Epiphyseal Research Articles

Characteristics of Scoliosis in Mice Induced by Chondrocyte-specific Inactivation of L-type Amino Acid Transporter 1.

A mouse study of the Slc7a5 gene using conditional knockout to assess the effects of its inactivation on spinal deformity. This study aimed to investigate whether the mice with scoliosis [induced by chondrocyte-specific inactivation of L-type amino acid transporter 1 (LAT1)] show a developmental process similar to that of pediatric scoliosis and to examine the relationship between reduced bone mineral density (BMD) and scoliosis. Furthermore, we aimed to obtain insights into elucidating the etiology and pathophysiology of scoliosis. The etiology and pathogenesis of scoliosis are not fully understood despite substantial investigative efforts. LAT1 is an amino acid transporter that mediates the cellular uptake of large neutral amino acids. A recent study revealed that chondrocyte-specific inactivation of LAT1 in mice results in scoliosis (Col2a1-Cre;Slc7a5fl/fl mice: "Sko mice"). Body length, body weight, Cobb angle, vertebral body rotation angle, and BMD at 1, 2, 4, 6, and 8 weeks of age were examined and statistically compared with those of normal control mice. Pathologic and morphologic evaluation was performed on specimens from 10-week-old euthanized mice. The Sko mice developed thoracic scoliosis in infancy without congenital malformations. This spinal deformity progressed rapidly during growth, with diverse curve patterns and hypoplastic vertebral bodies. Pathologic examination revealed thickening of the growth plates and decreased osteoblasts, suggesting that impaired endochondral ossification was the cause of the scoliosis. Sko mice were also observed to have decreased BMD and degraded bone microstructure. Reduced BMD and bone quality may not be the causes of the onset and progression of scoliosis in the Sko mice. In Sko mice, the characteristics of scoliosis and vertebral pathology showed many similarities with syndromic scoliosis in humans. Endochondral ossification defects may impair growth, leading to scoliosis and decreased BMD.

OR21-03 Dose Responsiveness Of LUM-201 As Measured By Acute GH Response And IGF-1 And Annualized Height Velocity (AHV) Measured At 6 Months In The Interim Analysis Of The OraGrowtH212 Study In Idiopathic Pediatric Growth Hormone Deficiency (iPGHD)

