OpenLB
Open Library of Bioscience
Advanced Search
Disease models & mechanisms
May 01, 2024;17 (5):

Genetic regulation of injury-induced heterotopic ossification in adult zebrafish.

Arun-Kumar Kaliya-Perumal, Cenk Celik, Tom J Carney, Matthew P Harris, Philip W Ingham
Author Information
  1. Arun-Kumar Kaliya-Perumal: Lee Kong Chian School of Medicine, Nanyang Technological University, 59 Nanyang Drive 636921, Singapore. ORCID
  2. Cenk Celik: Department of Genetics, Evolution and Environment, Genetics Institute, University College London, London WC1E 6BT, UK. ORCID
  3. Tom J Carney: Lee Kong Chian School of Medicine, Nanyang Technological University, 59 Nanyang Drive 636921, Singapore. ORCID
  4. Matthew P Harris: Department of Genetics, Harvard Medical School, Boston, MA 02115, USA. ORCID
  5. Philip W Ingham: Lee Kong Chian School of Medicine, Nanyang Technological University, 59 Nanyang Drive 636921, Singapore. ORCID
PMID: 38736327 DOI: 10.1242/dmm.050724

Abstract

Heterotopic ossification is the inappropriate formation of bone in soft tissues of the body. It can manifest spontaneously in rare genetic conditions or as a response to injury, known as acquired heterotopic ossification. There are several experimental models for studying acquired heterotopic ossification from different sources of damage. However, their tenuous mechanistic relevance to the human condition, invasive and laborious nature and/or lack of amenability to chemical and genetic screens, limit their utility. To address these limitations, we developed a simple zebrafish injury model that manifests heterotopic ossification with high penetrance in response to clinically emulating injuries, as observed in human myositis ossificans traumatica. Using this model, we defined the transcriptional response to trauma, identifying differentially regulated genes. Mutant analyses revealed that an increase in the activity of the potassium channel Kcnk5b potentiates injury response, whereas loss of function of the interleukin 11 receptor paralogue (Il11ra) resulted in a drastically reduced ossification response. Based on these findings, we postulate that enhanced ionic signalling, specifically through Kcnk5b, regulates the intensity of the skeletogenic injury response, which, in part, requires immune response regulated by Il11ra.

Keywords

Contusion Heterotopic ossification Interleukin 11 Myositis ossificans Potassium channels

