibrodysplasia ossificans progressiva in China: a report of 72 cases. Bone, 2013, 57: 386-391

[18] Carvalho DR, Navarro MM, Martins BJ et al Mutational screening of ACVR1 gene in Brazilian fibrodysplasia ossificans progressiva patients. Clin Genet, 2010, 77: 171-176

[19] Kaplan FS, Xu M, Seemann P et al Classic and atypical fibrodysplasia ossificans progressiva (FOP) phenotypes are caused by mutations in the bone morphogenetic protein (BMP) type I receptor ACVR1. Hum Mutat, 2009, 30: 379-390

[20] Nakajima M, Haga N, Takikawa K et al The ACVR1 617G>A mutation is also recurrent in three Japanese patients with fibrodysplasia ossificans progressiva. J Hum Genet, 2007, 52: 473-475

[21] Al-Haggar M, Ahmad N, Yahia S et al Sporadic fibrodysplasia ossificans progressiva in an Egyptian infant with c.617G>A mutation in ACVR1 gene: a case report and review of literature. Case Rep Genet, 2013, 2013: 834605

[22] Furuya H, Ikezoe K, Wang L et al A unique case of fibrodysplasia ossificans progressiva with an ACVR1 mutation, G356D, other than the common mutation (R206H). Am J Med Genet A, 2008, 146: 459-463

[23] Cohen RB, Hahn GV, Tabas JA et al The natural history of heterotopic ossification in patients who have fibrodysplasia ossificans progressiva. A study of forty-four patients. J Bone Joint Surg Am, 1993, 75: 215-219

[24] Connor JM, Evans DA. Fibrodysplasia ossificans progressiva. The clinical features and natural history of 34 patients. J Bone Joint Surg Br, 1982, 64: 76-83

[25] Virdi AS, Shore EM, Oreffo RO et al Phenotypic and molecular heterogeneity in fibrodysplasia ossificans progressiva. Calcif Tissue Int, 1999, 65: 250-255

[26] Bocciardi R, Bordo D, Di Duca M et al Mutational analysis of the ACVR1 gene in Italian patients affected with fibrodysplasia ossificans progressiva: confirmations and advancements. Eur J Hum Genet, 2009, 17: 311-318

[27] Ratbi I, Borcciadi R, Regragui A et al Rarely occurring mutation of ACVR1 gene in Moroccan patient with fibrodysplasia ossificans progressiva. Clin Rheumatol, 2010, 29: 119-121

[28] Morales-Piga A, Bachiller-Corral J, Trujillo-Tiebas MJ et al Fibrodysplasia ossificans progressiva in Spain: epidemiological, clinical, and genetic aspects. Bone, 2012, 51: 748-755

[29] Gregson CL, Hollingworth P, Williams M et al A novel ACVR1 mutation in the glycine/serine-rich domain found in the most benign case of a fibrodysplasia ossificans progressiva variant reported to date. Bone, 2011, 48: 654-658

[30] Nakahara Y, Katagiri T, Ogata N et al ACVR1 (587T>C) mutation in a variant form of fibrodysplasia ossificans progressiva: second report. Am J Med Genet A, 2014, 164: 220-224

[31] Petrie KA, Lee WH, Bullock AN et al Novel mutations in ACVR1 result in atypical features in two fibrodysplasia ossificans progressiva patients. PLoS One, 2009, 4: e5005

[32] Yu PB, Deng DY, Lai CS et al BMP type I receptor inhibition reduces heterotopic [corrected] ossification. Nat Med, 2008, 14: 1363-1369

[33] Chakkalakal SA, Zhang D, Culbert AL et al An Acvr1 R206H knock-in mouse has fibrodysplasia ossificans progressiva. J Bone Miner Res, 2012, 27: 1746-1756

[34] Takahashi M, Katagiri T, Furuya H et al Disease-causing allele-specific silencing against the ALK2 mutants, R206H and G356D, in fibrodysplasia ossificans progressiva. Gene Ther, 2012, 19: 781-785

[35] Fukuda T, Kanomata K, Nojima J et al A unique mutation of ALK2, G356D, found in a patient with fibrodysplasia ossificans progressiva is a moderately activated BMP type I receptor. Biochem Biophys Res Commun, 2008, 377: 905-909

