Noncoding RNAs (ncRNA) participate in epigenetic regulation but are poorly understood. Here we characterize the transcriptional landscape of the four human
HOX loci at five base pair resolution in 11 ...anatomic sites and identify 231
HOX ncRNAs that extend known transcribed regions by more than 30 kilobases.
HOX ncRNAs are spatially expressed along developmental axes and possess unique sequence motifs, and their expression demarcates broad chromosomal domains of differential histone methylation and RNA polymerase accessibility. We identified a 2.2 kilobase ncRNA residing in the
HOXC locus, termed HOTAIR, which represses transcription in trans across 40 kilobases of the
HOXD locus. HOTAIR interacts with Polycomb Repressive Complex 2 (PRC2) and is required for PRC2 occupancy and histone H3 lysine-27 trimethylation of
HOXD locus. Thus, transcription of ncRNA may demarcate chromosomal domains of gene silencing at a distance; these results have broad implications for gene regulation in development and disease states.
Purpose of Review
This review summarizes recent investigations into the cellular and molecular effects of skeletal aging on the inflammatory response and stem cell function after fracture.
Recent ...Findings
Proper regulation of the inflammatory phase of fracture healing is essential. Aging is associated with chronic inflammation, which inhibits bone formation and promotes bone resorption. Osteogenic differentiation and anti-senescence pathways in skeletal stem cells are impaired in geriatric fractures.
Summary
As the population ages, fragility fractures will continue to represent a significant clinical problem, which will require innovative clinical solutions. Skeletal stem cells in geriatric individuals demonstrate defects in anti-senescence pathways that lead to impaired osteogenic differentiation in vitro in humans. Small molecule-based therapies can partially reverse the aging phenotype. In the future, molecular- or cell-based therapies modulating either inflammatory cells or skeletal stem cells represent potential therapeutic targets to augment contemporary fracture healing interventions in osteoporotic or aging individuals.
The bones of the mammalian skull vault form through intramembranous ossification. Skull bones ossify directly, in a process regulated by β-catenin, instead of passing through a cartilage ...intermediate. We tested whether β-catenin is necessary for fate selection of intramembranous bone progenitors in the skull. Here, we show in mice that removal of β-catenin from skull bone progenitors results in the near complete transformation of the skull bones to cartilage, whereas constitutive β-catenin activation inhibits skull bone fate selection. β-catenin directly activated Twist1 expression in skull progenitors, conditional Twist1 deletion partially phenocopied the absence of β-catenin, and Twist1 deletion partially restored bone formation in the presence of constitutive β-catenin activation. Finally, Twist1 bound robustly to the 3'UTR of Sox9, the central initiator of chondrogenesis, suggesting that Twist1 might directly repress cartilage formation through Sox9. These findings provide insight into how β-catenin signaling via Twist1 actively suppresses the formation of cartilage and promotes intramembranous ossification in the skull.
At early stages of development, the faces of vertebrate embryos look remarkably similar, yet within a very short timeframe they adopt species-specific facial characteristics. What are the mechanisms ...underlying this regional specification of the vertebrate face? Using transgenic Wnt reporter embryos we found a highly conserved pattern of Wnt responsiveness in the developing mouse face that later corresponded to derivatives of the frontonasal and maxillary prominences. We explored the consequences of disrupting Wnt signaling, first using a genetic approach. Mice carrying compound null mutations in the nuclear mediators Lef1 and Tcf4 exhibited radically altered facial features that culminated in a hyperteloric appearance and a foreshortened midface. We also used a biochemical approach to perturb Wnt signaling and found that in utero delivery of a Wnt antagonist, Dkk1, produced similar midfacial malformations. We tested the hypothesis that Wnt signaling is an evolutionarily conserved mechanism controlling facial morphogenesis by determining the pattern of Wnt responsiveness in avian faces, and then by evaluating the consequences of Wnt inhibition in the chick face. Collectively, these data elucidate a new role for Wnt signaling in regional specification of the vertebrate face, and suggest possible mechanisms whereby species-specific facial features are generated.
•In a cadaveric femur model, addition of a medial plate significantly increases stability.•Dual plated specimens demonstrate less displacement and greater stiffness.•Surgeons may wish to consider ...supplemental fixation of distal femur lateral plates.
