Novel regulators of bone formation:​ molecular clones and activities

Wozney, John M.; Rosen, Vicki; Celeste, Anthony J.; Mitsock, Lisa M.; Whitters, Matthew J.; Kriz, Ronald W.; Hewick, Rodney M.; Wang, Elizabeth A.

Affiliations

¹Tissue Growth and Repair Program at Genetics Institute, Inc., 87 CambridgePark Drive, Cambridge, MA 02140

Abstract

Protein extracts derived from bone can initiate the process that begins with cartilage formation and ends in de novo bone formation. The critical components of this extract, termed bone morphogenetic protein (BMP), that direct cartilage and bone formation as well as the constitutive elements supplied by the animal during this process have long remained unclear. Amino acid sequence has been derived from a highly purified preparation of BMP from bovine bone. Now, human complementary DNA clones corresponding to three polypeptides present in this BMP preparation have been isolated, and expression of the recombinant human proteins have been obtained. Each of the three (BMP-1, BMP-2A, and BMP-3) appears to be independently capable of inducing the formation of cartilage in vivo. Two of the encoded proteins (BMP-2A and BMP-3) are new members of the TGF-beta supergene family, while the third, BMP-1, appears to be a novel regulatory molecule.

Links

DOI: 10.1126/science.3201241

PubMed: 3201241

WoS: A1988R365100029

History

Received: 1988-08-11

Accepted: 1988-11-14

Cited By (49)

