Genetic association studies in osteonecrosis of the femoral head: mini review of the literature

Hadjigeorgiou, Georgios M.; Dardiotis, Efthimios; Dardioti, Maria; Karantanas, Apostolos H.; Dimitroulias, Apostolos; Malizos, Konstantinos N.

doi:10.1007/s00256-007-0395-2

Cited by 41 publications

(27 citation statements)

References 40 publications

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“…Genetic defects resulting in hypofibrinolysis or thrombophilia may lead to increased thrombi formation and impaired blood flow in the osseous circulation [1,32,[55][56][57]. Hypofibrinolysis secondary to high levels of plasminogen activator inhibitor (PAI) was noted in 31 % of patients with ON compared to 3 % of controls in a prospective cohort study of patients with known ON of the femoral head [55].…”

Section: Intravascular Occlusionmentioning

confidence: 99%

Pathophysiology and risk factors for osteonecrosis

Shah

Racine

Jones

et al. 2015

Curr Rev Musculoskelet Med

218

150

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Osteonecrosis, also known as avascular necrosis or AVN, is characterized by a stereotypical pattern of cell death and a complex repair process of bone resorption and formation. It is not the necrosis itself but rather the resorptive component of the repair process that results in loss of structural integrity and subchondral fracture. Most likely, a common pathophysiological pathway exists involving compromised subchondral microcirculation. Decreased femoral head blood flow can occur through three mechanisms: vascular interruption by fractures or dislocation, intravascular occlusion from thrombi or embolic fat, or intraosseous extravascular compression from lipocyte hypertrophy or Gaucher cells. In this review, we emphasize etiologic relationships derived mostly from longitudinal cohort studies or meta-analyses whose causal relationships to osteonecrosis can be estimated with confidence. Understanding risk factors and pathophysiology has therapeutic implications since several treatment regimens are available to optimize femoral head circulation, interrupt bone resorption, and preserve the subchondral bone.

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Section: Intravascular Occlusionmentioning

confidence: 99%

Pathophysiology and risk factors for osteonecrosis

Shah

Racine

Jones

et al. 2015

Curr Rev Musculoskelet Med

218

150

View full text Add to dashboard Cite

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“…7 Hypercoagulability 15,19 and hyperlipidemia 20 have been associated with osteonecrosis in clinical settings outside of ALL treatment. Multiple candidate gene studies have indicated several polymorphisms in genes putatively related to the development of osteonecross, such as SERPINE 1, 21 VDR, 5 and CYP3A4, 22 but there are conflicting results, 21,23 no genome-wide association studies (GWAS) have been performed, and most genomic studies have failed to account extensively for nongenetic risk factors.…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetic, pharmacodynamic, and pharmacogenetic determinants of osteonecrosis in children with acute lymphoblastic leukemia

Kawedia

Kaste

Pei

et al. 2011

Blood

214

213

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Osteonecrosis is a severe glucocorticoidinduced complication of acute lymphoblastic leukemia treatment. We prospectively screened children (n ‫؍‬ 364) with magnetic resonance imaging of hips and knees, regardless of symptoms; the cumulative incidence of any (grade 1-4) versus symptomatic (grade 2-4) osteonecrosis was 71.8% versus 17.6%, respectively. We investigated whether age, race, sex, acute lymphoblastic leukemia treatment arm, body mass, serum lipids, albumin and cortisol levels, dexamethasone pharmacokinetics, and genome-wide germline genetic polymorphisms were associated with symptomatic osteonecrosis. Age more than 10 years (odds ratio, ‫؍‬ 4.85; 95% confidence interval, 2.5-9.2; P ‫؍‬ .00001) and more intensive treatment (odds ratio ‫؍‬ 2.5; 95% confidence interval, 1.2-4.9; P ‫؍‬ .011) were risk factors and included as covariates in all analyses. Lower albumin (P ‫؍‬ .05) and elevated cholesterol (P ‫؍‬ .02) associated with symptomatic osteonecrosis, and severe (grade 3 or 4) osteonecrosis was linked to poor dexamethasone clearance (P ‫؍‬ .0005). Adjusting for clinical features, polymorphisms of ACP1 (eg, rs12714403, P ‫؍‬ 1.9 ؋ 10 ؊6 , odds ratio ‫؍‬ 5.6; 95% confidence interval, 2.7-11.3), which regulates lipid levels and osteoblast differentiation, were associated with risk of osteonecrosis as well as with lower albumin and higher cholesterol. Overall, older age, lower albumin, higher lipid levels, and dexamethasone exposure were associated with osteonecrosis and may be linked by inherited genomic variation. (Blood. 2011;117(8): 2340-2347)

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“…Plasminogen-activating inhibitor-1 (PAI-1) gene 4G/4G genotype and 5,10-methylenetetrahydrofolate reductase (MTHFR) gene 677C/T heterozygote variant were over-presented in idiopathic ONFH patients. Furthermore, 4a/b variable number of tandem repeats (VNTR) polymorphism in intron 4 of nitric oxide synthase (eNOS) gene increased the risk of ONFH [3]. A comparative serum proteome analysis supports these genomic results and demonstrates that serum PAI-1 level is upregulated in ONFH [4].…”

Section: Introductionmentioning

confidence: 88%

“…Two gene subsets contained two types of bone ECM forming components, collagens (14 genes) and non-collagen molecules (8 genes). The ONFH candidate genes group (6 genes) comprised of genes that has been shown to be in association with the pathogenesis of femoral head osteonecrosis [3,5,18,19]. We selected marker genes of bone cell metabolism and osteoblast/osteoclast differentiation and activation (9 genes) [20][21][22][23].…”

Section: Canonical Variates Analysis Of Onfh Samplesmentioning

confidence: 99%

Gene Expression Changes in Femoral Head Necrosis of Human Bone Tissue

et al. 2011

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Abstract. Osteonecrosis of the femoral head (ONFH) is the result of an interruption of the local circulation and the injury of vascular supply of bone. Multiple factors have been implicated in the development of the disease. However the mechanism of ischemia and necrosis in non-traumatic ONFH is not clear. The aim of our investigation was to identify genes that are differently expressed in ONFH vs. non-ONFH human bone and to describe the relationships between these genes using multivariate data analysis. Six bone tissue samples from ONFH male patients and 8 bone tissue samples from non-ONFH men were examined. The expression differences of selected 117 genes were analyzed by TaqMan probe-based quantitative real-time RT-PCR system. The significance test indicated marked differences in the expression of nine genes between ONFH and non-ONFH individuals. These altered genes code for collagen molecules, an extracellular matrix digesting metalloproteinase, a transcription factor, an adhesion molecule, and a growth factor. Canonical variates analysis demonstrated that ONFH and non-ONFH bone tissues can be distinguished by the multiple expression profile analysis of numerous genes controlled via canonical TGFB pathway as well as genes coding for extracellular matrix composing collagen type molecules. The markedly altered gene expression profile observed in the ONFH of human bone tissue may provide further insight into the pathogenetic process of osteonecrotic degeneration of bone.

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Genetic association studies in osteonecrosis of the femoral head: mini review of the literature

Cited by 41 publications

References 40 publications

Pathophysiology and risk factors for osteonecrosis

Pathophysiology and risk factors for osteonecrosis

Pharmacokinetic, pharmacodynamic, and pharmacogenetic determinants of osteonecrosis in children with acute lymphoblastic leukemia

Gene Expression Changes in Femoral Head Necrosis of Human Bone Tissue

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