Introduction: Bridge plating of distal femur fractures with lateral locking plates is susceptible to varus collapse, fixation failure, and nonunion. While medial and lateral dual plating has been described in clinical series, the biomechanical effects of dual plating of distal femur fractures have yet to be clearly defined. The purpose of this study was to compare dual plating to lateral locked bridge plating alone in a cadaveric distal femur gap osteotomy model.
Materials and Methods: Gap osteotomies were created in eight matched pairs of cadaveric female distal femurs (average age: 64 yrs (standard deviation ± 4.4 yrs); age range: 57–68 yrs;) to simulate comminuted extraarticular distal femur fractures (AO/OTA 33A). Eight femurs underwent fixation with lateral locked plates alone and were matched with eight femurs treated with dual plating: lateral locked plates with supplemental medial small fragment non-locking fixation. Mechanical testing was performed on an ElectroPuls E10000 materials testing system using a 10 kN/100 Nm biaxial load cell. Specimens were subject to 25,000 cycles of cyclic loading from 100-1000 N at 2 Hz.
Results: Two (2/8) specimens in the lateral only group failed catastrophically prior to completion of testing. All dual plated specimens survived the testing regimen. Dual plated specimens demonstrated significantly less coronal plane displacement (median 0.2 degrees, interquartile range IQR, 0.0–0.5 degrees) compared to 2.0 degrees (IQR 1.9-3.3, p = 0.02) in the lateral plate only group. Dual plated specimens demonstrated greater bending stiffness compared to the lateral plated group (median 29.0 kN/degree, IQR 1.5–68.2 kN/degree vs median 0.50 kN/degree, IQR 0.23–2.28 kN/degree, p = 0.03).
Conclusion: Contemporary fixation methods with a distal femur fractures are susceptible to mechanical failure and nonunion with lateral plates alone. Dual plate fixation in a cadaveric model of distal femur fractures underwent significantly less displacement under simulated weight bearing conditions and demonstrated greater stiffness than lateral plating alone. Given the significant clinical failure rates of lateral bridge plating in distal femur fractures, supplemental fixation should be considered, and dual plating of distal femurs augments mechanical stability in a clinically relevant magnitude.
Displaced tongue-type calcaneus fractures are frequently associated with severe soft tissue injuries, and urgent relief of the displaced tongue fragment on the posterior soft tissues is essential to ...preventing soft tissue complications. If there is a complex articular injury, the soft tissue envelope often needs time for swelling to resolve to allow for a safe open anatomic reduction because premature open reduction internal fixation is often associated with increased complications. We have found that in high-energy tongue-type calcaneus fractures with complex articular injuries, a staged protocol consisting of initial percutaneous reduction and fixation with later definitive reconstruction is soft tissue friendly, allows early restoration of calcaneal morphology, and affords extensile approaches for eventual reconstruction. The purpose of this study was to describe our protocol of staged treatment of high-energy tongue-type calcaneus fractures, along with postoperative surgical outcomes, in a case series of 53 patients.Our series of patients had a high rate of intra-articular injury with marked initial displacement (mean Bohler angle -8.4 ± 20.8 degrees). They were treated initially with percutaneous reduction and fixation at median 1 day postinjury (interquartile range IQR 0-1) and definitively at median 16 days postinjury (IQR 10-33). In this series, 2 of 53 (3.8%) patients developed a deep wound infection.In high-energy tongue-type calcaneus fractures at risk for soft tissue compromise or with a significantly displaced tongue fragment without initial soft tissue compromise, we found that staged management represents a feasible management strategy to mitigate risk of soft tissue complications and therefore helps facilitate safe definitive open treatment.