[36] Shen Q, Little SC, Xu M et al The fibrodysplasia ossificans progressiva R206H ACVR1 mutation activates BMP-independent chondrogenesis and zebrafish embryo ventralization. J Clin Invest, 2009, 119: 3462-3472

[37] Ohte S, Shin M, Sasanuma H et al A novel mutation of ALK2, L196P, found in the most benign case of fibrodysplasia ossificans progressiva activates BMP-specific intracellular signaling equivalent to a typical mutation, R206H. Biochem Biophys Res Commun, 2011, 407: 213-218

[38] Wieser R, Wrana JL, Massague J. GS domain mutations that constitutively activate T beta R-I, the downstream signaling component in the TGF-beta receptor complex. EMBO J, 1995, 14: 2199-2208

[39] Culbert AL, Chakkalakal SA, Theosmy EG et al Alk2 regulates early chondrogenic fate in fibrodysplasia ossificans progressiva heterotopic endochondral ossification. Stem Cells, 2014, 32: 1289-1300

[40] Yano M, Kawao N, Tamura Y et al A novel factor, Tmem176b, induced by activin-like kinase 2 signal promotes the differentiation of myoblasts into osteoblasts. Exp Clin Endocrinol Diabetes, 2014, 122: 7-14

[41] van Dinther M, Visser N, de Gorter DJ et al ALK2 R206H mutation linked to fibrodysplasia ossificans progressiva confers constitutive activity to the BMP type I receptor and sensitizes mesenchymal cells to BMP-induced osteoblast differentiation and bone formation. J Bone Miner Res, 2010, 25: 1208-1215

[42] Shi S, Cai J, de Gorter DJ et al Antisense-oligonucleotide mediated exon skipping in activin-receptor-like kinase 2: inhibiting the receptor that is overactive in fibrodysplasia ossificans progressiva. PLoS One, 2013, 8: e69096

[43] Kaplan J, Kaplan FS, Shore EM. Restoration of normal BMP signaling levels and osteogenic differentiation in FOP mesenchymal progenitor cells by mutant allele-specific targeting. Gene Ther, 2012, 19: 786-790

[44] Agarwal S, Loder SJ, Brownley C et al BMP signaling mediated by constitutively active Activin type 1 receptor (ACVR1) results in ectopic bone formation localized to distal extremity joints. Dev Biol, 2015, 400: 202-209

[45] Zhang D, Schwarz EM, Rosier RN et al ALK2 functions as a BMP type I receptor and induces Indian hedgehog in chondrocytes during skeletal development. J Bone Miner Res, 2003, 18: 1593-1604

[46] Liu F, Kohlmeier S, Wang CY. Wnt signaling and skeletal development. Cell Signal, 2008, 20: 999-1009

[47] Yano M, Kawao N, Okumoto K et al Fibrodysplasia ossificans progressiva-related activated activin-like kinase signaling enhances osteoclast formation during heterotopic ossification in muscle tissues. J Biol Chem, 2014, 289: 16966-16977

[48] Kawao N, Yano M, Tamura Y et al. Role of osteoclasts in heterotopic ossification enhanced by fibrodysplasia ossificans progressiva-related activin-like kinase 2 mutation in mice. J Bone Miner Metab 2015. [E-pub ahead of print].

[49] Zhang J, Niu C, Ye L et al Identification of the haematopoietic stem cell niche and control of the niche size. Nature, 2003, 425: 836-841

[50] Dewulf N, Verschueren K, Lonnoy O et al Distinct spatial and temporal expression patterns of two type I receptors for bone morphogenetic proteins during mouse embryogenesis. Endocrinology, 1995, 136: 2652-2663

[51] Kaps C, Hoffmann A, Zilberman Y et al Distinct roles of BMP receptors Type IA and IB in osteo-/chondrogenic differentiation in mesenchymal progenitors (C3H10T1/2). Biofactors, 2004, 20: 71-84

[52] Macias-Silva M, Hoodless PA, Tang SJ et al Specific activation of Smad1 signaling pathways by the BMP7 type I receptor, ALK2. J Biol Chem, 1998, 273: 25628-25636

[53] Singhatanadgit W, Olsen I. Endogenous BMPR-IB signaling is required for early osteoblast differentiation of human bone cells. In Vitro Cell Dev Biol Anim, 2011, 47: 251-259

