Epiphyseal Research Articles

Clinical analysis of 1301 children with hand and foot fractures and growth plate injuries.

Fractures of hands and feet are common in children, but relevant epidemiological studies are currently lacking. We aim to study the epidemiological characteristics of hand and foot fractures and growth plate injuries in children and provide a theoretical basis for their prevention, diagnosis, and treatment. We retrospectively analyzed the data of children with hand and foot fractures who were hospitalized at Shenzhen Children's Hospital between July 2015 and December 2020. Data on demographic characteristics, fracture site, treatment method, etiology of injury, and accompanying injuries were collected. The children were divided into four age groups: infants, preschool children, school children, and adolescents. The fracture sites were classified as first-level (the first-fifth finger/toe, metacarpal, metatarsal, carpal, and tarsal) and second-level (the first-fifth: proximal phalanx, middle phalanx, distal phalanx, metacarpal, and metatarsal) sites. The changing trends in fracture locations and injury causes among children in each age group were analyzed. Overall, 1301 children (1561 fractures; 835 boys and 466 girls) were included. The largest number of fractures occurred in preschool children (n = 549, 42.20%), with the distal phalanx of the third finger being the most common site (n = 73, 15.57%). The number of fractures in adolescents was the lowest (n = 158, 12.14%), and the most common fracture site was the proximal phalanx of the fifth finger (n = 45, 29.61%). Of the 1561 fractures, 1143 occurred in the hands and 418 in the feet. The most and least common first-level fracture sites among hand fractures were the fifth (n = 300, 26.25%) and first (n = 138, 12.07%) fingers, respectively. The most and least common first-level foot fracture locations were the first (n = 83, 19.86%) and fourth (n = 26, 6.22%) toes, respectively. The most common first-level and second level etiologies were life related injuries (n = 1128, 86.70%) and clipping injuries (n = 428, 32.90%), respectively. The incidence of sports injuries gradually increased with age, accounting for the highest proportion in adolescents (26.58%). Hand and foot fractures had many accompanying injuries, with the top three being nail bed injuries (570 cases, 36.52%), growth plate injuries (296 cases, 18.96%), and distal severed fracture (167 cases, 10.70%). Among the 296 growth plate injuries, 246 occurred on the hands and 50 on the feet. In contrast to previous epidemiological studies on pediatric hand and foot fractures, we mapped the locations of these fractures, including proximal, shaft, distal, and epiphyseal plate injuries. We analyzed the changing trends in fracture sites and injury etiologies with age. Hand and foot fractures have many accompanying injuries that require attention during diagnosis and treatment. Doctors should formulate accident protection measures for children of different ages, strengthen safety education, and reduce the occurrence of accidental injuries.

Impact of the arginine silicate inositol complex on bone metabolism in broiler chickens with tibial dyschondroplasia caused by manganese deficiency

ABSTRACT 1. Tibial dyschondroplasia (TD) is a skeletal disorder in broilers that has financial implications, necessitating dietary modifications to reduce the prevalence of this disease. This study explored how arginine silicate inositol complex (ASI) supplementation affected tibial growth plate (TGP) and overall bone health in broilers with manganese (Mn) deficiency-induced TD. 2. A total of 240 broiler chicks were divided into four groups, each consisting of 60 birds (15 replicates of four broilers each) as follows: i) Control, with 60 mg Mn per kg of diet; ii) ASI, with 60 mg Mn and 1 g ASI per kg of diet; iii) TD, with 22 mg Mn per kg of diet, and iv) TD+ASI, with 22 mg Mn and 1 g ASI per kg of diet. 3. It was found that ASI supplementation increased tibial bone length in Mn-deficient TD broilers (p = 0.007). There was no Mn x ASI interaction for other bone morphometry variables (p > 0.05). However, both tibial bone mineral content and density were affected by Mn and ASI (p < 0.05). With ASI supplementation, serum bone-specific alkaline phosphatase and osteocalcin levels were elevated in the TD+ASI group compared to the TD group (p < 0.001). In the TD group, osteoprotegerin (OPG) levels in the TGP decreased compared to the control groups (p < 0.001). 4. In contrast, ASI supplementation in the TD broilers counteracted the decrease in OPG compared to TD broilers without ASI supplementation (p < 0.001). The Mn level and ASI supplementation significantly influenced the OPG/receptor activator of the nuclear factor-κB ligand ratio (p < 0.001). 5. In conclusion, the results demonstrated that inclusion of ASI in broiler diets could enhance bone formation variables by controlling OPG levels in the TGP, potentially serving as an effective method to decrease the occurrence of TD.