The cranial bones and dermis differentiate from mesenchyme beneath the surface ectoderm. Fate selection in cranial mesenchyme requires the canonical Wnt effector molecule β-catenin, but the relative ...contribution of Wnt ligand sources in this process remains unknown. Here we show Wnt ligands are expressed in cranial surface ectoderm and underlying supraorbital mesenchyme during dermal and osteoblast fate selection. Using conditional genetics, we eliminate secretion of all Wnt ligands from cranial surface ectoderm or undifferentiated mesenchyme, to uncover distinct roles for ectoderm- and mesenchyme-derived Wnts. Ectoderm Wnt ligands induce osteoblast and dermal fibroblast progenitor specification while initiating expression of a subset of mesenchymal Wnts. Mesenchyme Wnt ligands are subsequently essential during differentiation of dermal and osteoblast progenitors. Finally, ectoderm-derived Wnt ligands provide an inductive cue to the cranial mesenchyme for the fate selection of dermal fibroblast and osteoblast lineages. Thus two sources of Wnt ligands perform distinct functions during osteoblast and dermal fibroblast formation.
Dystrophin, the main component of the dystrophin–glycoprotein complex, plays an important role in maintaining the structural integrity of cells. It is also involved in the formation of the ...blood–brain barrier (BBB). To elucidate the impact of dystrophin disruption in vivo, we characterized changes in cerebral perfusion and diffusion in dystrophin-deficient mice (mdx) by magnetic resonance imaging (MRI). Arterial spin labeling (ASL) and diffusion-weighted MRI (DWI) studies were performed on 2-month-old and 10-month-old mdx mice and their age-matched wild-type controls (WT). The imaging results were correlated with Evan's blue extravasation and vascular density studies. The results show that dystrophin disruption significantly decreased the mean cerebral diffusivity in both 2-month-old (7.38±0.30×10-4mm2/s) and 10-month-old (6.93±0.53×10-4mm2/s) mdx mice as compared to WT (8.49±0.24×10-4, 8.24±0.25×10-4mm2/s, respectively). There was also an 18% decrease in cerebral perfusion in 10-month-old mdx mice as compared to WT, which was associated with enhanced arteriogenesis. The reduction in water diffusivity in mdx mice is likely due to an increase in cerebral edema or the existence of large molecules in the extracellular space from a leaky BBB. The observation of decreased perfusion in the setting of enhanced arteriogenesis may be caused by an increase of intracranial pressure from cerebral edema. This study demonstrates the defects in water handling at the BBB and consequently, abnormal perfusion associated with the absence of dystrophin.
•Cerebral perfusion/diffusion in dystrophin-null mdx mice were evaluated by MRI.•Cerebral vasculature was assessed with cryoimaging and immunohistochemistry.•Decreased diffusion was observed in young and adult mdx mice, suggesting edema.•Decreased perfusion but enhanced arteriogenesis were observed in adult mdx mice.•Decreased perfusion may be due to edema-related increases in intracranial pressure.
To compare complications and functional outcomes of treatment with primary distal femoral replacement (DFR) versus open reduction and internal fixation (ORIF).
PubMed, Embase, and Cochrane databases ...were searched for English language studies up to May 19, 2020, identifying 913 studies.
Studies that assessed complications of periprosthetic distal femur fractures with primary DFR or ORIF were included. Studies with sample size ≤5, mean age <55, nontraumatic indications for DFR, ORIF with nonlocking plates, native distal femoral fractures, or revision surgeries were excluded. Selection adhered to the PRISMA criteria.
Study quality was assessed using previously reported criteria. There were 40 Level IV studies, 17 Level III studies, and 1 Level II study.
Fifty-eight studies with 1484 patients were included in the meta-analysis. Complications assessed {incidence rate ratio IRR 95% confidence interval (CI): 0.78 0.59-1.03} and reoperation or revision IRR (95% CI): 0.71 (0.49-1.04) were similar between the DFR and ORIF cohorts. The mean knee range of motion was greater in the ORIF cohort (DFR: 90.47 vs. ORIF: 100.36, P < 0.05). The mean Knee Society Score (KSS) (DFR: 79.41 vs. ORIF: 82.07, P = 0.35) and return to preoperative ambulatory status were similar IRR (95% CI): 0.82 (0.48-1.41).
In comparing complications among patients treated for periprosthetic distal femur fracture with DFR or ORIF, there was no difference between the groups. There were also no differences in functional outcomes, although knee range of motion was greater in the ORIF group. This systematic review and meta-analysis highlights the need for future prospective trials evaluating the outcomes of these divergent treatment strategies.
Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.
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