Disruption of LRP6 in osteoblasts blunts the bone anabolic activity of PTH

Journal of Bone and Mineral Research

Volumn 28, Issue 10, 2013, Pages 2094-2108

  Li, Changjun ^a,b   Xing, Qiujuan ^a,c   Yu, Bing ^a   Xie, Hui ^a   Wang, Weishan ^b   Shi, Chenhui ^b   Crane, Janet L ^a   Cao, Xu ^a   Wan, Mei ^a  

^a JOHNS HOPKINS UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b SHIHEZI UNIVERSITY   (China)

^c SHANGHAI UNIVERSITY OF TRADITIONAL CHINESE MEDICINE   (China)

Author keywords

bone remodeling; LRP6; osteoblast apoptosis; osteoblast differentiation; PTH

Indexed keywords

CALCEIN; LOW DENSITY LIPOPROTEIN RECEPTOR RELATED PROTEIN 6; PARATHYROID HORMONE;

ANIMAL EXPERIMENT; APOPTOSIS; ARTICLE; BONE MASS; BONE REMODELING; CONTROLLED STUDY; CORTICAL BONE; IMMUNOHISTOCHEMISTRY; MALE; MORPHOMETRICS; MOUSE; NONHUMAN; OSSIFICATION; OSTEOBLAST; TRABECULAR BONE;

BONE REMODELING; LRP6; OSTEOBLAST APOPTOSIS; OSTEOBLAST DIFFERENTIATION; PTH;

ANABOLIC AGENTS; ANIMALS; APOPTOSIS; BETA CATENIN; BONE AND BONES; BONE REMODELING; BONE RESORPTION; CELL DIFFERENTIATION; CYCLIC AMP-DEPENDENT PROTEIN KINASES; GENE DELETION; GENE EXPRESSION REGULATION; GTP-BINDING PROTEIN ALPHA SUBUNITS; HUMANS; INTEGRASES; LOW DENSITY LIPOPROTEIN RECEPTOR-RELATED PROTEIN-6; MICE; MICE, KNOCKOUT; ORGAN SIZE; OSTEOBLASTS; OSTEOGENESIS; PARATHYROID HORMONE; PHENOTYPE; SIGNAL TRANSDUCTION;

EID: 84884514896     PISSN: 08840431     EISSN: 15234681     Source Type: Journal    
DOI: 10.1002/jbmr.1962     Document Type: Article

References (62)