Lithium loss, resistance growth, electrode expansion, gas evolution, and Li plating: Analyzing performance and failure of commercial large-format NMC-Gr lithium-ion pouch cells

Analysis of the performance evolution and failure mechanisms of commercial Li-ion batteries is crucial for improving testing methods, accurately modeling battery performance, and ensuring safe battery operation. Here, we present the results of a 2-year aging study conducted on commercial large-format LiNiMnCoO2-graphite pouch cells. Loss of lithium inventory (LLI) and loss of positive electrode active material (LAMPE) are shown to dominate capacity fade, as quantified by differential voltage-capacity analysis; only a small amount of LAMPE was measured in extracted electrode material, indicating that LAMPE in full cells was due to electrode dry-out. Resistance evolution, observed by direct current pulses and electrochemical impedance spectroscopy analyzed using the distribution of relaxation times, shows complex trends. Particle cracking and electrode expansion is theorized to cause most changes to resistance. Post-mortem measurements reveal a 10% increase in electrode stack thickness and substantial gas generation, with lithium plating observed in extreme cycling conditions, causing large resistance increases. Circumstantial evidence for self-discharge via redox shuttle, which decomposes the electrolyte, is shown. Overall, electrolyte stability was determined to be the limiting factor for cell lifetime. The impacts of many degradation mechanisms on diagnostic signals substantially overlap, making it challenging to monitor cell health and safety.

Glenohumeral internal rotation deficit: insights into pathologic, clinical, diagnostic, and therapeutic characteristics.

Overhead athletes undergo significant biomechanical adaptations due to repetitive overhead movements, primarily affecting the glenohumeral joint. These adaptations can lead to glenohumeral internal rotation deficit (GIRD), which is characterized by posterior capsule stiffness that results in glenohumeral joint translation and a shift in the center of gravity. The severity of GIRD is dependent upon the presence of asymmetry between gained external and lost internal rotation, which is defined clinically as an asymmetry exceeding 20º; this reduces the total range of motion compared to the unaffected limb or baseline measurements. Diagnosis is challenging, as it can be mistaken for chronic scapular adaptations. To mitigate misdiagnosis, a high clinical suspicion is crucial in overhead athletes, especially those who began performing forceful overhead movements before closure of growth plates. Periodic physical examinations should establish baseline values for glenohumeral rotation and track changes in glenohumeral motion to aid in diagnosis. Symptoms of GIRD include shoulder pain, stiffness, and decreased force exertion. Magnetic resonance imaging is the preferred imaging method for evaluating GIRD and assessing concomitant soft tissue pathologies. Untreated GIRD can lead to rotator cuff strength imbalances. Treatment mainly involves conservative measures, such as physical therapy, to improve internal rotation and alleviate posterior tightness. Surgical interventions are considered when symptoms persist despite conservative treatment with physical therapy or in the presence of concomitant pathologies.

Uncovering Molecular Mechanisms of Mechanical Force Stimulation on Bone Tissue: A Bioinformatics Approach

This study employed multiple bioinformatics approaches to uncover the potential molecular mechanisms underlying the effects of mechanical force stimulation on bone tissue. RNA sequencing data from 132 cortical bone samples were initially retrieved from the SRA database and subjected to quality control, sequence alignment, and expression matrix generation as preprocessing steps. Subsequently, WGCNA was applied for gene co-expression network analysis, followed by the selection of approximately 3,500 genes for further investigation and the exclusion of outliers. Clustering and correlation analyses revealed sets of genes highly associated with mechanical force stimulation. To gain insight into the functional characteristics of these genes, PPI network construction and GO and KEGG enrichment analyses were performed. Results indicated distinct functional properties of different modules under various conditions. For instance, genes within the MEsalmon module were mainly associated with actin cytoskeleton and calmodulin in response to mechanical force stimulation; whereas genes within the MEbrown module, when considering growth plates and other skeletal regions, primarily involved ribosomal proteins and energy metabolism. With prolonged treatment time, genes within the MEblack module exhibited increased energy metabolic activity. These findings suggest that mechanical force stimulation can alter the expression levels of specific genes in bone tissue, thereby affecting their biological functions. This study provides a new perspective on how mechanical force stimulation regulates bone tissue and may have positive implications for therapeutic strategies in fracture healing and bone diseases.

