A Shifting Paradigm: Transformation of Cartilage to Bone During Bone Repair

Overview

Journal J Dent Res

Specialty Dentistry

Date 2022 Oct 28

PMID 36303415

Authors

R S Marcucio

T Miclau 3rd

C S Bahney

Affiliations

Soon will be listed here.

Abstract

While formation and regeneration of the skeleton have been studied for a long period of time, significant scientific advances in this field continue to emerge based on an unmet clinical need to improve options to promote bone repair. In this review, we discuss the relationship between mechanisms of bone formation and bone regeneration. Data clearly show that regeneration is not simply a reinduction of the molecular and cellular programs that were used for development. Instead, the mechanical environment exerts a strong influence on the mode of repair, while during development, cell-intrinsic processes drive the mode of skeletal formation. A major advance in the field has shown that cell fate is flexible, rather than terminal, and that chondrocytes are able to differentiate into osteoblasts and other cell types during development and regeneration. This is discussed in a larger context of regeneration in vertebrates as well as the clinical implication that this shift in understanding presents.

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References

Kayal R, Siqueira M, Alblowi J, McLean J, Krothapalli N, Faibish D . TNF-alpha mediates diabetes-enhanced chondrocyte apoptosis during fracture healing and stimulates chondrocyte apoptosis through FOXO1. J Bone Miner Res. 2010; 25(7):1604-15. PMC: 3154002. DOI: 10.1002/jbmr.59. View

Park J, Gebhardt M, Golovchenko S, Perez-Branguli F, Hattori T, Hartmann C . Dual pathways to endochondral osteoblasts: a novel chondrocyte-derived osteoprogenitor cell identified in hypertrophic cartilage. Biol Open. 2015; 4(5):608-21. PMC: 4434812. DOI: 10.1242/bio.201411031. View

Zhou X, von der Mark K, Henry S, Norton W, Adams H, de Crombrugghe B . Chondrocytes transdifferentiate into osteoblasts in endochondral bone during development, postnatal growth and fracture healing in mice. PLoS Genet. 2014; 10(12):e1004820. PMC: 4256265. DOI: 10.1371/journal.pgen.1004820. View

Haraguchi R, Kitazawa R, Imai Y, Kitazawa S . Growth plate-derived hedgehog-signal-responsive cells provide skeletal tissue components in growing bone. Histochem Cell Biol. 2018; 149(4):365-373. DOI: 10.1007/s00418-018-1641-5. View

Kashiwagi M, Hojo H, Kitaura Y, Maeda Y, Aini H, Takato T . Local administration of a hedgehog agonist accelerates fracture healing in a mouse model. Biochem Biophys Res Commun. 2016; 479(4):772-778. DOI: 10.1016/j.bbrc.2016.09.134. View

Yu Y, Lieu S, Hu D, Miclau T, Colnot C . Site specific effects of zoledronic acid during tibial and mandibular fracture repair. PLoS One. 2012; 7(2):e31771. PMC: 3281002. DOI: 10.1371/journal.pone.0031771. View

Messal H, Cremona C, Lan L, Behrens A . Paligenosis: prepare to regenerate!. EMBO J. 2018; 37(7). PMC: 5881624. DOI: 10.15252/embj.201899206. View

Bahney C, Hu D, Taylor A, Ferro F, Britz H, Hallgrimsson B . Stem cell-derived endochondral cartilage stimulates bone healing by tissue transformation. J Bone Miner Res. 2013; 29(5):1269-82. PMC: 4802866. DOI: 10.1002/jbmr.2148. View

Miclau K, Brazina S, Bahney C, Hankenson K, Hunt T, Marcucio R . Stimulating Fracture Healing in Ischemic Environments: Does Oxygen Direct Stem Cell Fate during Fracture Healing?. Front Cell Dev Biol. 2017; 5:45. PMC: 5416746. DOI: 10.3389/fcell.2017.00045. View

10.

Javaheri B, Caetano-Silva S, Kanakis I, Bou-Gharios G, Pitsillides A . The Chondro-Osseous Continuum: Is It Possible to Unlock the Potential Assigned Within?. Front Bioeng Biotechnol. 2018; 6:28. PMC: 5871702. DOI: 10.3389/fbioe.2018.00028. View

11.

Goldenring J, Mills J . Cellular Plasticity, Reprogramming, and Regeneration: Metaplasia in the Stomach and Beyond. Gastroenterology. 2021; 162(2):415-430. PMC: 8792220. DOI: 10.1053/j.gastro.2021.10.036. View

12.

Tomlinson R, Li Z, Li Z, Minichiello L, Riddle R, Venkatesan A . NGF-TrkA signaling in sensory nerves is required for skeletal adaptation to mechanical loads in mice. Proc Natl Acad Sci U S A. 2017; 114(18):E3632-E3641. PMC: 5422802. DOI: 10.1073/pnas.1701054114. View

13.

Liu X, McKenzie J, Maschhoff C, Gardner M, Silva M . Exogenous hedgehog antagonist delays but does not prevent fracture healing in young mice. Bone. 2017; 103:241-251. PMC: 5568453. DOI: 10.1016/j.bone.2017.07.017. View

14.

Zhai Y, Schilling K, Wang T, Khatib M, Vinogradov S, Brown E . Spatiotemporal blood vessel specification at the osteogenesis and angiogenesis interface of biomimetic nanofiber-enabled bone tissue engineering. Biomaterials. 2021; 276:121041. PMC: 8477312. DOI: 10.1016/j.biomaterials.2021.121041. View

15.

Rivera K, Russo F, Boileau R, Tomlinson R, Miclau T, Marcucio R . Local injections of β-NGF accelerates endochondral fracture repair by promoting cartilage to bone conversion. Sci Rep. 2020; 10(1):22241. PMC: 7747641. DOI: 10.1038/s41598-020-78983-y. View

16.

Paul S, Schindler S, Giovannone D, de Millo Terrazzani A, Mariani F, Crump J . Ihha induces hybrid cartilage-bone cells during zebrafish jawbone regeneration. Development. 2016; 143(12):2066-76. PMC: 4920169. DOI: 10.1242/dev.131292. View

17.

Bhandari M, Schemitsch E, Karachalios T, Sancheti P, Poolman R, Caminis J . Romosozumab in Skeletally Mature Adults with a Fresh Unilateral Tibial Diaphyseal Fracture: A Randomized Phase-2 Study. J Bone Joint Surg Am. 2020; 102(16):1416-1426. DOI: 10.2106/JBJS.19.01008. View

18.

Steiner M, Claes L, Ignatius A, Simon U, Wehner T . Disadvantages of interfragmentary shear on fracture healing--mechanical insights through numerical simulation. J Orthop Res. 2014; 32(7):865-72. DOI: 10.1002/jor.22617. View

19.

Ono N, Ono W, Nagasawa T, Kronenberg H . A subset of chondrogenic cells provides early mesenchymal progenitors in growing bones. Nat Cell Biol. 2014; 16(12):1157-67. PMC: 4250334. DOI: 10.1038/ncb3067. View

20.

Li Z, Meyers C, Chang L, Lee S, Li Z, Tomlinson R . Fracture repair requires TrkA signaling by skeletal sensory nerves. J Clin Invest. 2019; 129(12):5137-5150. PMC: 6877307. DOI: 10.1172/JCI128428. View