1. Tang Y, Wu X, Lei W, Pang L, Wan C, Shi Z, Zhao L, Nagy TR, Peng X, Hu J, Feng X, Van HW, Wan M, Cao X., TGF-beta1-induced migration of bone mesenchymal stem cells couples bone resorption with formation. Nat Med. 2009; 15: 757-65.
2. Wu X, Pang L, Lei W, Lu W, Li J, Li Z, Frassica FJ, Chen X, Wan M, Cao X., Inhibition of Sca-1-positive skeletal stem cell recruitment by alendronate blunts the anabolic effects of parathyroid hormone on bone remodeling. Cell Stem Cell. 2010; 7: 571-80.
3. Xian L, Wu X, Pang L, Lou M, Rosen CJ, Qiu T, Crane J, Frassica F, Zhang L, Rodriguez JP, Xiaofeng J, Shoshana Y, Shouhong X, Argiris E, Mei W, Xu C., Matrix IGF-1 maintains bone mass by activation of mTOR in mesenchymal stem cells. Nat Med. 2012; 18: 1095-101.
4. Murray TM, Rao LG, Divieti P, Bringhurst FR., Parathyroid hormone secretion and action: evidence for discrete receptors for the carboxyl-terminal region and related biological actions of carboxyl-terminal ligands. Endocr Rev. 2005; 26: 78-113.
5. Hodsman AB, Bauer DC, Dempster DW, Dian L, Hanley DA, Harris ST, Kendler DL, McClung MR, Miller PD, Olszynski WP, Orwoll E, Yuen CK., Parathyroid hormone and teriparatide for the treatment of osteoporosis: a review of the evidence and suggested guidelines for its use. Endocr Rev. 2005; 26: 688-703.
6. Tam CS, Heersche JN, Murray TM, Parsons JA., Parathyroid hormone stimulates the bone apposition rate independently of its resorptive action: differential effects of intermittent and continuous administration. Endocrinology. 1982; 110: 506-12.
7. Jilka RL., Molecular and cellular mechanisms of the anabolic effect of intermittent PTH. Bone. 2007; 40: 1434-46.
8. Qin L, Raggatt LJ, Partridge NC., Parathyroid hormone: a double-edged sword for bone metabolism. Trends Endocrinol Metab. 2004; 15: 60-5.
9. Tamai K, Semenov M, Kato Y, Spokony R, Liu C, Katsuyama Y, Hess F, Saint-Jeannet JP, He X., LDL-receptor-related proteins in Wnt signal transduction. Nature. 2000; 407: 530-5.
10. Pinson KI, Brennan J, Monkley S, Avery BJ, Skarnes WC., An LDL-receptor-related protein mediates Wnt signalling in mice. Nature. 2000; 407: 535-8.
11. Huelsken J, Birchmeier W., New aspects of Wnt signaling pathways in higher vertebrates. Curr Opin Genet Dev. 2001; 11: 547-53.
12. Mao J, Wang J, Liu B, Pan W, Farr GH III, Flynn C, Yuan H, Takada S, Kimelman D, Li L, Wu D., Low-density lipoprotein receptor-related protein-5 binds to Axin and regulates the canonical Wnt signaling pathway. Mol Cell. 2001; 7: 801-9.
13. Tamai K, Zeng X, Liu C, Zhang X, Harada Y, Chang Z, He X., A mechanism for Wnt coreceptor activation. Mol Cell. 2004; 13: 149-56.
14. Gong Y, Slee RB, Fukai N, Rawadi G, Roman-Roman S, Reginato AM, Wang H, Cundy T, Glorieux FH, Lev D, Zacharin M, Oexle K, Marcelino J, Suwairi W, Heeger S, Sabatakos G, Apte S, Adkins WN, Allgrove J, Arslan-Kirchner M, Batch JA, Beighton P, Black GC, Boles RG, Boon LM, Borrone C, Brunner HG, Carle GF, Dallapiccola B, De Paepe A, Floege B, Halfhide ML, Hall B, Hennekam RC, Hirose T, Jans A, Juppner H, Kim CA, Keppler-Noreuil K, Kohlschuetter A, LaCombe D, Lambert M, Lemyre E, Letteboer T, Peltonen L, Ramesar RS, Romanengo M, Somer H, Steichen-Gersdorf E, Steinmann B, Sullivan B, Superti-Furga A, Swoboda W, van den Boogaard MJ, Van HW, Vikkula M, Votruba M, Zabel B, Garcia T, Baron R, Olsen BR, Warman ML., LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell. 2001; 107: 513-23.
15. Little RD, Recker RR, Johnson ML., High bone density due to a mutation in LDL-receptor-related protein 5. N Engl J Med. 2002; 347: 943-4.