UCL Throwing Injuries in Nonprofessional Baseball Players: A 14-Year Retrospective Study.

This study evaluated treatment modality (surgical vs nonoperative) of medial ulnar collateral ligament (UCL) injuries in nonprofessional throwing baseball athletes by comparing type, severity, and location of UCL injury. Baseball players with closed medial epicondyle physes and concomitant throwing-related UCL injury will be more likely to undergo surgical intervention than players with open medial epicondyle physes. Retrospective. Level 5. A total of 119 baseball players with a mean age of 16.9 ± 2.5 years (range, 11-25 years) were included in the study. Datapoints included sex, age at time of injury, severity, and location of UCL injury, growth plate status, operative versus conservative management, and concomitant flexor forearm injury. A total of 75 players were treated conservatively; 43 underwent UCL reconstruction (UCL-R), and 1 had an unknown treatment outcome. No significant difference was found for age related to treatment type, UCL-R (17.2 ± 2.2) versus conservative treatment (16.8 ± 2.6). Athletes with closed medial epicondylar growth plates were more likely to undergo UCL-R than athletes with open medial epicondylar growth plates (P = 0.02). There were no significant differences between UCL injury location (42 distal, 37 proximal, 18 combined tear locations, 11 complete tears, and 11 intact UCLs with inflammation) by treatment type (P = 0.09). There was a significant difference for UCL severity (11 complete tears, 96 partial tears) by treatment type (P = 0.03). Nonprofessional athletes with closed medial epicondylar growth plates and throwing-related UCL injuries were more likely to be treated surgically. Baseball athletes with partial tears, if skeletally immature, require further long-term evaluation. Continued knowledge gains in this area of throwing medicine will further improve our treatment algorithms in nonprofessional baseball players.

Periodic static compression of micro-strain pattern regulates endochondral bone formation.

Introduction: Developmental engineering based on endochondral ossification has been proposed as a potential strategy for repairing of critical bone defects. Bone development is driven by growth plate-mediated endochondral ossification. Under physiological conditions, growth plate chondrocytes undergo compressive forces characterized by micro-mechanics, but the regulatory effect of micro-mechanical loading on endochondral bone formation has not been investigated. Methods: In this study, a periodic static compression (PSC) model characterized by micro-strain (with 0.5% strain) was designed to clarify the effects of biochemical/mechanical cues on endochondral bone formation. Hydrogel scaffolds loaded with bone marrow mesenchymal stem cells (BMSCs) were incubated in proliferation medium or chondrogenic medium, and PSC was performed continuously for 14 or 28days. Subsequently, the scaffold pretreated for 28days was implanted into rat femoral muscle pouches and femoral condylar defect sites. The chondrogenesis and bone defect repair were evaluated 4 or 10weeks post-operation. Results: The results showed that PSC stimulation for 14days significantly increased the number of COL II positive cells in proliferation medium. However, the chondrogenic efficiency of BMSCs was significantly improved in chondrogenic medium, with or without PSC application. The induced chondrocytes (ichondrocytes) spontaneously underwent hypertrophy and maturation, but long-term mechanical stimulation (loading for 28days) significantly inhibited hypertrophy and mineralization in ichondrocytes. In the heterotopic ossification model, no chondrocytes were found and no significant difference in terms of mineral deposition in each group; However, 4weeks after implantation into the femoral defect site, all scaffolds that were subjected to biochemical/mechanical cues, either solely or synergistically, showed typical chondrocytes and endochondral bone formation. In addition, simultaneous biochemical induction/mechanical loading significantly accelerated the bone regeneration. Discussion: Our findings suggest that microstrain mechanics, biochemical cues, and in vivo microenvironment synergistically regulate the differentiation fate of BMSCs. Meanwhile, this study shows the potential of micro-strain mechanics in the treatment of critical bone defects.

