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Micro-CT Analysis of Cranial Bone and Tooth Density in Mice Deficient for GDF11 or Myostatin

  • Suh, Joonho (Department of Molecular Genetics & Dental Pharmacology, School of Dentistry and Dental Research Institute, Seoul National University) ;
  • Kim, Na-Kyung (Department of Molecular Genetics & Dental Pharmacology, School of Dentistry and Dental Research Institute, Seoul National University) ;
  • Lee, Yun-Sil (Department of Molecular Genetics & Dental Pharmacology, School of Dentistry and Dental Research Institute, Seoul National University)
  • Received : 2020.10.18
  • Accepted : 2020.10.21
  • Published : 2020.12.30

Abstract

Purpose: Growth differentiation factor 11 (GDF11) and myostatin (MSTN) are closely-related transforming growth factor β family members reported to play crucial roles in bone formation. We previously reported that, in contrast to MSTN, GDF11 promotes osteogenesis of vertebrae and limbs. GDF11 has been also reported as an important regulator in tooth development by inducing differentiation of pulp stem cells into odontoblasts for reparative dentin formation. The goal of this study was to investigate the differential roles of GDF11 and MSTN in dental and cranial bone formation. Methods: Micro-computed tomography analysis was performed on cranial bones, including frontal, parietal, and interparietal bones, and lower incisors of wild-type, Gdf11 knockout (Gdf11-/-), and Mstn knockout (Mstn-/-) mice. Tissue volume, thickness, and mineral density were evaluated for both cranial bone and lower incisors. Lower incisor lengths were also measured. Because Gdf11-/- mice die shortly after birth, analysis was performed on newborn (P0) mice. Results: Compared to those of Mstn-/- mice, cranial bone volume, thickness, and mineral density levels were all significantly diminished in Gdf11-/- mice. Tissue mineral density of Gdf11-/- mice were also significantly decreased compared to wild-type mice. Likewise, lower incisor length, tissue volume, thickness, and mineral density levels were all significantly reduced in Gdf11-/- mice compared to Mstn-/- mice. Incisor length was also significantly decreased in Gdf11-/- mice compared to wild-type mice. Mstn-/- mice exhibited mildly increased levels of tissue volume, thickness, and density in cranial bone and lower incisor compared to wild-type mice although statistically not significant. Conclusions: Our findings suggest that GDF11, unlike MSTN, endogenously promotes cranial bone and tooth development.