16. Boyden LM, Mao J, Belsky J, Mitzner L, Farhi A, Mitnick MA, Wu D, Insogna K, Lifton RP., High bone density due to a mutation in LDL-receptor-related protein 5. N Engl J Med. 2002; 346: 1513-21.
17. Little RD, Carulli JP, Del Mastro RG, Dupuis J, Osborne M, Folz C, Manning SP, Swain PM, Zhao SC, Eustace B, Lappe MM, Spitzer L, Zweier S, Braunschweiger K, Benchekroun Y, Hu X, Adair R, Chee L, FitzGerald MG, Tulig C, Caruso A, Tzellas N, Bawa A, Franklin B, McGuire S, Nogues X, Gong G, Allen KM, Anisowicz A, Morales AJ, Lomedico PT, Recker SM, Van EP, Recker RR, Johnson ML., A mutation in the LDL receptor-related protein 5 gene results in the autosomal dominant high-bone-mass trait. Am J Hum Genet. 2002; 70: 11-9.
18. Mani A, Radhakrishnan J, Wang H, Mani A, Mani MA, Nelson-Williams C, Carew KS, Mane S, Najmabadi H, Wu D, Lifton RP., LRP6 mutation in a family with early coronary disease and metabolic risk factors. Science. 2007; 315: 1278-82.
19. van Meurs JB, Rivadeneira F, Jhamai M, Hugens W, Hofman A, van Leeuwen JP, Pols HA, Uitterlinden AG., Common genetic variation of the low-density lipoprotein receptor-related protein 5 and 6 genes determines fracture risk in elderly white men. J Bone Miner Res. 2006; 21: 141-50.
20. van Meurs JB, Trikalinos TA, Ralston SH, Balcells S, Brandi ML, Brixen K, Kiel DP, Langdahl BL, Lips P, Ljunggren O, Lorenc R, Obermayer-Pietsch B, Ohlsson C, Pettersson U, Reid DM, Rousseau F, Scollen S, Van HW, Agueda L, Akesson K, Benevolenskaya LI, Ferrari SL, Hallmans G, Hofman A, Husted LB, Kruk M, Kaptoge S, Karasik D, Karlsson MK, Lorentzon M, Masi L, McGuigan FE, Mellstrom D, Mosekilde L, Nogues X, Pols HA, Reeve J, Renner W, Rivadeneira F, van Schoor NM, Weber K, Ioannidis JP, Uitterlinden AG., Large-scale analysis of association between LRP5 and LRP6 variants and osteoporosis. JAMA. 2008; 299: 1277-90.
21. Kato M, Patel MS, Levasseur R, Lobov I, Chang BH, Glass DA, Hartmann C, Li L, Hwang TH, Brayton CF, Lang RA, Karsenty G, Chan L., Cbfa1-independent decrease in osteoblast proliferation, osteopenia, and persistent embryonic eye vascularization in mice deficient in Lrp5, a Wnt coreceptor. J Cell Biol. 2002; 157: 303-14.
22. Kelly OG, Pinson KI, Skarnes WC., The Wnt co-receptors Lrp5 and Lrp6 are essential for gastrulation in mice. Development. 2004; 131: 2803-15.
23. Holmen SL, Giambernardi TA, Zylstra CR, Buckner-Berghuis BD, Resau JH, Hess JF, Glatt V, Bouxsein ML, Ai M, Warman ML, Williams BO., Decreased BMD and limb deformities in mice carrying mutations in both Lrp5 and Lrp6. J Bone Miner Res. 2004; 19: 2033-40.
24. Wan M, Yang C, Li J, Wu X, Yuan H, Ma H, He X, Nie S, Chang C, Cao X., Parathyroid hormone signaling through low-density lipoprotein-related protein 6. Genes Dev. 2008; 22: 2968-79.
25. Qiu T, Wu X, Zhang F, Clemens TL, Wan M, Cao X., TGF-beta type II receptor phosphorylates PTH receptor to integrate bone remodelling signalling. Nat Cell Biol. 2010; 12: 224-34.
26. Yu B, Zhao X, Yang C, Crane J, Xian L, Lu W, Wan M, Cao X., Parathyroid hormone induces differentiation of mesenchymal stromal/stem cells by enhancing bone morphogenetic protein signaling. J Bone Miner Res. 2012; 27: 2001-14.
27. Wan M, Li J, Herbst K, Zhang J, Yu B, Wu X, Qiu T, Lei W, Lindvall C, Williams BO, Ma H, Zhang F, Cao X., LRP6 mediates cAMP generation by G protein-coupled receptors through regulating the membrane targeting of Galpha(s). Sci Signal. 2011; 4: ra15.