Subperiosteal delivery of transforming growth factor beta 1and human growth hormone from mineralized PCL films.

The ability to locally deliver bioactive molecules to distinct regions of the skeleton may provide a novel means by which to improve fracture healing, treat neoplasms or infections, or modulate growth. In this study, we constructed single-sided mineral-coated poly-ε-caprolactone membranes capable of binding and releasing transforming growth factor beta 1 (TGF-β1) and human growth hormone (hGH). After demonstrating biological activity in vitro and characterization of their release, these thin bioabsorbable membranes were surgically implanted using an immature rabbit model. Membranes were circumferentially wrapped under the periosteum, thus placed in direct contact with the proximal metaphysis to assess its bioactivity in vivo. The direct effects on the metaphyseal bone, bone marrow, and overlying periosteum were assessed using radiography and histology. Effects of membrane placement at the tibial growth plate were assessed via physeal heights, tibial growth rates (pulsed fluorochrome labeling), and tibial lengths. Subperiosteal placement of the mineralized membranes induced greater local chondrogenesis in the plain mineral and TGF-β1 samples than the hGH. More exuberant and circumferential ossification was seen in the TGF-β1 treated tibiae. The TGF-β1 membranes also induced hypocellularity of the bone marrow with characteristics of gelatinous degeneration not seen in the other groups. While the proximal tibial growth plates were taller in the hGH treated than TGF-β1, no differences in growth rates or overall tibial lengths were found. In conclusion, these data demonstrate the feasibility of using bioabsorbable mineral coated membranes to deliver biologically active compounds subperiosteally in a sustained fashion to affect cells at the insertion site, bone marrow, and even growth plate.

Hypoxic environment promotes angiogenesis and bone bridge formation by activating Notch/RBPJ signaling pathway in HUVECs

After epiphyseal fracture, the epiphyseal plate is prone to ischemia and hypoxia, leading to the formation of bone bridge and deformity. However, the exact mechanism controlling the bone bridge formation remains unclear. Notch/RBPJ signaling axis has been indicated to regulate angiogenesis and osteogenic differentiation. Our study aims to investigate the mechanism of bone bridge formation after epiphyseal plate injury, and to provide a theoretical basis for new therapeutic approaches to prevent the bone bridge formation. The expression of DLL4 and RBPJ was significantly up-regulated in HUVECs after ischemia and hypoxia treatment. Notch/RBPJ pathway positively regulated the osteogenic differentiation of BMSCs. HUVECs can induce osteogenic differentiation of BMSCs under ischemia and hypoxia. Notch/RBPJ pathway is involved in the regulation of the trans-epiphyseal bridge formation. Notch/RBPJ in HUVECs is associated with osteogenic differentiation of BMSCs and may participate in the regulation of the bone bridge formation across the epiphyseal plate.

Estrogen Receptor 1 Gene Polymorphism and its Association with Idiopathic Short Stature in a North Indian Population

In the hypothalamic-pituitary-gonadotrophin axis, estrogen plays a key role in the regulation of bone maturation and growth plate closure. This study was designed to explore the link between single nucleotide polymorphisms (SNPs) in the estrogen receptor 1 (ESR1) gene with idiopathic short stature (ISS) susceptibility in a North Indian population. Four SNPs of ESR1 (rs543650, rs6557177, rs2234693 and rs9340799) were genotyped by Sanger sequencing in ISS patients and controls. Linkage disequilibrium (LD) and haplotyping were done by SNPStat and SHEsisPlus software. The extent of LD was determined by calculating D’ and R2 values in SNP paired combinations. Fifty-two ISS patients were compared with 68 controls. A significant positive association was found between rs6557177 and rs543650 genotype and ISS susceptibility. The frequencies of the rs6557177 CC genotype [p=0.030; odds ratio (OR)=0.13; 95% confidence interval (CI): 0.01-1.10] and rs543650 genotype TT (p=0.043; OR=0.29; 95% CI: 0.09-0.92) were increased in the ISS group compared with controls. However, no significant correlation was observed between clinical parameters of patients and these SNPs. rs543650 showed strong LD with rs2234693 and rs9340799, similarly rs2234693 and rs9340799. Our study showed that the CC genotype at rs6557177 and TT genotype at rs543650 of ESR1 constituted a risk factor for developing ISS in North Indian children. These findings may lead to a better understanding of the SNPs associated with ISS susceptibility.

