دورية أكاديمية
Loss-of-function of ACVR1 in osteoblasts increases bone mass and activates canonical Wnt signaling through suppression of Wnt inhibitors SOST and DKK1.
العنوان: | Loss-of-function of ACVR1 in osteoblasts increases bone mass and activates canonical Wnt signaling through suppression of Wnt inhibitors SOST and DKK1. |
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المؤلفون: | Kamiya N; Center for Excellence in Hip Disorders, Texas Scottish Rite Hospital for Children, Dallas, TX 75219, USA. Nobby.kamiya@tsrh.org, Kaartinen VM, Mishina Y |
المصدر: | Biochemical and biophysical research communications [Biochem Biophys Res Commun] 2011 Oct 22; Vol. 414 (2), pp. 326-30. Date of Electronic Publication: 2011 Sep 17. |
نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
اللغة: | English |
بيانات الدورية: | Publisher: Elsevier Country of Publication: United States NLM ID: 0372516 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1090-2104 (Electronic) Linking ISSN: 0006291X NLM ISO Abbreviation: Biochem Biophys Res Commun Subsets: MEDLINE |
أسماء مطبوعة: | Publication: <2002- >: San Diego, CA : Elsevier Original Publication: New York, Academic Press. |
مواضيع طبية MeSH: | Activin Receptors, Type I/*physiology , Bone and Bones/*anatomy & histology , Glycoproteins/*metabolism , Intercellular Signaling Peptides and Proteins/*metabolism , Osteoblasts/*enzymology , Osteogenesis/*genetics , Wnt Proteins/*metabolism, Activin Receptors, Type I/genetics ; Adaptor Proteins, Signal Transducing ; Animals ; Bone Morphogenetic Protein 7/metabolism ; Bone and Bones/enzymology ; Mice ; Mice, Transgenic ; Up-Regulation ; Wnt Proteins/antagonists & inhibitors ; Wnt Signaling Pathway |
مستخلص: | BMPs (Bone morphogenetic proteins) such as BMP2 and BMP7 have been used about one decade as bone anabolic agents in orthopaedics. The BMP receptor ACVR1, which is a key receptor of BMP7, is expressed in bone. The pathological role of ACVR1 in humans has been reported: a point mutation in ACVR1 can cause fibrodysplasia ossificans progressiva (FOP) in which ectopic ossification occurs in skeletal muscles and deep connective tissues. The physiological function of ACVR1 in bone, however, is totally unknown. The purpose of this study is to investigate the endogenous role of ACVR1 in osteoblasts, one of the most dominant cell-types in bone. We generated Acvr1-null mice in an osteoblast-specific manner using an inducible Cre-loxP system. Surprisingly, we found that bone mass was increased in the Acvr1-null mice. Interestingly, canonical Wnt signaling was increased and expression levels of Wnt inhibitors Sost and Dkk1 were both suppressed in the null bones during the developmental stages. In addition, we confirmed that expression levels of both Sost and Dkk1 were upregulated by BMP7 dose-dependently in vitro. These results suggest that the Acvr1-deficiency can increase bone mass by activating Wnt signaling in which both Sost and Dkk1 expression levels are diminished. This study leads to a new concept of the BMP7-ACVR1-SOST/DKK1 axis in osteoblasts, in which BMP7 signaling through ACVR1 can reduce Wnt signaling via SOST/DKK1 and then inhibits osteogenesis. Although this concept is beyond the current known function of BMP7, it can explain the varied outcomes of BMP7 treatment. We believe BMP signaling can exhibit multifaceted effects by context and cell type. (Copyright © 2011 Elsevier Inc. All rights reserved.) |
