Single Nucleotide Polymorphisms in Osteogenic Genes in Atrophic Delayed Fracture-Healing

Sathyendra, Vikram; Donahue, Henry J.; Vrana, Kent E.; Berg, Arthur; Fryzel, David; Gandhi, Jonathan; Reid, J. Spence

doi:10.2106/jbjs.m.00453

Cited by 22 publications

(36 citation statements)

References 52 publications

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“…Since myofibroblast numbers are increased during the development of a joint contracture and reach a peak level about 2 weeks after trauma in human tissues and animal models, we have chose a period of 2 weeks for our experiment. 6,88 In our study, the number of myofibroblasts in the posterior joint capsule fell by 40% in rats receiving treatment with losartan and by nearly 70% after atorvastatin administration in comparison to the control. Likewise, the area percentage of myofibroblasts was significantly reduced by about 55% (losartan) and 60% (atorvastatin), respectively.…”

Section: Atorvastatin Inferior Capsulementioning

confidence: 44%

<p>Effects of losartan and atorvastatin on the development of early posttraumatic joint stiffness in a rat model</p>

Baranowski

Schlemmer

Förster

et al. 2019

DDDT

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Background After a trauma, exuberant tissue healing with fibrosis of the joint capsule can lead to posttraumatic joint stiffness (PTJS). Losartan and atorvastatin have both shown their antifibrotic effects in different organ systems. Objective The purpose of this study was the evaluation of the influence of losartan and atorvastatin on the early development of joint contracture. In addition to joint angles, the change in myofibroblast numbers and the distribution of bone sialoprotein (BSP) were assessed. Study design and methods In this randomized and blinded experimental study with 24 rats, losartan and atorvastatin were compared to a placebo. After an initial joint injury, rat knees were immobilized with a Kirschner wire. Rats received either losartan, atorvastatin or a placebo orally daily. After 14 days, joint angle measurements and histological assessments were performed. Results Losartan increased the length of the inferior joint capsule. Joint angle and other capsule length measurements did not reveal significant differences between both drugs and the placebo. At cellular level both losartan and atorvastatin reduced the total number of myofibroblasts (losartan: 191±77, atorvastatin: 98±58, placebo: 319±113 per counting field, p <0.01) and the percentage area of myofibroblasts (losartan: 2.8±1.8% [ p <0.05], atorvastatin: 2.5±1.7% [ p <0.01], vs control [6.4±4%], respectively). BSP was detectable in equivalent amounts in the joint capsules of all groups with only a trend toward a reduction of the BSP-stained area by atorvastatin. Conclusion Both atorvastatin and losartan reduced the number of myofibroblasts in the posterior knee joint capsule of rat knees 2 weeks after trauma and losartan increased the length of the inferior joint capsule. However, these changes at the cellular level did not translate an increase in range of motion of the rats´ knee joints during early contracture development.

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Section: Atorvastatin Inferior Capsulementioning

confidence: 44%

<p>Effects of losartan and atorvastatin on the development of early posttraumatic joint stiffness in a rat model</p>

Baranowski

Schlemmer

Förster

et al. 2019

DDDT

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“…Sathyendra et al observed genetic risk factors for atrophic nonunion in their study, and they reported that identification of a patient as having a genetic risk of delayed or impaired fracture healing at the time of a fracture may justify more aggressive initial treatment of the fracture. 18 Our hypothesis is similar: if a genetic risk factor can be identified for PJI, more aggressive initial treatment, such as use of antibiotic-laden bone cement for primary joint arthroplasty surgery, may be justified.…”

Section: Discussionmentioning

confidence: 89%

“…No statistically significant association was found between the serum and synovial fluid levels of biomarkers and gene polymorphisms in septic and aseptic groups. Although there is currently no study regarding the relationship between PJI and genetic polymorphisms, several studies 18 , 19 have described a relationship between genetic polymorphisms and bone atrophic nonunion in the orthopedic literature. Sathyendra et al observed genetic risk factors for atrophic nonunion in their study, and they reported that identification of a patient as having a genetic risk of delayed or impaired fracture healing at the time of a fracture may justify more aggressive initial treatment of the fracture.…”

Section: Discussionmentioning

confidence: 99%

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Proinflammatory biomarkers' level and functional genetic polymorphisms in periprosthetic joint infection