Skeletal abnormalities in mice with Dnmt3a missense mutations

Overgrowth and intellectual disability disorders in humans are typified by length/height and/or head circumference ≥ 2 standard deviations above the mean as well as intellectual disability and behavioral comorbidities, including autism and anxiety. Tatton-Brown-Rahman Syndrome is one type of overgrowth and intellectual disability disorder caused by heterozygous missense mutations in the DNA methyltransferase 3A (DNMT3A) gene. Numerous DNMT3A mutations have been identified in Tatton-Brown-Rahman Syndrome patients and may be associated with varying phenotype severities of clinical presentation. Two such mutations are the R882H and P904L mutations which result in severe and mild phenotypes, respectively. Mice with paralogous mutations (Dnmt3aP900L/+ and Dnmt3aR878H/+) exhibit overgrowth in their long bones (e.g., femur, humerus), but the mechanisms responsible for their skeletal overgrowth remain unknown. The goal of this study is to characterize skeletal phenotypes in mouse models of Tatton-Brown-Rahman Syndrome and identify potential cellular mechanisms involved in the skeletal overgrowth phenotype. We report that mature mice with the Dnmt3aP900L/+ or Dnmt3aR878H/+ mutation exhibit tibial overgrowth, cortical bone thinning, and weakened bone mechanical properties. Dnmt3aR878H/+ mutants also contain larger bone marrow adipocytes while Dnmt3aP900L/+ mutants show no adipocyte phenotype compared to control animals. To understand the potential cellular mechanisms regulating these phenotypes, growth plate chondrocytes, osteoblasts, and osteoclasts were assessed in juvenile mutant mice using quantitative static histomorphometry and dynamic histomorphometry. Tibial growth plates appeared thicker in mutant juvenile mice, but no changes were observed in osteoblast activity or osteoclast number in the femoral mid-diaphysis. These studies reveal new skeletal phenotypes associated with Tatton-Brown-Rahman Syndrome in mice and provide a rationale to extend clinical assessments of patients with this condition to include bone density and quality testing. These findings may be also informative for skeletal characterization of other mouse models presenting with overgrowth and intellectual disability phenotypes.

Abstract 139: Modeling and genomic profiling of osteosarcoma development in murine chondrocyte-origin models

Abstract Osteosarcoma (OS) manifests during puberty, coinciding with rapid bone growth, a feature requiring exploration. We selectively deleted p53 or both p53 and Rb1 alleles in growth-dependent chondrocyte-origin models, utilizing Col10a1-Cre or Agc-CreERT2, incorporating with ROSA-Tomato for tracing and isolating the mutant cell collection. Col10p53flfl(tm) and Col10p53flflRbfl+(tm) mutants exhibited 100% penetrance in osteoblastic OS, with the latter displaying shortened latencies (mean: 335 vs 265 days) and increased metastases. Tamoxifen-induced AgcCreERT2 models highlighted growth stage-dependent OS development, correlating penetrance inversely and latencies positively with mouse age at tamoxifen treatment. Tumors exclusively occurred in endochondral bones, near growth plates. Whole-genome profiling of tm+ tumor cells revealed genetic variations, including SNPs, Indels, CNVs, and SVs. CNVs involved genes altered in human OS, emphasizing losses in Dmd and gains in Myc, Vegfa, Foxm1, Akt1, Aurkb, and Ccen1. A common CNV (losses, Chr. 10: 34,158,531-34,443,999, Log ratio ←0.05) occurred in all sequenced primary and metastatic samples, with male specimens sharing a loss in the Y chr. p region (approximately 725,200-799,409). Orthotopic transplantation of tm+ p53− stromal cells from 4-month-old Col10p53flfltm mice gave rise to bone tumors and lung migration in wild-type recipients, explicitly establishing the transplanted cells as the direct origin of the cancer precursors within early tm+ p53− stromal populations. Whole-genome sequencing unveiled a discernible progression of genomic alterations from 1 to 4-month-old tm+ p53− stromal cells, culminating in donor-derived tumors. Notably, only these specific donor-derived tumors, and not the early tm+ p53− stromal cells, exhibited the Chr. 10 CNV observed in autochthonous malignancies. Micro-metastases, identified by fluorescence imaging, were prevalent, alongside macro-metastases (~10% in Col10p53flflRbfl+tm and ~25% in AgcCreERT2p53flflRbfl+tm cohorts). Notably, amputation of primary OS sites in mice surviving longer revealed larger and more abundant tm+ cell clusters. Some micro-metastases not only expressed signature genes typical of macro-lung metastases but also shared genomic variations with corresponding primaries, including the prevalent loss in Chr. 10. Enhanced immune cell infiltration was evident in lungs hosting micro-metastases, suggesting a potential immune response triggered by pre-tumor early seeding cells. Murine OS models faithfully replicate human OS features, underscoring chondrocytes as significant contributors to OS cell sources. The inclusion of a tomato reporter enables precise tracking, rendering these models invaluable for studying OS etiology, particularly in unraveling pre-tumor molecular events in both primary and metastatic settings. Citation Format: Xin Zhou, Hannah Beird, Yanhua Yi, Zhaohui Xu, Zhongting Zhang, Harjeet Singh, Wendong Zhang, Yifei Wang, Sylvester Jusu, Michael Roth, Jonatha Gill, Richard Gorlick. Modeling and genomic profiling of osteosarcoma development in murine chondrocyte-origin models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 139.