References

  1. J Bone Miner Res. 2023 Mar;38(3):381-394 [PMID: 36583535]
  2. Bone. 2016 Nov;92:29-36 [PMID: 27492611]
  3. Front Cell Dev Biol. 2022 Mar 24;10:812094 [PMID: 35399528]
  4. Dev Genes Evol. 2009 Mar;219(3):147-57 [PMID: 19255778]
  5. Proc R Soc Med. 1924;17(Sect Orthop):19-22 [PMID: 19984013]
  6. Biomedicines. 2020 Dec 14;8(12): [PMID: 33327623]
  7. J Osteoporos. 2010 Dec 20;2011:786752 [PMID: 21209784]
  8. Bone. 2018 Apr;109:241-250 [PMID: 28754575]
  9. J Vis Exp. 2009 Aug 07;(30): [PMID: 19684565]
  10. J Bone Joint Surg Am. 1949 Oct;31A(4):765-75 [PMID: 18142918]
  11. Ann Surg. 1918 Dec;68(6):591-637 [PMID: 17864029]
  12. Best Pract Res Clin Rheumatol. 2008 Mar;22(1):191-205 [PMID: 18328989]
  13. Innovation (Camb). 2021 Jul 01;2(3):100141 [PMID: 34557778]
  14. Comp Biochem Physiol A Mol Integr Physiol. 2002 Dec;133(4):1087-99 [PMID: 12485693]
  15. J Bone Miner Res. 2011 Aug;26(8):1685-93 [PMID: 21538513]
  16. JBMR Plus. 2019 Feb 27;3(4):e10172 [PMID: 31044187]
  17. Transl Res. 2017 Aug;186:95-111 [PMID: 28668522]
  18. Zebrafish. 2018 Dec;15(6):536-545 [PMID: 30183553]
  19. Clin Orthop Relat Res. 2011 Dec;469(12):3469-76 [PMID: 21369767]
  20. J Trauma. 1988 Aug;28(8):1207-13 [PMID: 3137364]
  21. Clin Orthop Surg. 2014 Dec;6(4):480-3 [PMID: 25436075]
  22. Am J Hum Genet. 2009 Mar;84(3):406-11 [PMID: 19249007]
  23. Bone. 2006 Mar;38(3):322-32 [PMID: 16226065]
  24. Hum Mol Genet. 2015 Jan 15;24(2):471-9 [PMID: 25205110]
  25. Proc Natl Acad Sci U S A. 2019 Jul 23;116(30):15106-15115 [PMID: 31270239]
  26. Ann Surg. 1903 Sep;38(3):423-40 [PMID: 17861354]
  27. Genome Biol. 2014;15(12):550 [PMID: 25516281]
  28. Front Mol Neurosci. 2020 Jun 09;13:99 [PMID: 32581710]
  29. Cell Mol Biol Lett. 2021 Jul 27;26(1):34 [PMID: 34315404]
  30. Elife. 2020 Sep 08;9: [PMID: 32897189]
  31. J Biol Chem. 2002 Dec 13;277(50):49011-8 [PMID: 12384500]
  32. J Med Case Rep. 2013 Apr 04;7:90 [PMID: 23556500]
  33. Am J Hum Genet. 2008 Aug;83(2):193-9 [PMID: 18678320]
  34. Science. 2018 Oct 26;362(6413): [PMID: 30262634]
  35. J Bone Miner Res. 2000 Nov;15(11):2084-94 [PMID: 11092391]
  36. Clin Orthop Relat Res. 1983 Jun;(176):273-81 [PMID: 6406125]
  37. Science. 2020 Sep 4;369(6508): [PMID: 32883834]
  38. Orthop Traumatol Surg Res. 2015 Apr;101(2):209-13 [PMID: 25701160]
  39. Am J Med Genet A. 2006 Feb 15;140(4):312-21 [PMID: 16419128]
  40. J Orthop Surg (Hong Kong). 2023 Jan-Apr;31(1):10225536231163466 [PMID: 36943428]
  41. Dis Model Mech. 2012 Nov;5(6):756-62 [PMID: 23115204]
  42. J Pathol Bacteriol. 1953 Jul;66(1):1-18 [PMID: 13109613]
  43. Bone Rep. 2021 Sep 10;15:101127 [PMID: 34584904]
  44. J Surg Res. 1961 Jul;1:132-41 [PMID: 13749910]
  45. JMIR Res Protoc. 2019 Feb 22;8(2):e12107 [PMID: 30794203]
  46. J Bone Joint Surg Am. 2009 Mar 1;91(3):652-63 [PMID: 19255227]
  47. Stem Cells. 2009 Jan;27(1):150-6 [PMID: 18832590]
  48. J Bone Miner Res. 2022 Oct;37(10):1891-1902 [PMID: 35854638]
  49. Bone. 2017 Aug;101:162-171 [PMID: 28476577]
  50. J Bone Joint Surg Am. 2003 Dec;85(12):2332-42 [PMID: 14668502]
  51. Front Genet. 2021 Jun 17;12:650874 [PMID: 34220936]
  52. PLoS Genet. 2014 Jan;10(1):e1004080 [PMID: 24453984]
  53. Clin Orthop Relat Res. 1994 May;(302):266-72 [PMID: 8168312]
  54. Clin Orthop Relat Res. 1998 Oct;(355):35-46 [PMID: 9917589]
  55. Cell. 2001 May 18;105(4):511-9 [PMID: 11371347]
  56. Sci Transl Med. 2016 Nov 23;8(366):366ra163 [PMID: 27881824]
  57. Nat Commun. 2017 Sep 8;8(1):495 [PMID: 28887447]
  58. Cells. 2020 Aug 17;9(8): [PMID: 32824602]