Abstract Disclosure: F. Cassorla: Research Investigator; Self; Lumos Pharma, Inc. Speaker; Self; Lumos Pharma, Inc. R. Román: Research Investigator; Self; Lumos Pharma, Inc. M.L. Johnson: Consulting Fee; Self; Lumos Pharma, Inc. A. Avila: Research Investigator; Self; Lumos Pharma, Inc. G. Iñiguez: Research Investigator; Self; Lumos Pharma, Inc. I. Baier: Research Investigator; Self; Lumos Pharma, Inc. D. Said: Research Investigator; Self; Lumos Pharma, Inc. A. Bruchey: Employee; Self; Lumos Pharma, Inc. Stock Owner; Self; Lumos Pharma, Inc. C. Smith: Employee; Self; Lumos Pharma, Inc. Stock Owner; Self; Lumos Pharma, Inc. E.L. Brincks: Employee; Self; Lumos Pharma, Inc. Stock Owner; Self; Lumos Pharma, Inc. J.C. McKew: None. D.B. Karpf: Employee; Self; Lumos Pharma, Inc. Stock Owner; Self; Lumos Pharma, Inc. M.O. Thorner: Consulting Fee; Self; Lumos Pharma, Inc. Stock Owner; Self; Lumos Pharma, Inc. Objective: To evaluate acute GH, IGF-1, AHV at 6 mos of treatment of iPGHD subjects. Background: LUM-201 is an investigational oral GH secretagogue (GHS) currently in 3 Phase 2 iPGHD trials. The LUM-201 predictive enrichment marker (PEM) may be used to identify patients previously diagnosed with iPGHD who are likely to respond to LUM-201. PEM positivity is defined as a baseline IGF-1 level >30 ng/mL and a peak GH of ≥5 ng/mL in response to a single 0.8 mg/kg LUM-201 dose. LUM-201, a potent, durable oral GHS agonist, acts on the GHS Receptor 1a in the hypothalamus and anterior pituitary. LUM-201 enhances the amplitude of endogenous GH pulsatile release over 24 hrs, while also acting as a functional antagonist of the somatostatin receptor. The increased IGF-1 and GH reach the growth plates and promote linear growth. Three advantages of LUM-201 as a potential therapeutic for iPGHD are that it is a small oral tablet, it enhances natural GH pulses over 24 hr, and GH release is subject to the endogenous negative feedback mechanisms, so serum IGF-1 is expected to remain within the normal range. Method: Each subject is screened with the PEM test, which includes determining the max GH concentration in the first 90 min after a single 0.8 mg/kg dose of LUM-201. Additionally, each of these PEM positive subjects was assessed for increasing doses of LUM-201 to induce further acute GH secretion on their first day of therapeutic dosing with either a 1.6 or 3.2 mg/kg dose. The first 10 subjects with 6 months of growth on LUM-201 (5 subjects on each dose) were evaluated on their IGF-1 levels and AHVs. Results: The mean (+SD, n) peak GH for the 0.8 mg/kg dose was 26.04 ng/mL (+10.6, 22), at the 1.6 mg/kg dose 35.50 ng/mL (+17.5, 9), and at a 3.2 mg/kg dose 38.34 ng/mL (+10.4, 8). Serum IGF-1 levels of the 5 subjects in each cohort were monitored at baseline and at 6 months of treatment. The mean (+ SD) serum IGF-1 levels showed a change from baseline of 84.6 ng/mL (+30.1) at 6 months for the 1.6 mg/kg cohort and 113.8 (+49.9) at the 3.2 mg/kg dose. The pretreatment HV were 4.9 (+ 0.4) at 1.6 mg/kg and 4.3 (+ 0.9) cm/year at 3.2 mg/kg respectively and the respective mean AHVs (+ SD) at 6 months were 7.14 cm/year (+0.65) and 8.60 cm/year (+1.22). The acute GH response demonstrated a dose response between the 0.8 and 1.6 mg/kg doses, but the 1.6 and 3.2 mg/kg doses produced similar GH responses. These two doses of LUM-201 induced comparable changes from baseline values of IGF-1 after 6 months of treatment. In addition to these pharmacodynamic changes, the AHVs generated from each dose also appear similar. Conclusion: LUM-201 generated the expected AHV in this naive iPGHD population. The dose-response for GH secretion after an initial dose of LUM-201 and increases from baseline of serum IGF-1 after 6 months of treatment suggest that 1.6 mg/kg/day is the optimum dose for efficacy and durability. The results from this small study are corroborated by the larger OraGrowtH210 study data. Presentation: Saturday, June 17, 2023

OR21-05 Low-dose Infigratinib, An Oral Selective Fibroblast Growth Factor Receptor (FGFR) Tyrosine Kinase Inhibitor, Demonstrates Activity In Murine Models Of Achondroplasia And Hypochondroplasia

Abstract Disclosure: E. Muslimova: Employee; Self; QED Therapeutics. Stock Owner; Self; QED Therapeutics. B. Demuynck: None. L. Loisay: None. M. Paull: Employee; Self; QED Therapeutics. Stock Owner; Self; QED Therapeutics. L. Legeai-Mallet: None. Background: FGFR3 is a negative regulator of bone growth and gain-of-function mutations in the FGFR3 gene result in different skeletal osteochondrodysplasias, including achondroplasia (ACH) and hypochondroplasia (HCH). ACH is the most common form of rhizomelic short stature, affecting between 1 in 15,000 and 1 in 30,000 live births worldwide. The incidence of HCH is thought to be approximately the same as ACH. Currently, there is only one approved therapy for ACH and no approved therapies for HCH. Previously we demonstrated that the oral, selective FGFR 1-3 tyrosine kinase inhibitor (TKI) infigratinib has preclinical activity in a mouse model mimicking ACH (Fgfr3Y367C/+). We hypothesized that infigratinib could improve defective endochondral ossification and ameliorate the phenotype in a mouse model of HCH (Fgfr3N534K/+), which is the first and only HCH mouse model that expresses the most frequent human heterozygous mutation p.Asn540Lys.Methods:Fgfr3N534K/+ mice were given subcutaneous injections of infigratinib or vehicle control every 3 days (1 mg/kg) or daily (1 mg/kg) for 15 days (post-natal day [PND] 4-19) or 21 days (PND 3-24), respectively. Results:Fgfr3N534K/+ mice treated with 1 mg/kg infigratinib daily for a total of 21 days showed a statistically significant increase in appendicular and axial skeleton (tibia +3.18%, femur +3.16%, humerus +3.04%, ulna +2.94%, radius +3.01%). Treatment with infigratinib modified skull shape, length of the mandible, and foramen magnum length (+3.72%). Cartilage growth plate organization, in particular the hypertrophic chondrocyte area, was modified, indicating that chondrocyte differentiation is improved. These results, although of a lower magnitude, are in line with those previously reported from the Fgfr3Y367C/+ mouse model of ACH, which showed a statistically significant improvement in upper limbs (humerus +7.3%, ulna +11.1%, radius +14.2 %), lower limbs (femur +10.4%, tibia +16.8%), and foramen magnum length (+3.76%), when infigratinib was administered at a dose of 0.5 mg/kg. Conclusions: Low-dose treatment with infigratinib in the Fgfr3N534K/+ HCH mouse model ameliorated the clinical hallmarks of human pathology and significantly lengthened the axial skeleton, the appendicular skeleton and improved foramen magnum length. Development of infigratinib in ACH is currently ongoing. These latest findings with infigratinib in this mouse model of HCH support the rationale for targeting FGFR3 with a specific TKI such as infigratinib for the treatment of children with HCH. Presentation: Saturday, June 17, 2023