28. Sawakami K, Robling AG, Ai M, Pitner ND, Liu D, Warden SJ, Li J, Maye P, Rowe DW, Duncan RL, Warman ML, Turner CH., The Wnt co-receptor LRP5 is essential for skeletal mechanotransduction but not for the anabolic bone response to parathyroid hormone treatment. J Biol Chem. 2006; 281: 23698-711.
29. Iwaniec UT, Wronski TJ, Liu J, Rivera MF, Arzaga RR, Hansen G, Brommage R., PTH stimulates bone formation in mice deficient in Lrp5. J Bone Miner Res. 2007; 22: 394-402.
30. Qin L, Qiu P, Wang L, Li X, Swarthout JT, Soteropoulos P, Tolias P, Partridge NC., Gene expression profiles and transcription factors involved in parathyroid hormone signaling in osteoblasts revealed by microarray and bioinformatics. J Biol Chem. 2003; 278: 19723-31.
31. Lombardi G, Di SC, Rubino M, Faggiano A, Vuolo L, Guerra E, Contaldi P, Savastano S, Colao A., The roles of parathyroid hormone in bone remodeling: prospects for novel therapeutics. J Endocrinol Invest. 2011; 34: 18-22.
32. Zylstra CR, Wan C, VanKoevering KK, Sanders AK, Lindvall C, Clemens TL, Williams BO., Gene targeting approaches in mice: assessing the roles of LRP5 and LRP6 in osteoblasts. J Musculoskelet Neuronal Interact. 2008; 8: 291-3.
33. Joeng KS, Schumacher CA, Zylstra-Diegel CR, Long F, Williams BO., Lrp5 and Lrp6 redundantly control skeletal development in the mouse embryo. Dev Biol. 2011; 359: 222-9.
34. Zhang M, Xuan S, Bouxsein ML, von SD, Akeno N, Faugere MC, Malluche H, Zhao G, Rosen CJ, Efstratiadis A, Clemens TL., Osteoblast-specific knockout of the insulin-like growth factor (IGF) receptor gene reveals an essential role of IGF signaling in bone matrix mineralization. J Biol Chem. 2002; 277: 44005-12.
35. Canalis E, Parker K, Feng JQ, Zanotti S., Osteoblast lineage-specific effects of notch activation in the skeleton. Endocrinology. 2013; 154: 623-34.
36. Jho EH, Zhang T, Domon C, Joo CK, Freund JN, Costantini F., Wnt/beta-catenin/Tcf signaling induces the transcription of Axin2, a negative regulator of the signaling pathway. Mol Cell Biol. 2002; 22: 1172-83.
37. Leung JY, Kolligs FT, Wu R, Zhai Y, Kuick R, Hanash S, Cho KR, Fearon ER., Activation of AXIN2 expression by beta-catenin-T cell factor. A feedback repressor pathway regulating Wnt signaling. J Biol Chem. 2002; 277: 21657-65.
38. Lustig B, Jerchow B, Sachs M, Weiler S, Pietsch T, Karsten U, van de Wetering M, Clevers H, Schlag PM, Birchmeier W, Behrens J., Negative feedback loop of Wnt signaling through upregulation of conductin/axin2 in colorectal and liver tumors. Mol Cell Biol. 2002; 22: 1184-93.
39. Rousset R, Mack JA, Wharton KA Jr, Axelrod JD, Cadigan KM, Fish MP, Nusse R, Scott MP., Naked cuticle targets dishevelled to antagonize Wnt signal transduction. Genes Dev. 2001; 15: 658-71.
40. Waldrop S, Chan CC, Cagatay T, Zhang S, Rousset R, Mack J, Zeng W, Fish M, Zhang M, Amanai M, Wharton KA Jr., An unconventional nuclear localization motif is crucial for function of the Drosophila Wnt/wingless antagonist Naked cuticle. Genetics. 2006; 174: 331-48.
41. Kim JS, Crooks H, Dracheva T, Nishanian TG, Singh B, Jen J, Waldman T., Oncogenic beta-catenin is required for bone morphogenetic protein 4 expression in human cancer cells. Cancer Res. 2002; 62: 2744-8.
42. Glass DA, Bialek P, Ahn JD, Starbuck M, Patel MS, Clevers H, Taketo MM, Long F, McMahon AP, Lang RA, Karsenty G., Canonical Wnt signaling in differentiated osteoblasts controls osteoclast differentiation. Dev Cell. 2005; 8: 751-64.
43. Holmen SL, Zylstra CR, Mukherjee A, Sigler RE, Faugere MC, Bouxsein ML, Deng L, Clemens TL, Williams BO., Essential role of beta-catenin in postnatal bone acquisition. J Biol Chem. 2005; 280: 21162-8.