  59. J Orthop Trauma. 2018 Jun;32(6):283-287 [PMID: 29533305]
  60. Indian J Orthop. 2017 Jul-Aug;51(4):368-376 [PMID: 28790465]
  61. Nat Rev Neurosci. 2001 Mar;2(3):175-84 [PMID: 11256078]
  62. J Bone Joint Surg Am. 1973 Dec;55(8):1629-32 [PMID: 4217797]
  63. J Anat. 2018 Feb;232(2):186-199 [PMID: 29148042]
  64. J Intensive Care Med. 2011 Mar-Apr;26(2):73-87 [PMID: 21464062]
  65. Cells. 2020 May 26;9(6): [PMID: 32466405]
  66. J Bone Miner Res. 2008 Mar;23(3):305-13 [PMID: 17967130]
  67. Clin Orthop Relat Res. 2002 Oct;(403 Suppl):S110-9 [PMID: 12394459]
  68. Development. 2021 Jun 1;148(11): [PMID: 34061172]
  69. J Clin Orthop Trauma. 2021 Mar 13;17:123-127 [PMID: 33816108]
  70. J Pathol. 1983 Apr;139(4):419-30 [PMID: 6220140]
  71. Biochimie. 2022 May;196:171-181 [PMID: 34715269]
  72. Genetics. 2020 Aug;215(4):1067-1084 [PMID: 32546498]
  73. Front Biosci. 2007 May 01;12:3068-92 [PMID: 17485283]
  74. Development. 2012 Feb;139(4):709-19 [PMID: 22219353]
  75. J Bone Joint Surg Br. 2009 Nov;91(11):1493-8 [PMID: 19880896]
  76. Acta Orthop Belg. 2014 Mar;80(1):2-10 [PMID: 24873078]
  77. J Musculoskelet Neuronal Interact. 2012 Dec;12(4):230-40 [PMID: 23196266]
  78. Sci Adv. 2021 Sep 10;7(37):eabg6497 [PMID: 34516874]
  79. Bone. 2010 Feb;46(2):369-78 [PMID: 19836476]
  80. J Biomed Biotechnol. 2011;2011:309287 [PMID: 20981294]
  81. J Am Acad Orthop Surg. 2015 Oct;23(10):612-22 [PMID: 26320160]
  82. Methods. 2001 Dec;25(4):402-8 [PMID: 11846609]
  83. FEBS J. 2024 Apr;291(8):1597-1614 [PMID: 36440547]
  84. J Bone Joint Surg Am. 2015 Jul 1;97(13):1101-11 [PMID: 26135077]
  85. Ann N Y Acad Sci. 2011 Nov;1237:5-10 [PMID: 22082359]
  86. Dev Dyn. 2010 Feb;239(2):446-57 [PMID: 20034107]
  87. Front Genet. 2021 Aug 05;12:675331 [PMID: 34490030]
  88. Proc Natl Acad Sci U S A. 2013 Aug 13;110(33):13416-21 [PMID: 23901114]
  89. Dev Biol. 2018 Dec 1;444 Suppl 1:S297-S307 [PMID: 29571612]
  90. Dev Biol. 2019 Dec 15;456(2):164-178 [PMID: 31472116]
  91. Dis Model Mech. 2019 Sep 3;12(9): [PMID: 31383797]
  92. Curr Osteoporos Rep. 2019 Dec;17(6):387-394 [PMID: 31721068]
  93. Biol Open. 2015 Nov 24;4(12):1727-32 [PMID: 26603470]
  94. Proc Natl Acad Sci U S A. 2015 Dec 15;112(50):15438-43 [PMID: 26621707]
  95. J Bone Joint Surg Am. 2009 May;91(5):1084-91 [PMID: 19411456]
  96. Dev Dyn. 2003 Nov;228(3):337-57 [PMID: 14579374]
  97. Nat Methods. 2017 Apr;14(4):417-419 [PMID: 28263959]
  98. Clin Transl Oncol. 2007 Jan;9(1):28-31 [PMID: 17272227]
  99. Pediatr Endocrinol Rev. 2013 Jun;10 Suppl 2:437-48 [PMID: 23858627]
  100. Biomed Res Int. 2019 Nov 20;2019:1253710 [PMID: 31828085]
  101. Zebrafish. 2017 Aug;14(4):293-304 [PMID: 28394244]
  102. Int J Mol Sci. 2019 Sep 22;20(19): [PMID: 31546739]
  103. J Bone Miner Res. 2012 May;27(5):1004-17 [PMID: 22307978]
  104. Clin Orthop Relat Res. 1991 Feb;(263):49-58 [PMID: 1899637]
  105. Cell Rep. 2021 Jul 13;36(2):109380 [PMID: 34260913]
  106. Diagnostics (Basel). 2023 May 12;13(10): [PMID: 37238196]
  107. Zool Res. 2021 May 18;42(3):362-376 [PMID: 33998184]
  108. Acta Biomed. 2019 Jan 10;90(1-S):92-97 [PMID: 30715005]

Grants

  1. /Toh Kian Chui foundation
  2. /Toh Kian Chui Foundation
  3. /Lee Kong Chian School of Medicine, Nanyang Technological University
  4. /University of Bath

MeSH Term

Animals
Zebrafish
Ossification, Heterotopic
Zebrafish Proteins
Gene Expression Regulation
Aging
Wounds and Injuries
Disease Models, Animal
Mutation

Chemicals

Zebrafish Proteins
Journal Article
Article has an altmetric score of 3

Word Cloud

Similar Articles

Cited By