DIAGNOSTIC IMAGING AND OROTRACHEAL INTUBATION IN CLINICALLY HEALTHY WILD SUNDA PANGOLINS (MANIS JAVANICA) IN SINGAPORE.

Pangolins are amongst the most overexploited species in the world and all eight species of pangolins are threatened with extinction. These animals are rare in zoological collections and often suffer high mortality rates in captivity. Maintaining healthy populations in captivity has become more important with the declining populations in the wild, but knowledge of veterinary care of these animals is limited. Interpreting radiography and ultrasonography images in a patient can be challenging without knowledge of normal findings. The Wildlife Healthcare and Research Center (WHRC) at Mandai Wildlife Reserve (MWR) admits an average of 25 Sunda pangolins (Manis javanica) annually, which is a Critically Endangered species native to Singapore. All the pangolins are triaged on admission and anesthetized for a health assessment before release into the wild. Endotracheal intubation using an otoscope and stylet is a novel technique in the species that has been developed and is commonly performed with these pangolins. A retrospective study was done on 20 clinically healthy wild pangolins to determine normal ultrasonography and radiography findings in the species. Notable findings include the presence of radio-opaque particles in the stomachs of all pangolins, the presence of free fluid cranial to the left kidney (13/20), a spleen with multifocal hypoechoic regions (6/20), and open epiphyseal plates of long bones even in large individuals weighing as heavy as 6.8 kg. Ultrasonographic images and measurements of kidney, spleen, and adrenal gland sizes as well as intestinal, gallbladder, and urinary bladder wall thickness were also described. These diagnostic imaging findings can advance the veterinary care of captive and wild pangolins.

Robust hyperparameter tuned deep Elman neural network for the diagnosis of osteosarcoma on histology images

Osteosarcomas are a type of bone tumour that can develop anywhere in the bone but most typically do so around the metaphyseal growth plates at the ends of long bones. Death rates can be lowered by early detection. Manual osteosarcoma identification can be difficult and requires specialised knowledge. With the aid of contemporary technology, medical photographs may now be automatically analysed and categorised, enabling quicker and more effective data processing. This paper proposes a novel hyperparameter-tuned deep learning (DL) approach for predicting osteosarcoma on histology images with effective feature selection mechanism which aims to improve the prediction accuracy of the classification system for bone tumor detection. The proposed system mainly consists of ‘6’ phases: data collection, preprocessing, segmentation, feature extraction, feature selection, and classification. Firstly, the dataset of histology images is gathered from openly available sources. Then Median Filtering (MEF) is utilized as the preprocessing step that enhances the quality of the input images for accurate prediction by eliminating unwanted information from them. Afterwards, the pre-processed image was segmented using Harmonic Mean-based Otsu Thresholding (HMOTH) approach to obtain the tumor-affected regions from the pre-processed data. Then the features from the segmented tumor portions are extracted using the Self-Attention Mechanism-based MobileNet (SAMMNet) model. A Van der Corput sequence and Adaptive Inertia Weight included Reptile Search Optimization Algorithm (VARSOA) is used to select the more relevant features from the extracted features. Finally, a Hyperparameter-Tuned Deep Elman Neural Network (HTDENN) is utilized to diagnose and classify osteosarcoma, in which the hyperparameters of the neural network are obtained optimally using the VARSOA. The proposed HTDENN attains the higher accuracy of 0.9531 for the maximum of 200 epochs, whereas the existing DENN, MLP, RF, and SVM attains the accuracies of 0.9492, 0.9427, 0.9413, and 0.9387. Likewise, the proposed model attains the better results for precision (0.9511), f-measure (0.9423), sensitivity (0.9345) and specificity (0.9711) than the existing approaches for the maximum of 200 epochs. Simulation outcomes proved that the proposed model outperforms existing research frameworks for osteosarcoma prediction and classification.