44. Baron R, Hesse E., Update on bone anabolics in osteoporosis treatment: rationale, current status, and perspectives. J Clin Endocrinol Metab. 2012; 97: 311-25.
45. 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. J Biol Chem. 2003; 278: 50259-72.
46. Chen HL, Demiralp B, Schneider A, Koh AJ, Silve C, Wang CY, McCauley LK., Parathyroid hormone and parathyroid hormone-related protein exert both pro- and anti-apoptotic effects in mesenchymal cells. J Biol Chem. 2002; 277: 19374-81.
47. McCauley LK, Koh-Paige AJ, Chen H, Chen C, Ontiveros C, Irwin R, McCabe LR., Parathyroid hormone stimulates fra-2 expression in osteoblastic cells in vitro and in vivo. Endocrinology. 2001; 142: 1975-81.
48. Pearman AT, Chou WY, Bergman KD, Pulumati MR, Partridge NC., Parathyroid hormone induces c-fos promoter activity in osteoblastic cells through phosphorylated cAMP response element (CRE)-binding protein binding to the major CRE. J Biol Chem. 1996; 271: 25715-21.
49. Tyson DR, Swarthout JT, Partridge NC., Increased osteoblastic c-fos expression by parathyroid hormone requires protein kinase A phosphorylation of the cyclic adenosine 3′,5′-monophosphate response element-binding protein at serine 133. Endocrinology. 1999; 140: 1255-61.
50. Selvamurugan N, Chou WY, Pearman AT, Pulumati MR, Partridge NC., Parathyroid hormone regulates the rat collagenase-3 promoter in osteoblastic cells through the cooperative interaction of the activator protein-1 site and the runt domain binding sequence. J Biol Chem. 1998; 273: 10647-57.
51. Partridge NC, Walling HW, Bloch SR, Omura TH, Chan PT, Pearman AT, Chou WY., The regulation and regulatory role of collagenase in bone. Crit Rev Eukaryot Gene Expr. 1996; 6: 15-27.
52. Kramer I, Halleux C, Keller H, Pegurri M, Gooi JH, Weber PB, Feng JQ, Bonewald LF, Kneissel M., Osteocyte Wnt/beta-catenin signaling is required for normal bone homeostasis. Mol Cell Biol. 2010; 30: 3071-85.
53. 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. J Biol Chem. 2002; 277: 48868-75.
54. Fu Q, Manolagas SC, O'Brien CA., Parathyroid hormone controls receptor activator of NF-kappaB ligand gene expression via a distant transcriptional enhancer. Mol Cell Biol. 2006; 26: 6453-68.
55. Kim S, Yamazaki M, Shevde NK, Pike JW., Transcriptional control of receptor activator of nuclear factor-kappaB ligand by the protein kinase A activator forskolin and the transmembrane glycoprotein 130-activating cytokine, oncostatin M, is exerted through multiple distal enhancers. Mol Endocrinol. 2007; 21: 197-214.
56. Swarthout JT, D'Alonzo RC, Selvamurugan N, Partridge NC., Parathyroid hormone-dependent signaling pathways regulating genes in bone cells. Gene. 2002; 282: 1-17.
57. Datta NS, Abou-Samra AB., PTH and PTHrP signaling in osteoblasts. Cell Signal. 2009; 21: 1245-54.
58. Schipani E, Kronenberg HM., Adult mesenchymal stem cells. Camridge, MA: StemBook; 2008.
59. Ohishi M, Schipani E., PTH and stem cells. J Endocrinol Invest. 2011; 34: 552-6.
60. Mendez-Ferrer S, Michurina TV, Ferraro F, Mazloom AR, Macarthur BD, Lira SA, Scadden DT, Ma'ayan A, Enikolopov GN, Frenette PS., Mesenchymal and haematopoietic stem cells form a unique bone marrow niche. Nature. 2010; 466: 829-34.
61. Li JY, Adams J, Calvi LM, Lane TF, Dipaolo R, Weitzmann MN, Pacifici R., PTH expands short-term murine hemopoietic stem cells through T cells. Blood. 2012; 120: 4352-62.
62. Calvi LM, Adams GB, Weibrecht KW, Weber JM, Olson DP, Knight MC, Martin RP, Schipani E, Divieti P, Bringhurst FR, Milner LA, Kronenberg HM, Scadden DT., Osteoblastic cells regulate the haematopoietic stem cell niche. Nature. 2003; 425: 841-6.