[54] Chen D, Ji X, Harris MA et al Differential roles for bone morphogenetic protein (BMP) receptor type IB and IA in differentiation and specification of mesenchymal precursor cells to osteoblast and adipocyte lineages. J Cell Biol, 1998, 142: 295-305

[55] Mishina Y, Suzuki A, Ueno N et al Bmpr encodes a type I bone morphogenetic protein receptor that is essential for gastrulation during mouse embryogenesis. Genes Dev, 1995, 9: 3027-3037

[56] Baek JA, Lan Y, Liu H et al Bmpr1a signaling plays critical roles in palatal shelf growth and palatal bone formation. Dev Biol, 2011, 350: 520-531

[57] Park D, Spencer JA, Koh BI et al Endogenous bone marrow MSCs are dynamic, fate-restricted participants in bone maintenance and regeneration. Cell Stem Cell, 2012, 10: 259-272

[58] Kamiya N, Ye L, Kobayashi T et al Disruption of BMP signaling in osteoblasts through type IA receptor (BMPRIA) increases bone mass. J Bone Miner Res, 2008, 23: 2007-2017

[59] Okamoto M, Murai J, Imai Y et al Conditional deletion of Bmpr1a in differentiated osteoclasts increases osteoblastic bone formation, increasing volume of remodeling bone in mice. J Bone Miner Res, 2011, 26: 2511-2522

[60] Kamiya N, Ye L, Kobayashi T et al BMP signaling negatively regulates bone mass through sclerostin by inhibiting the canonical Wnt pathway. Development, 2008, 135: 3801-3811

[61] Mishina Y, Starbuck MW, Gentile MA et al Bone morphogenetic protein type IA receptor signaling regulates postnatal osteoblast function and bone remodeling. J Biol Chem, 2004, 279: 27560-27566

[62] Simonet WS, Lacey DL, Dunstan CR et al Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell, 1997, 89: 309-319

[63] Lacey DL, Timms E, Tan HL et al Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell, 1998, 93: 165-176

[64] Wan M, Shi X, Feng X et al Transcriptional mechanisms of bone morphogenetic protein-induced osteoprotegrin gene expression. J Biol Chem, 2001, 276: 10119-10125

[65] Kamiya N, Kobayashi T, Mochida Y et al Wnt inhibitors Dkk1 and Sost are downstream targets of BMP signaling through the type IA receptor (BMPRIA) in osteoblasts. J Bone Miner Res, 2010, 25: 200-210

[66] Glass DA 2nd, Bialek P, Ahn JD et al Canonical Wnt signaling in differentiated osteoblasts controls osteoclast differentiation. Dev Cell, 2005, 8: 751-764

[67] Holmen SL, Zylstra CR, Mukherjee A et al Essential role of beta-catenin in postnatal bone acquisition. J Biol Chem, 2005, 280: 21162-21168

[68] Moester MJ, Papapoulos SE, Lowik CW et al Sclerostin: current knowledge and future perspectives. Calcif Tissue Int, 2010, 87: 99-107

[69] van Bezooijen RL, Roelen BA, Visser A et al Sclerostin is an osteocyte-expressed negative regulator of bone formation, but not a classical BMP antagonist. J Exp Med, 2004, 199: 805-814

[70] MacDonald BT, Joiner DM, Oyserman SM et al Bone mass is inversely proportional to Dkk1 levels in mice. Bone, 2007, 41: 331-339

[71] Monroe DG, McGee-Lawrence ME, Oursler MJ et al Update on Wnt signaling in bone cell biology and bone disease. Gene, 2012, 492: 1-18

[72] Kubota K, Sakikawa C, Katsumata M et al Platelet-derived growth factor BB secreted from osteoclasts acts as an osteoblastogenesis inhibitory factor. J Bone Miner Res, 2002, 17: 257-265

[73] Lee SH, Rho J, Jeong D et al v-ATPase V0 subunit d2-deficient mice exhibit impaired osteoclast fusion and increased bone formation. Nat Med, 2006, 12: 1403-1409

[74] Li CY, Jepsen KJ, Majeska RJ et al Mice lacking cathepsin K maintain bone remodeling but develop bone fragility despite high bone mass. J Bone Miner Res, 2006, 21: 865-875