Decoupling stiffness and toughness of self-healing hydrogels for complex tissue regeneration via 3D bioprinting

Although polysaccharides are attractive biocompatible materials compared with synthetic polymers, most polysaccharide-based hydrogels exhibit suboptimal mechanical properties. In this study, we fabricated a hyaluronate (HA)-based self-healing hydrogel with enhanced toughness that can be used as a 3D bioink for complex tissue regeneration. We hypothesized that the incorporation of oxidation, aimed at minimizing the reduction in the molecular weight of HA, along with the introduction of a double network to the hydrogel, could facilitate the construction of 3D structures with decoupled stiffness and toughness. Various physicochemical properties of hydrogels comprising oxidized and hydrazide-modified HAs for potential use as bioinks were assessed. Bilayered constructs containing primary chondrocytes and osteoblasts were designed and fabricated using 3D printing to mimic the growth plate structure. Transplantation of the 3D-printed construct into a mouse model revealed the controlled differentiation stages of chondrocytes. This strategy for tailoring 3D scaffolds and addressing the limitations of polysaccharide-based hydrogels may hold promise for applications in the biomedical field, including the regeneration of complex tissues and organs.

Metabolic regulation of skeletal cell fate and function.

Bone development and bone remodelling during adult life are highly anabolic processes requiring an adequate supply of oxygen and nutrients. Bone-forming osteoblasts and bone-resorbing osteoclasts interact closely to preserve bone mass and architecture and are often located close to blood vessels. Chondrocytes within the developing growth plate ensure that bone lengthening occurs before puberty, but these cells function in an avascular environment. With ageing, numerous bone marrow adipocytes appear, often with negative effects on bone properties. Many studies have now indicated that skeletal cells have specific metabolic profiles that correspond to the nutritional microenvironment and their stage-specific functions. These metabolic networks provide not only skeletal cells with sufficient energy, but also biosynthetic intermediates that are necessary for proliferation and extracellular matrix synthesis. Moreover, these metabolic pathways control redox homeostasis to avoid oxidative stress and safeguard cell survival. Finally, several intracellular metabolites regulate the activity of epigenetic enzymes and thus control the fate and function of skeletal cells. The metabolic profile of skeletal cells therefore not only reflects their cellular state, but can also drive cellular activity. Insight into skeletal cell metabolism will thus not only advance our understanding of skeletal development and homeostasis, but also of skeletal disorders, such as osteoarthritis, diabetic bone disease and bone malignancies.

A comparative analysis of TonEBP conditional knockout mouse models reveals inter-dependency between compartments of the intervertebral disc.