References: | Development. 1999 Oct;126(20):4557-68. (PMID: 10498690) J Bone Miner Res. 2006 Jul;21(7):1022-33. (PMID: 16813523) Dev Biol. 1999 Sep 15;213(2):314-26. (PMID: 10479450) Biofactors. 2011 Mar-Apr;37(2):75-82. (PMID: 21488130) J Bone Miner Res. 2010 Feb;25(2):200-10. (PMID: 19874086) Dev Biol. 2005 Oct 1;286(1):299-310. (PMID: 16140292) J Bone Miner Res. 2008 Dec;23(12):2007-17. (PMID: 18684091) J Med Genet. 2002 Feb;39(2):91-7. (PMID: 11836356) Lancet. 2011 Apr 9;377(9773):1276-87. (PMID: 21450337) Annu Rev Biochem. 1998;67:753-91. (PMID: 9759503) Science. 1965 Nov 12;150(3698):893-9. (PMID: 5319761) Dev Dyn. 2007 Feb;236(2):512-7. (PMID: 17117439) Ann N Y Acad Sci. 2007 Nov;1116:149-64. (PMID: 18083926) Best Pract Res Clin Rheumatol. 2008 Mar;22(1):191-205. (PMID: 18328989) Development. 2008 Nov;135(22):3801-11. (PMID: 18927151) Nat Med. 2010 Dec;16(12):1400-6. (PMID: 21102460) Curr Top Dev Biol. 2006;76:103-27. (PMID: 17118265) J Bone Miner Res. 2008 Jun;23(6):860-9. (PMID: 18269310) J Biol Chem. 1998 Oct 2;273(40):25628-36. (PMID: 9748228) Growth Factors. 2004 Dec;22(4):233-41. (PMID: 15621726) Hum Mol Genet. 2001 Mar 1;10(5):537-43. (PMID: 11181578) J Clin Invest. 2006 May;116(5):1202-9. (PMID: 16670761) J Bone Joint Surg Am. 2009 Mar 1;91(3):652-63. (PMID: 19255227) J Bone Miner Res. 2006 Jun;21(6):934-45. (PMID: 16753024) J Biol Chem. 1992 Oct 5;267(28):20352-62. (PMID: 1328198) J Orthop Res. 2004 Sep;22(5):1008-15. (PMID: 15304273) Nat Genet. 2006 May;38(5):525-7. (PMID: 16642017) Cell. 1992 Jun 26;69(7):1067-70. (PMID: 1319842) J Bone Joint Surg Am. 2003 Aug;85(8):1544-52. (PMID: 12925636) Bone. 2006 Oct;39(4):754-66. (PMID: 16730481) Cochrane Database Syst Rev. 2010 Jun 16;(6):CD006950. (PMID: 20556771) Int Orthop. 2007 Dec;31(6):735-41. (PMID: 17962946) J Biol Chem. 2002 Feb 15;277(7):4883-91. (PMID: 11729207) J Bone Joint Surg Am. 2010 Feb;92(2):411-26. (PMID: 20124069) J Bone Miner Metab. 2008;26(6):521-30. (PMID: 18979151) Genesis. 2001 Nov;31(3):126-9. (PMID: 11747203) Methods. 2001 Dec;25(4):402-8. (PMID: 11846609) |
معلومات مُعتمدة: | R01DE013085 United States DE NIDCR NIH HHS; R01DE020843 United States DE NIDCR NIH HHS; R01 DE020843 United States DE NIDCR NIH HHS; R01 DE013085 United States DE NIDCR NIH HHS; R01 DE013085-12 United States DE NIDCR NIH HHS; R01 DE020843-01 United States DE NIDCR NIH HHS |
المشرفين على المادة: | 0 (Adaptor Proteins, Signal Transducing) 0 (Bone Morphogenetic Protein 7) 0 (Dkk1 protein, mouse) 0 (Glycoproteins) 0 (Intercellular Signaling Peptides and Proteins) 0 (Sost protein, mouse) 0 (Wnt Proteins) 0 (bmp7 protein, mouse) EC 2.7.11.30 (Activin Receptors, Type I) EC 2.7.11.30 (Acvr1 protein, mouse) |
تواريخ الأحداث: | Date Created: 20110928 Date Completed: 20111219 Latest Revision: 20211020 |
رمز التحديث: | 20221213 |
مُعرف محوري في PubMed: | PMC3200475 |
DOI: | 10.1016/j.bbrc.2011.09.060 |
PMID: | 21945937 |
قاعدة البيانات: | MEDLINE |
تدمد: | 1090-2104 |
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DOI: | 10.1016/j.bbrc.2011.09.060 |