Year	Entry
1991	Kahn AJ, Partridge NC. Bone resorption in vivo. In: Hall BK, ed. Bone. Volume 2: The Osteoclast. Boca Raton, FL: Inc., CRC Press; 1991:119-140.
1992	Centrella M, McCarthy TL, Canalis E. Growth factors and cytokines. In: Hall BK, ed. Bone. Volume 4: Bone Metabolism and Mineralization. Boca Raton, FL: Inc., CRC Press; 1992:47-72.
1992	Korhonen LK, Väänänen K. Bone inductive molecules and enhancement of repair and regeneration. In: Hall BK, ed. Bone. Volume 5: Fracture Repair and Regeneration. Boca Raton, FL: Inc., CRC Press; 1992:209-232.
1992	Wlodarski KH. Bone formation in soft tissues. In: Hall BK, ed. Bone. Volume 5: Fracture Repair and Regeneration. Boca Raton, FL: Inc., CRC Press; 1992:313-337.
1992	Simmons DJ. Circadian aspects of bone biology. In: Hall BK, ed. Bone. Volume 6: Bone Growth — A. Boca Raton, FL: Inc., CRC Press; 1992:91-128.
2001	Majeska RJ. Cell biology of bone. In: Cowin SC, ed. Bone Mechanics Handbook. 2nd ed. Boca Raton, FL: CRC Press; 2001:2-1–2-24.
1990	Hauschka PV. Growth factor effects in bone. In: Hall BK, ed. Bone. Volume 1: The Osteoblast and Osteocyte. Caldwell, NJ: Inc., The Telford Press; 1990:103-170.
2011	Boerckel JD, Kolambkar YM, Dupont KM, Uhrig BA, Phelps EA, Stevens HY, García AJ, Guldberg RE. Effects of protein dose and delivery system on BMP-mediated bone regeneration. Biomaterials. November 2011;32(22):5241-5251.
2020	Sharma T, Cotney J, Singh V, Sanjay A, Reichenberger EJ, Ueki Y, Maye P. Investigating global gene expression changes in a murine model of cherubism. Bone. June 2020;135:115315.
2020	Wilkinson JM. The use of bisphosphonates to meet orthopaedic challenges. Bone. August 2020;137:115443.
2020	Tsukamoto S, Kuratani M, Katagiri T. Functional characterization of a unique mutant of ALK2, p.K400E, that is associated with a skeletal disorder, diffuse idiopathic skeletal hyperostosis. Bone. August 2020;137:115410.
2020	Sanchez-Duffhues G, Williams E, Goumans M-J, Heldin C-H, ten Dijke P. Bone morphogenetic protein receptors: structure, function and targeting by selective small molecule kinase inhibitors. Bone. September 2020;138:115472.
2020	Sampath TK, Reddi AH. Discovery of bone morphogenetic proteins: a historical perspective. Bone. November 2020;140:115548.
2020	Chen CH, Hsu EL, Stupp SI. Supramolecular self-assembling peptides to deliver bone morphogenetic proteins for skeletal regeneration. Bone. December 2020;141:115565.
2020	Sampath TK, Vukicevic S. Biology of bone morphogenetic protein in bone repair and regeneration: a role for autologous blood coagulum as carrier. Bone. December 2020;141:115602.
2023	Dashti P, Thaler R, Hawse JR, Galvan ML, van der Eerden BJ, van Wijnen AJ, Dudakovic A. G-protein coupled receptor 5C (GPRC5C) is required for osteoblast differentiation and responds to EZH2 inhibition and multiple osteogenic signals. Bone. November 2023;176:116866.
1997	Komori T, Yagi H, Nomura S, Yamaguchi A, Sasaki K, Deguchi K, Shimizu Y, Bronson RT, Gao Y-H, Inada M, Sato M, Okamoto R, Kitamura Y, Yoshiki S, Kishimoto T. Targeted disruption of Cbfa1 results in a complete lack of bone formation owing to maturational arrest of osteoblasts. Cell. May 30, 1997;89(5):755-764.
1994	Wakitani S, Goto T, Pineda SJ, Young RG, Mansour JM, Caplan AI, Goldberg VM. Mesenchymal cell-based repair of large, full-thickness defects of articular cartilage. J Bone Joint Surg. April 1994;76A(4):579-592.
2002	Lieberman JR, Daluiski A, Einhorn TA. The role of growth factors in the repair of bone: biology and clinical applications. J Bone Joint Surg. June 2002;84A(6):1032-1044.
2006	Swiontkowski MF, Aro HT, Donell S, Esterhai JL, Goulet J, Jones A, Kregor PJ, Nordsletten L, Paiement G, Patel A. Recombinant human bone morphogenetic protein-2 in open tibial fractures: a subgroup analysis of data combined from two prospective randomized studies. J Bone Joint Surg. June 2006;88A(6):1258-1265.
2002	Cho T-J, Gerstenfeld LC, Einhorn TA. Differential temporal expression of members of the transforming growth factor β superfamily during murine fracture healing. J Bone Miner Res. March 2002;17(3):513-520.
2020	Qian Z, Zhang Y, Kang X, Li H, Zhang Y, Jin X, Gao X, Xu M, Ma Z, Zhao L, Zhang Z, Sun H, Wu S. Postnatal conditional deletion of Bmal1 in osteoblasts enhances trabecular bone formation via increased BMP2 signals. J Bone Miner Res. August 2020;35(8):1481-1493.
2003	Gerstenfeld LC, Cullinane DM, Barnes GL, Graves DT, Einhorn TA. Fracture healing as a post‐natal developmental process: molecular, spatial, and temporal aspects of its regulation. J Cell Biochem. April 2003;88(5):873-884.