Erdemli¹,

Özbek²,

Başarır³

et al. 2018

Acta Orthopaedica et Traumatologica Turcica

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ObjectiveThe aims of this study were 1) to identify the level of inflammatory biomarkers interleukin (IL)-1α, IL-1β, IL-6, IL-8, IL-17, C-reactive protein (CRP), granulocyte colony-stimulating factor (GCSF), ferritin, and tumor necrosis factor (TNF)-α in serum and synovial fluid samples of patients who underwent revision arthroplasty surgery; 2) to establish the relationship between serum and synovial fluid levels; 3) to determine if any of the 11 genetic polymorphisms of TNFα, IL-1, IL-6, IL-8, IL-17, and GCSF on the encoding genes was associated with periprosthetic joint infection (PJI).MethodsSynovial fluid and serum was collected from 88 patients who underwent revision arthroplasty surgery. The Musculoskeletal Infection Society definition was used to classify these patients into 2 groups: 36 PJIs and 52 aseptic failures. Synovial fluid and serum samples were tested for 9 biomarkers using a micro enzyme-linked immunosorbent assay. Genetic polymorphisms were evaluated with polymerase chain reaction and restriction endonuclease analysis.ResultsSynovial fluid-derived IL-1α, IL-1β, IL-8, IL-17, CRP, GCSF, TNFα, and serum-derived IL-6, IL-17, ferritin, CRP were found suitable to classify PJI and aseptic failure. In addition, IL-17 and CRP levels demonstrated a positive correlation between synovial fluid and serum. TNFα-238, IL6-174, GCSF3R, and IL1 RN-VNTR genetic polymorphisms occurred more frequently in individuals with septic failure.ConclusionSignificant differences between the two groups were observed in the functional polymorphisms of the genes encoding the cytokines investigated. These differences could be interpreted as indicating that there is an association between PJI and genetic polymorphisms.Level of evidenceLevel III, diagnostic study.

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“…In one of the first genetic studies of nonunion, 62 individuals with atrophic nonunion were contrasted with 47 individuals with normal healing at a set of common variants in bone morphogenetic protein (BMP) pathway genes (BMP‐2, BMP‐7, NOGGIN, and SMAD6) . Another investigation characterized 33 individuals with nonunion and 29 without, at 144 SNPs across 30 genes . A third study examined 101 individuals with uneventful healing and 66 with nonunion, across five genes (AM5C, BMP4, FGF3, FGF10, and FGFR1) .…”

Section: Discussionmentioning

confidence: 99%

Genomewide Association Study of Fracture Nonunion Using Electronic Health Records

et al. 2018

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Nonunion is a clinically significant complication of fracture associated with worse outcomes, including increased pain, disability, and higher healthcare costs. The risk for nonunion is likely to be complex and multifactorial, and as such, the biology underlying such risk remains poorly understood. Genetic studies represent one approach to identify implicated biology for further investigation, but to date the lack of large cohorts for study has limited such efforts. We utilized the electronic health records of two large academic medical centers in Boston to identify individuals with fracture nonunion and control individuals with fracture but no evidence of nonunion. We conducted a genomewide association study among 1760 individuals of Northern European ancestry with upper or lower extremity fracture, including 131 with nonunion, to examine whether common variants were associated with nonunion in this cohort. In all, one locus in the Calcyon (CALY) gene exceeded a genomewide threshold for statistical significance (p = 1.95e–8), with eight additional loci associated with p < 5e–7. Previously reported candidate genes were not supported by this analysis. Electronic health records should facilitate identification of common genetic variations associated with adverse orthopedic outcomes. The loci we identified in this small cohort require replication and further study to characterize mechanism of action, but represent a starting point for the investigation of genetic liability for this costly outcome. © 2018 American Society for Bone and Mineral Research.

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Single Nucleotide Polymorphisms in Osteogenic Genes in Atrophic Delayed Fracture-Healing

Abstract: Impaired fracture union may have genetic contributions.

Cited by 22 publications

References 52 publications

<p>Effects of losartan and atorvastatin on the development of early posttraumatic joint stiffness in a rat model</p>

<p>Effects of losartan and atorvastatin on the development of early posttraumatic joint stiffness in a rat model</p>

Proinflammatory biomarkers' level and functional genetic polymorphisms in periprosthetic joint infection

Genomewide Association Study of Fracture Nonunion Using Electronic Health Records

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