Interactions between notochord and sclerotome are required for normal embryonic spine patterning, but whether the postnatal derivatives of these tissues also require interactions for postnatal intervertebral disc (IVD) growth and maintenance is less established. We report here the comparative analysis of four conditional knockout mice deficient for TonEBP, a transcription factor known to allow cells to adapt to changes in extracellular osmotic pressure, in specific compartments of the IVD. We show that TonEBP deletion in nucleus pulposus (NP) cells does not affect their survival or aggrecan expression, but promoted cell proliferation in the NP and in adjacent vertebral growth plates (GPs). In cartilage end plates/GPs, TonEBP deletion induced cell death, but also structural alterations in the adjacent NP cells and vertebral bodies. Embryonic or postnatal TonEBP loss generated similar IVD changes. In addition to demonstrating the requirement of TonEBP in the different compartments of the IVD, this comparative analysis uncovers the in vivo interdependency of the different IVD compartments during the growth of the postnatal IVD-vertebral units.

Patterns of structural variants within TP53 introns and relocation of the TP53 promoter: a commentary†.

Gene disruption from double-strand DNA breaks within introns is a mechanism of inactivating the tumor suppressor TP53. This occurs more frequently in osteosarcoma and biliary adenocarcinoma compared with other cancer types. The patterns of intron breakpoints within TP53 do not correlate with prevalence, intron length, or overall genome-wide levels of rearrangements. Therefore, these breakpoints appear to be selected for reasons other than to disrupt TP53. A recent article published by Saba et al in The Journal of Pathology illustrates a benefit to having breakpoints within intron 1 using high-quality matched genomic and transcriptomic osteosarcoma sequencing data as well as in vitro validation. The authors describe how the rearrangement results in relocation of the TP53 promoter region to regions upstream of genes that encode members of cartilage, growth plate development, osteoclast formation, and other TP53-related pathways. The upregulation of these genes by the TP53 promoter are gain-of-function events that are likely to promote tumor development and growth. Therefore, this article presents a potential new paradigm in which a single mutation would result in both the loss of a tumor suppressor and the gain of an oncogenic program. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Return to Play in Youth Athletes: Role of the Radiologist with Focus on the Upper Extremity.

Increase in youth sports participation, longer duration of play, and earlier starting points have increased the prevalence of acute and repetitive overuse musculoskeletal injuries. This rise in injury rates has led to increased efforts to better understand the susceptible sites of injury that are unique to the growing immature skeleton. Upper extremity injuries are currently the best studied, particularly those that occur among pediatric baseball players and gymnasts. The weak link in skeletally immature athletes is the growth plate complex that includes those injuries located at the epiphyseal and apophyseal primary physes and the peripherally located secondary physes. This article reviews the anatomy and function of these growth plate complexes, followed by a discussion of the pathophysiologic mechanisms, spectrum of imaging findings, and existing evidence-based guidelines for injury prevention and return to play.

Endothelial SMAD1/5 signaling couples angiogenesis to osteogenesis in juvenile bone

Skeletal development depends on coordinated angiogenesis and osteogenesis. Bone morphogenetic proteins direct bone formation in part by activating SMAD1/5 signaling in osteoblasts. However, the role of SMAD1/5 in skeletal endothelium is unknown. Here, we found that endothelial cell-conditional SMAD1/5 depletion in juvenile mice caused metaphyseal and diaphyseal hypervascularity, resulting in altered trabecular and cortical bone formation. SMAD1/5 depletion induced excessive sprouting and disrupting the morphology of the metaphyseal vessels, with impaired anastomotic loop formation at the chondro-osseous junction. Endothelial SMAD1/5 depletion impaired growth plate resorption and, upon long-term depletion, abrogated osteoprogenitor recruitment to the primary spongiosa. Finally, in the diaphysis, endothelial SMAD1/5 activity was necessary to maintain the sinusoidal phenotype, with SMAD1/5 depletion inducing formation of large vascular loops and elevated vascular permeability. Together, endothelial SMAD1/5 activity sustains skeletal vascular morphogenesis and function and coordinates growth plate remodeling and osteoprogenitor recruitment dynamics in juvenile mouse bone.

Microwave Ablation of the Pig Growth Plate: Proof of Concept for Minimally Invasive Epiphysiodesis.