[75] Nakamura A, Ly C, Cipetic M et al Osteoclast inhibitory lectin (OCIL) inhibits osteoblast differentiation and function in vitro. Bone, 2007, 40: 305-315

[76] Kaneko H, Arakawa T, Mano H et al Direct stimulation of osteoclastic bone resorption by bone morphogenetic protein (BMP)-2 and expression of BMP receptors in mature osteoclasts. Bone, 2000, 27: 479-486

[77] Itoh K, Udagawa N, Katagiri T et al Bone morphogenetic protein 2 stimulates osteoclast differentiation and survival supported by receptor activator of nuclear factor-kappaB ligand. Endocrinology, 2001, 142: 3656-3662

[78] Yamashita M, Otsuka F, Mukai T et al Simvastatin inhibits osteoclast differentiation induced by bone morphogenetic protein-2 and RANKL through regulating MAPK, AKT and Src signaling. Regul Pept, 2010, 162: 99-108

[79] Jensen ED, Pham L, Billington CJ et al Bone morphogenic protein 2 directly enhances differentiation of murine osteoclast precursors. J Cell Biochem, 2010, 109: 672-682

[80] Fujii M, Takeda K, Imamura T et al Roles of bone morphogenetic protein type I receptors and Smad proteins in osteoblast and chondroblast differentiation. Mol Biol Cell, 1999, 10: 3801-3813

[81] Yoon BS, Ovchinnikov DA, Yoshii I et al Bmpr1a and Bmpr1b have overlapping functions and are essential for chondrogenesis in vivo. Proc Natl Acad Sci USA, 2005, 102: 5062-5067

[82] Kobayashi T, Lyons KM, McMahon AP et al BMP signaling stimulates cellular differentiation at multiple steps during cartilage development. Proc Natl Acad Sci USA, 2005, 102: 18023-18027

[83] Rountree RB, Schoor M, Chen H et al BMP receptor signaling is required for postnatal maintenance of articular cartilage. PLoS Biol, 2004, 2: e355

[84] Jing J, Ren Y, Zong Z et al BMP receptor 1A determines the cell fate of the postnatal growth plate. Int J Biol Sci, 2013, 9: 895-906

[85] Jing J, Hinton RJ, Feng JQ. Bmpr1a signaling in cartilage development and endochondral bone formation. Vitam Horm, 2015, 99: 273-291

[86] Jing J, Hinton RJ, Mishina Y et al Critical role of Bmpr1a in mandibular condyle growth. Connect Tissue Res, 2014, 55: 73-78

[87] Ashique AM, Fu K, Richman JM. Signalling via type IA and type IB bone morphogenetic protein receptors (BMPR) regulates intramembranous bone formation, chondrogenesis and feather formation in the chicken embryo. Int J Dev Biol, 2002, 46: 243-253

[88] Yi SE, Daluiski A, Pederson R et al The type I BMP receptor BMPRIB is required for chondrogenesis in the mouse limb. Development, 2000, 127: 621-630

[89] Ishidou Y, Kitajima I, Obama H et al Enhanced expression of type I receptors for bone morphogenetic proteins during bone formation. J Bone Miner Res, 1995, 10: 1651-1659

[90] Demirhan O, Turkmen S, Schwabe GC et al A homozygous BMPR1B mutation causes a new subtype of acromesomelic chondrodysplasia with genital anomalies. J Med Genet, 2005, 42: 314-317

[91] Nishihara A, Fujii M, Sampath TK et al Bone morphogenetic protein signaling in articular chondrocyte differentiation. Biochem Biophys Res Commun, 2003, 301: 617-622

[92] Baur ST, Mai JJ, Dymecki SM. Combinatorial signaling through BMP receptor IB and GDF5: shaping of the distal mouse limb and the genetics of distal limb diversity. Development, 2000, 127: 605-619

[93] Zhao M, Harris SE, Horn D et al Bone morphogenetic protein receptor signaling is necessary for normal murine postnatal bone formation. J Cell Biol, 2002, 157: 1049-1060

[94] Bonewald LF. The amazing osteocyte. J Bone Miner Res, 2011, 26: 229-238

[95] Baud'huin M, Solban N, Cornwall-Brady M et al A soluble bone morphogenetic protein type IA receptor increases bone mass and bone strength. Proc Natl Acad Sci USA, 2012, 109: 12207-12212