1991	Caplan AI. Mesenchymal stem cells. J Orthop Res. September 1991;9(5):641-650.
2006	Tsuji K, Bandyopadhyay A, Harfe BD, Cox K, Kakar S, Gerstenfeld L, Einhorn T, Tabin CJ, Rosen V. BMP2 activity, although dispensable for bone formation, is required for the initiation of fracture healing. Nat Genet. December 2006;38(12):1424-1429.
2016	Salazar VS, Gamer LW, Rosen V. BMP signalling in skeletal development, disease and repair. Nat Rev Endocrinol. April 2016;12(4):203-221.
2014	Subramony SD. Nanofiber-Based Scaffold for Integrative Anterior Cruciate Ligament Reconstruction [PhD thesis]. Columbia University; 2014.
2014	Melville KM. Estrogen Receptor Alpha in Osteoblasts Mediates Bone Mass and Bone's Response to in Vivo Loading [PhD thesis]. Ithaca, NY: Cornell University; August 2014.
2002	West PA. Structural Analysis of Degenerative Cartilage Using an Infrared Fiber Optic Probe [PhD thesis]. New York, NY: The City University of New York; 2002.
2005	Murray AW. Fracture Healing in Osteopenic Bone and the Influence of Simvastatin [MD thesis]. Edinburgh, Scotland: University of Edinburgh; 2005.
2009	Kolambkar YM. Electrospun Nanofiber Meshes for the Functional Repair of Bone Defects [PhD thesis]. Atlanta, GA: Georgia Institute of Technology; December 2009.
2010	Dupont KM. Human Stem Cell Delivery and Programming for Functional Regeneration of Large Segmental Bone Defects [PhD thesis]. Atlanta, GA: Georgia Institute of Technology; May 2010.
2011	Boerckel JD. Mechanical Regulation of Bone Regeneration and Vascular Growth in Vivo [PhD thesis]. Atlanta, GA: Georgia Institute of Technology; August 2011.
2015	Allen AB. Modulation of Stem Cell Delivery Strategy by Platelet Lysate Utilization and Cell Aggregation for Enhanced Bone Regeneration [PhD thesis]. Atlanta, GA: Georgia Institute of Technology; August 2015.
2016	Hettiaratchi MH. Heparin Microparticle-Mediated Delivery of BMP-2 and Pluripotent Stem Cell Morphogens for Bone Repair [PhD thesis]. Atlanta, GA: Georgia Institute of Technology; December 2016.
206	Chen Y. Developing Bioactive Composite Scaffolds for Bone Tissue Engineering [PhD thesis]. Hong Kong Polytechnic University; October 206.
2011	Linares GR. Novel Molecules That Regulate Bone Formation and Bone Resorption [PhD thesis]. Loma Linda University; June 2011.
2003	Chan GK. Delineation of Regulatory Factors and Mechanisms That Govern the Differentiation of Mesenchymal Cells to the Osteoblastic Lineage [PhD thesis]. McGill University; June 2003.
2008	Wheeler CA. Cartilage Response to in Vitro Models of Injury in Combination With Growth Factor and Antioxidant Treatments [PhD thesis]. Cambridge, MA: Massachusetts Institute of Technology; February 2008.
2015	Noble GJ. Evaluation of a Press Fit, Percutaneous, Skeletally Anchored Endoprosthesis for Prosthetic Limb Attachment: Bone Response and the Effect of Low Intensity Vibration [PhD thesis]. The Ohio State University; 2015.
2010	Gurkan UA. Engineering of Bone Marrow in Vitro for Investigating the Role of Growth Factors and Their Mechanoresponsiveness in Osteogenesis [PhD thesis]. Purdue University; May 2010.
2004	De Ranieri A. Morphologic, Mechanical, and Molecular Aspects of TGF-Β2 Enhanced Implant Fixation [PhD thesis]. Rush University; 2004.
2004	Barber TA. Biomimetic Surface Engineering to Control Matrix Mineralization [PhD thesis]. Berkeley, CA: Berkeley, University of California; 2004.
2018	Wang X. Investigating the Role of PDGF-BB/PDGFR-Β in Periosteum-Mediated Bone Regeneration [PhD thesis]. Storrs, CT: University of Connecticut; 2018.
2004	Schek RM. The Use of Designed, Solid Free Form Scaffolds for Gene Therapy Directed Bone Tissue Engineering [PhD thesis]. University of Michigan; 2004.
2012	Mitsak AG. Bone Tissue Engineering Using High Permeability Poly-Ε-Caprolactone Scaffolds Conjugated With Bone Morphogenetic Protein-2 [PhD thesis]. University of Michigan; 2012.
1996	Santos EM. Bioactive Sol-Gel Derived Materials as Delivery Vehicles for Bone Growth Factors [PhD thesis]. Philadelphia, PA: University of Pennsylvania; 1996.
2011	Kempen DHR. Bone Regeneration Based on Growth Factor Releasing Polymer Composites [PhD thesis]. Utrecht University; 2011.
2015	Lipner JH. Development of Nanofiber Scaffolds With Controllable Structure and Mineral Content for Tendon-to-Bone Repair [PhD thesis]. St. Louis, MO: Washington University in St. Louis; May 2015.