Role of Hedgehog Signaling in the Pathogenesis and Therapy of Heterotopic Ossification

Overview

Journal Front Cell Dev Biol

Specialty Cell Biology

Date 2024 Oct 4

PMID 39364140

Authors

Yiran Pei

Fangzhou Liu

Yike Zhao

Hui Lin

Xiaoyan Huang

Affiliations

Soon will be listed here.

Abstract

Heterotopic ossification (HO) is a pathological process that generates ectopic bone in soft tissues. Hedgehog signaling (Hh signaling) is a signaling pathway that plays an important role in embryonic development and involves three ligands: sonic hedgehog (Shh), Indian hedgehog (Ihh) and desert hedgehog (Dhh). Hh signaling also has an important role in skeletal development. This paper discusses the effects of Hh signaling on the process of HO formation and describes several signaling molecules that are involved in Hh-mediated processes: parathyroid Hormone-Related Protein (PTHrP) and Fkbp10 mediate the expression of Hh during chondrogenesic differentiation. Extracellular signal-regulated kinase (ERK), GNAs and Yes-Associated Protein (YAP) interact with Hh signaling to play a role in osteogenic differentiation. Runt-Related Transcription Factor 2 (Runx2), Mohawk gene (Mkx) and bone morphogenetic protein (BMP) mediate Hh signaling during both chondrogenic and osteogenic differentiation. This paper also discusses possible therapeutic options for HO, lists several Hh inhibitors and explores whether they could serve as emerging targets for the treatment of HO.

References

Li G, Deng Y, Li K, Liu Y, Wang L, Wu Z . Hedgehog Signalling Contributes to Trauma-Induced Tendon Heterotopic Ossification and Regulates Osteogenesis through Antioxidant Pathway in Tendon-Derived Stem Cells. Antioxidants (Basel). 2022; 11(11). PMC: 9686894. DOI: 10.3390/antiox11112265. View

Sagi H, Jordan C, Barei D, Serrano-Riera R, Steverson B . Indomethacin prophylaxis for heterotopic ossification after acetabular fracture surgery increases the risk for nonunion of the posterior wall. J Orthop Trauma. 2014; 28(7):377-83. DOI: 10.1097/BOT.0000000000000049. View

Kan C, Chen L, Hu Y, Ding N, Lu H, Li Y . Conserved signaling pathways underlying heterotopic ossification. Bone. 2017; 109:43-48. PMC: 5801212. DOI: 10.1016/j.bone.2017.04.014. View

Ito Y, Toriuchi N, Yoshitaka T, Ueno-Kudoh H, Sato T, Yokoyama S . The Mohawk homeobox gene is a critical regulator of tendon differentiation. Proc Natl Acad Sci U S A. 2010; 107(23):10538-42. PMC: 2890854. DOI: 10.1073/pnas.1000525107. View

Holavanahalli R, Helm P, Parry I, Dolezal C, Greenhalgh D . Select practices in management and rehabilitation of burns: a survey report. J Burn Care Res. 2011; 32(2):210-23. DOI: 10.1097/BCR.0b013e31820aadd5. View

St-Jacques B, Hammerschmidt M, McMahon A . Indian hedgehog signaling regulates proliferation and differentiation of chondrocytes and is essential for bone formation. Genes Dev. 1999; 13(16):2072-86. PMC: 316949. DOI: 10.1101/gad.13.16.2072. View

Tu X, Joeng K, Long F . Indian hedgehog requires additional effectors besides Runx2 to induce osteoblast differentiation. Dev Biol. 2011; 362(1):76-82. PMC: 3254823. DOI: 10.1016/j.ydbio.2011.11.013. View

Yoshida C, Yamamoto H, Fujita T, Furuichi T, Ito K, Inoue K . Runx2 and Runx3 are essential for chondrocyte maturation, and Runx2 regulates limb growth through induction of Indian hedgehog. Genes Dev. 2004; 18(8):952-63. PMC: 395853. DOI: 10.1101/gad.1174704. View

Kim J, Lee J, Kim J, Gardner D, Beachy P . Arsenic antagonizes the Hedgehog pathway by preventing ciliary accumulation and reducing stability of the Gli2 transcriptional effector. Proc Natl Acad Sci U S A. 2010; 107(30):13432-7. PMC: 2922148. DOI: 10.1073/pnas.1006822107. View

10.

Lin H, Shi F, Gao J, Hua P . The role of Activin A in fibrodysplasia ossificans progressiva: a prominent mediator. Biosci Rep. 2019; 39(8). PMC: 6680371. DOI: 10.1042/BSR20190377. View

11.

Burd T, Lowry K, Anglen J . Indomethacin compared with localized irradiation for the prevention of heterotopic ossification following surgical treatment of acetabular fractures. J Bone Joint Surg Am. 2001; 83(12):1783-8. DOI: 10.2106/00004623-200112000-00003. View

12.

Regard J, Malhotra D, Gvozdenovic-Jeremic J, Josey M, Chen M, Weinstein L . Activation of Hedgehog signaling by loss of GNAS causes heterotopic ossification. Nat Med. 2013; 19(11):1505-12. PMC: 3917515. DOI: 10.1038/nm.3314. View

13.

Pan D . The hippo signaling pathway in development and cancer. Dev Cell. 2010; 19(4):491-505. PMC: 3124840. DOI: 10.1016/j.devcel.2010.09.011. View

14.

Almuraikhi N, Almasoud N, Binhamdan S, Younis G, Ali D, Manikandan M . Hedgehog Signaling Inhibition by Smoothened Antagonist BMS-833923 Reduces Osteoblast Differentiation and Ectopic Bone Formation of Human Skeletal (Mesenchymal) Stem Cells. Stem Cells Int. 2019; 2019:3435901. PMC: 6907053. DOI: 10.1155/2019/3435901. View

15.

Komori T . Regulation of Proliferation, Differentiation and Functions of Osteoblasts by Runx2. Int J Mol Sci. 2019; 20(7). PMC: 6480215. DOI: 10.3390/ijms20071694. View

16.

Galea G, Zein M, Allen S, Francis-West P . Making and shaping endochondral and intramembranous bones. Dev Dyn. 2020; 250(3):414-449. PMC: 7986209. DOI: 10.1002/dvdy.278. View

17.

Tukachinsky H, Lopez L, Salic A . A mechanism for vertebrate Hedgehog signaling: recruitment to cilia and dissociation of SuFu-Gli protein complexes. J Cell Biol. 2010; 191(2):415-28. PMC: 2958481. DOI: 10.1083/jcb.201004108. View

18.

Culbert A, Chakkalakal S, Theosmy E, Brennan T, Kaplan F, Shore E . Alk2 regulates early chondrogenic fate in fibrodysplasia ossificans progressiva heterotopic endochondral ossification. Stem Cells. 2014; 32(5):1289-300. PMC: 4419363. DOI: 10.1002/stem.1633. View

19.

Kan C, Chen L, Hu Y, Ding N, Li Y, McGuire T . Gli1-labeled adult mesenchymal stem/progenitor cells and hedgehog signaling contribute to endochondral heterotopic ossification. Bone. 2017; 109:71-79. PMC: 5801258. DOI: 10.1016/j.bone.2017.06.014. View

20.

Phillips D, de Kretser D, Hedger M . Activin and related proteins in inflammation: not just interested bystanders. Cytokine Growth Factor Rev. 2009; 20(2):153-64. DOI: 10.1016/j.cytogfr.2009.02.007. View