References

  1. Dudas M, Kaartinen V. Tgf-beta superfamily and mouse craniofacial development: interplay of morphogenetic proteins and receptor signaling controls normal formation of the face. Curr Top Dev Biol 2005;66:65-133. https://doi.org/10.1016/S0070-2153(05)66003-6
  2. McPherron AC, Lawler AM, Lee SJ. Regulation of anterior/posterior patterning of the axial skeleton by growth/differentiation factor 11. Nat Genet 1999;22:260-264. https://doi.org/10.1038/10320
  3. McPherron AC, Lawler AM, Lee SJ. Regulation of skeletal muscle mass in mice by a new TGF-beta superfamily member. Nature 1997;387:83-90. https://doi.org/10.1038/387083a0
  4. Suh J, Kim NK, Lee SH, et al. GDF11 promotes osteogenesis as opposed to MSTN, and follistatin, a MSTN/GDF11 inhibitor, increases muscle mass but weakens bone. Proc Natl Acad Sci U S A 2020;117:4910-4920. https://doi.org/10.1073/pnas.1916034117
  5. Nicholson EK, Stock SR, Hamrick MW, Ravosa MJ. Biomineralization and adaptive plasticity of the temporomandibular joint in myostatin knockout mice. Arch Oral Biol 2006;51:37-49. https://doi.org/10.1016/j.archoralbio.2005.05.008
  6. Hamrick MW. Increased bone mineral density in the femora of GDF8 knockout mice. Anat Rec A Discov Mol Cell Evol Biol 2003;272:388-391. https://doi.org/10.1002/ar.a.10044
  7. Williams SH, Lozier NR, Montuelle SJ, de Lacalle S. Effect of postnatal myostatin inhibition on bite mechanics in mice. PLoS One 2015;10:e0134854. https://doi.org/10.1371/journal.pone.0134854
  8. Vecchione L, Miller J, Byron C, et al. Age-related changes in craniofacial morphology in GDF-8 (myostatin)-deficient mice. Anat Rec (Hoboken) 2010;293:32-41. https://doi.org/10.1002/ar.21024
  9. Byron CD, Maness H, Yu JC, Hamrick MW. Enlargement of the temporalis muscle and alterations in the lateral cranial vault. Integr Comp Biol 2008;48:338-344. https://doi.org/10.1093/icb/icn020
  10. Vecchione L, Byron C, Cooper GM, et al. Craniofacial morphology in myostatin-deficient mice. J Dent Res 2007;86:1068-1072. https://doi.org/10.1177/154405910708601109
  11. Cray J Jr, Kneib J, Vecchione L, et al. Masticatory hypermuscularity is not related to reduced cranial volume in myostatin-knockout mice. Anat Rec (Hoboken) 2011;294:1170-1177. https://doi.org/10.1002/ar.21412
  12. Jeffery N, Mendias C. Endocranial and masticatory muscle volumes in myostatin-deficient mice. R Soc Open Sci 2014;1:140187. https://doi.org/10.1098/rsos.140187
  13. Ravosa MJ, Klopp EB, Pinchoff J, Stock SR, Hamrick MW. Plasticity of mandibular biomineralization in myostatin-deficient mice. J Morphol 2007;268:275-282. https://doi.org/10.1002/jmor.10517
  14. Harmon EB, Apelqvist AA, Smart NG, Gu X, Osborne DH, Kim SK. GDF11 modulates NGN3+ islet progenitor cell number and promotes beta-cell differentiation in pancreas development. Development 2004;131:6163-6174. https://doi.org/10.1242/dev.01535
  15. Esquela AF, Lee SJ. Regulation of metanephric kidney development by growth/differentiation factor 11. Dev Biol 2003;257:356-370. https://doi.org/10.1016/S0012-1606(03)00100-3
  16. Suh J, Eom JH, Kim NK, et al. Growth differentiation factor 11 locally controls anterior-posterior patterning of the axial skeleton. J Cell Physiol 2019;234:23360-23368. https://doi.org/10.1002/jcp.28904
  17. Cox TC, Lidral AC, McCoy JC, et al. Mutations in GDF11 and the extracellular antagonist, Follistatin, as a likely cause of Mendelian forms of orofacial clefting in humans. Hum Mutat 2019;40:1813-1825. https://doi.org/10.1002/humu.23793
  18. Nakashima M, Toyono T, Akamine A, Joyner A. Expression of growth/differentiation factor 11, a new member of the BMP/TGFbeta superfamily during mouse embryogenesis. Mech Dev 1999;80:185-189. https://doi.org/10.1016/S0925-4773(98)00205-6
  19. Nakashima M, Iohara K, Ishikawa M, et al. Stimulation of reparative dentin formation by ex vivo gene therapy using dental pulp stem cells electrotransfected with growth/differentiation factor 11 (Gdf11). Hum Gene Ther 2004;15:1045-1053. https://doi.org/10.1089/hum.2004.15.1045
  20. Nakashima M, Mizunuma K, Murakami T, Akamine A. Induction of dental pulp stem cell differentiation into odontoblasts by electroporation-mediated gene delivery of growth/differentiation factor 11 (Gdf11). Gene Ther 2002;9:814-818. https://doi.org/10.1038/sj.gt.3301692
  21. Lee YS, Lee SJ. Roles of GASP-1 and GDF-11 in dental and craniofacial development. J Oral Med Pain 2015;40:110-114. https://doi.org/10.14476/jomp.2015.40.3.110
  22. McPherron AC, Huynh TV, Lee SJ. Redundancy of myostatin and growth/differentiation factor 11 function. BMC Dev Biol 2009;9:24. https://doi.org/10.1186/1471-213X-9-24
  23. Walker RG, Poggioli T, Katsimpardi L, et al. Biochemistry and biology of GDF11 and myostatin: similarities, differences, and questions for future investigation. Circ Res 2016;118:1125-1141; discussion 1142. https://doi.org/10.1161/CIRCRESAHA.116.308391
  24. Yung LM, Yang P, Joshi S, et al. ACTRIIA-Fc rebalances activin/GDF versus BMP signaling in pulmonary hypertension. Sci Transl Med 2020;12:eaaz5660. https://doi.org/10.1126/scitranslmed.aaz5660
  25. Yu X, Chen X, Zheng XD, et al. Growth differentiation factor 11 promotes abnormal proliferation and angiogenesis of pulmonary artery endothelial cells. Hypertension 2018;71:729-741. https://doi.org/10.1161/HYPERTENSIONAHA.117.10350
  26. Zhang YH, Cheng F, Du XT, et al. GDF11/BMP11 activates both smad1/5/8 and smad2/3 signals but shows no significant effect on proliferation and migration of human umbilical vein endothelial cells. Oncotarget 2016;7:12063-12074. https://doi.org/10.18632/oncotarget.7642
  27. Jani P, Liu C, Zhang H, Younes K, Benson MD, Qin C. The role of bone morphogenetic proteins 2 and 4 in mouse dentinogenesis. Arch Oral Biol 2018;90:33-39. https://doi.org/10.1016/j.archoralbio.2018.02.004
  28. Nakashima M. Induction of dentine in amputated pulp of dogs by recombinant human bone morphogenetic proteins-2 and -4 with collagen matrix. Arch Oral Biol 1994;39:1085-1089. https://doi.org/10.1016/0003-9969(94)90062-0