Different surgical methods for epiphysiodesis of limb length discrepancy (LLD) have been described. Although these methods are variably effective, they are associated with morbidity (pain and limp) and potential complications. Microwave ablation is a less-invasive opportunity to halt growth by selectively destroying the growth plate via thermal energy to treat LLD in children. In this proof-of-concept study using an in vivo pig model, we asked: (1) What is the durability of response 2 to 4 months after microwave ablation of the tibial growth plate as measured by length and angulation of the tibia via a CT scan? (2) Was articular cartilage maintained as measured by standard histologic staining for articular cartilage viability? To develop an in vivo protocol for microwave ablation, we placed microwave antennas adjacent to the proximal tibia growth plate in the cadaveric hindlimbs of 18 3-month-old pigs. To determine the suitable time, we varied ablation from 90 to 270 seconds at 65-W power settings. After sectioning the tibia, we visually assessed for discoloration (implying growth plate destruction) that included the central growth plate but did not encroach into the epiphysis in a manner that could disrupt the articular surface. Using this information, we then performed microwave ablation on three live female pigs (3.5 to 4 months old) to evaluate physiologic changes and durability of response. A postprocedure MRI was performed to ensure the intervention led to spatial growth plate alterations similar to that seen in cadavers. This was followed by serial CT, which was used to assess the potential effect on local bone and growth until the animals were euthanized 2 to 4 months after the procedure. We analyzed LLD, angular deformity, and bony deformity using CT scans of both tibias. The visibility of articular cartilage was compared with that of the contralateral tibia via standard histologic staining, and growth rates of the proximal tibial growth plate were compared via fluorochrome labeling. Eighteen cadaveric specimens showed ablation zones across the growth plate without visual damage to the articular surface. The three live pigs did not exhibit changes in gait or require notable pain medication after the procedure. Each animal demonstrated growth plate destruction, expected limb shortening (0.8, 1.2, and 1.5 cm), and bony cavitation around the growth plate. Slight valgus bone angulation (4º, 5º, and 12º) compared with the control tibia was noted. No qualitatively observable articular cartilage damage was encountered from the histologic comparison with the contralateral tibia for articular cartilage thickness and cellular morphology. A microwave antenna placed into a pig's proximal tibia growth plate can slow the growth of the tibia without apparent pain and alteration of gait and function. Further investigation and refinement of our animal model is ongoing and includes shorter ablation times and comparison of dynamic ablation (moving the antennae during the ablation) as well as static ablation of the tibia from a medial and lateral portal. These refinements and planned comparison with standard mechanical growth arrest in our pig model may lead to a similar approach to ablate growth plates in children with LLD.

Skeletal Growth Status Agreement in a Group of Thai Children and Adolescents: A Comparative Analysis of Fishman's Skeletal Maturation and Baccetti's Cervical Vertebral Maturation Indices

This study aimed to determine the agreement of skeletal maturation (SM) assessed by hand-wrist radiographs and cervical vertebral maturation (CVM) assessed by lateral cephalometric radiographs. It also explored the feasibility of using CVM as an alternative to hand-wrist radiographs among Thai children and adolescents. The samples comprised 95 males and 67 females from Thailand, aged 7–17 years. A total of 162 hand-wrist radiographs and lateral cephalometric radiographs were included. Two experienced oral radiologists independently assessed SM (using Fishman’s method) and CVM (using Baccetti’s method); a third referee observer resolved any discrepancies. The correlation and agreement between the methods were evaluated. The results found a substantial agreement (weighted kappa = 0.594) between SM and CVM. The interobserver discrepancy in categorizing SM stages was mostly found at stage 5, while the most common discrepancy for CVM was at stage 6. A significant positive correlation (Spearman’s correlation coefficient = 0.677, P &lt; 0.001) indicated a moderate to strong association between SM and CVM. The substantial agreement and moderate to strong correlation between CVM and SM highlighted the feasibility of using CVM to assess skeletal growth. However, to ensure reliability, it was necessary to precisely evaluate the appearance of the capping of the epiphyseal plate for SM and the distinction between a rectangular and square cervical spine shape at C3 and C4 for CVM differentiation. Keywords: Cervical spine, Hand, Radiographic evaluation, Orthodontics