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Osteonecrosis of the femoral head: genetic basis

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ABSTRACT

Purpose

Genetic factors and hereditary forms of osteonecrosis of the femoral head (ONFH) have been elucidated through genetic association studies. The significance of these cases is that they suggest an alternative hypothesis to the development of the disease. This review presents a summary of single nucleotide polymorphisms (SNPs) and other genetic mutation variations found in association with ONFH, including our recent identification of a novel mutation in the transient receptor potential vanilloid 4 (TRPV4) gene in association with inherited ONFH. The purpose of this review is to consolidate and categorize genetic linkages according to physiological pathways.

Methods

A systematic review of literature from PubMed and Google Scholar was undertaken with a focus on genetic linkages and hereditary case studies of the disease. Recent genetic analysis studies published after 2007 were the focus of genetic linkages in non-hereditary cases.

Results

The summary of these genetic findings identifies biological processes believed to be involved in the development of ONFH, which include circulation, steroid metabolism, immunity, and the regulation of bone formation.

Conclusion

Taken together, these associations may lead to new pathways of bone repair and remodeling while opening new avenues for therapeutic targets. Knowledge of genetic variations could help identify individuals considered to be at higher risk of developing ONFH and prevent the multiple hit effect.

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Abbreviations

ABCB1:

adenosine triphosphate-binding cassette B1

ACE:

angiotensin I converting enzyme

ANXA2:

annexin A2

ApoB:

apoliprotein B

AVN:

avascular necrosis

BMP:

Bone morphogenetic protein

CAT:

catalase

CBP:

CREB-binding protein

COL2A1:

Collagen 2 aplha 1

CTDP1:

C-terminal domain of RNA polymerase II subunit A, phosphatase of subunit 1

CYP27C1:

cytochrome P450, family 27, subfamily C, polypeptide 1

eNOS:

endothelial nitric oxide synthase

GRIN3A:

Glutamate Receptor, Ionotropic, N-Methyl-D-Aspartate 3A

IGF:

Insulin-like growth factors

IGFBP3:

Insulin-like growth factor binding protein 3

IGFBP-3:

Insulin-like growth factors binding protein

IL:

Interleukin

KDR:

Kinase insert domain receptor

LCPD:

Legg-Calvé-Perthes disease

MDR1:

Multidrug resistance 1

MRI:

magnetic resonance imaging

MTHFR:

5, 10-methylenetetrahydrofolate reductase

NRP1:

Neuropilin 1

ONFH:

osteonecrosis of the femoral head

PAI-1:

Plasminogen activator inhibitor-1

P-gp:

P-glycoprotein

PLAT or TPA:

tissue plasminogen activator

PON-1:

paraoxonase 1

SNP:

single nucleotide polymorphism

SREBF1:

Sterol regulatory element-binding transcription factor 1

SREBF2:

Sterol regulatory element-binding transcription factor 2

TF:

Transferrin

TFPI:

Tissue factor pathway inhibitor

TGF-β:

Transforming growth factor

TNF-α:

Tumor necrosis factor

TRPV4:

Transient receptor potential vanilloid 4

VDR:

vitamin D receptor

VEGFC:

Vascular endothelial growth factor C

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Acknowledgements

The authors gratefully acknowledge Dr. Terry Chow for reviewing the manuscript. This work was supported by awards to C. Séguin from the Fonds de la Recherche en Santé du Québec (FRQ-S) and from the Montreal General Hospital Foundation. C. Séguin is also supported by awards from the Canadian and US Leukemia & Lymphoma Societies.

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Author notes

  1. Tracy Wang and Bouziane Azeddine contributed equally to this work.

Authors and Affiliations

  1. Vascular Biology Research lab, Research Institute (RI) McGill University Health Centre, C9 Montreal General Hospital, 1650 Cedar Avenue, Montreal, QC, H3G 1A4, Canada

    Tracy Wang, Bouziane Azeddine, Wayne Mah & Chantal Séguin

  2. Department Surgery, Division Orthopaedic Surgery, McGill University Health Centre, B5 Montreal General Hospital, 1650 Cedar Avenue, Montreal, QC, H3G 1A4, Canada

    Edward J. Harvey

  3. Department of Human Genetics, McGill University, Montreal, Quebec, Canada

    David Rosenblatt

  4. Department of Medicine, Division of Hematology and Oncology, McGill University Health Centre, Montreal, Quebec, H4A 3J1, Canada

    Chantal Séguin

  5. Glen Site, Cedars Cancer Centre, McGill University Health Centre, 1001 Décarie Blvd., room D02.7519, Montreal, Quebec, H4A 3J1, Canada

    Chantal Séguin

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  1. Tracy Wang
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  2. Bouziane Azeddine
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Contributions

All authors read and approved the final manuscript. TW performed the literature search and participated in writing the first draft, BA finalized the literature search and participated in writing of the manuscript, finalizing the last version. TW and BA participated equally to this manuscript. EJH and DR helped to draft the manuscript and made an extensive revision. CS participated in the design of the review, its coordination and helped to draft the manuscript and finalizing the last version.

Corresponding authors

Correspondence to Tracy Wang or Chantal Séguin.

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Wang, T., Azeddine, B., Mah, W. et al. Osteonecrosis of the femoral head: genetic basis. International Orthopaedics (SICOT) 43, 519–530 (2019). https://doi.org/10.1007/s00264-018-4172-8

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