A case of vitamin-D dependent type-1A rickets

Abstract Rickets is a disease of growing bones characterized by softening of bones as a result of defective mineralization of cartilage in the epiphyseal growth plate. The predominant cause is a deficiency or impaired metabolism of vitamin D. Some forms of rickets do not respond to regular doses of cholecalciferol, which leads to suspicion of vitamin D-dependent rickets (VDDR). VDDR is of two types: type I is due to defective renal tubular 25-hydroxyvitamin D 1-α hydroxylase, and type II is due to end-organ resistance to the active metabolite of vitamin D. Here, we describe a child with seizures and calcipenic rickets with biochemical profile suggestive of VDDR type 1 worsened by phenytoin which responded completely to calcium and calcitriol supplementation. Whole exome sequencing revealed a heterozygous missense mutation in exon 7 of the TRPV4 gene (chromosome 12,c.1292C>A), whereas no mutations in CYP2R1, CYP27B1, VDR, and CYP3A4 were detected.

Distraction Osteogenesis for the Brachytelephalangic Thumb - A Case Report.

Brachytelephalangy is a congenital condition characterised by the shortening of the distal phalanges, which affects appearance but does not cause severe functional disability. Therefore, most hand surgeons do not consider it to require surgical treatment, and there are limited options to improve the appearance of the affected digits. We present the case of a 55-year-old male patient with congenital brachytelephalangy of the thumb, who underwent a bone lengthening procedure using distraction osteogenesis with the Ilizarov minifixator. The distal phalanx was carefully osteotomised and gradually lengthened up to 5 mm with no adverse events observed. The patient was satisfied with the natural appearance of his thumb after the surgery. This gradual callus distraction method is a radical solution for people with brachytelephalangy, particularly after epiphyseal closure and can manage the external fixator on their own. Level of Evidence: Level V (Therapeutic).

Vitamin C Deficiency Deteriorates Bone Microarchitecture and Mineralization in a Sex-Specific Manner in Adult Mice.

Vitamin C (VitC) is essential for bone health, and low VitC serum levels increase the risk for skeletal fractures. If and how VitC affects bone mineralization is unclear. Using micro-computed tomography (μCT), histologic staining, as well as quantitative backscattered electron imaging (qBEI), we assessed the effects of VitC on femoral structure and microarchitecture, bone formation, and bone mineralization density distribution (BMDD) in the VitC incompetent Gulo-/- mouse model and wild-type mice. In particular, VitC-supplemented, 20-week-old mice were compared with age-matched counterparts where dietary VitC intake was excluded from week 15. VitC depletion in Gulo-/- mice severely reduced cortical thickness of the diaphyseal shaft and bone volume around the growth plate (eg, bone volume of the primary spongiosa -43%, p < 0.001). Loss of VitC also diminished the amount of newly formed bone tissue as visualized by histology and calcein labeling of the active mineralization front. BMDD analysis revealed a shift to higher calcium concentrations upon VitC supplementation, including higher average (~10% increase in female VitC deficient mice, p < 0.001) and peak calcium concentrations in the epiphyseal and metaphyseal spongiosa. These findings suggest higher bone tissue age. Importantly, loss of VitC had significantly more pronounced effects in female mice, indicating a higher sensitivity of their skeleton to VitC deficiency. Our results reveal that VitC plays a key role in bone formation rate, which directly affects mineralization. We propose that low VitC levels may contribute to the higher prevalence of bone-degenerative diseases in females and suggest leveraging this vitamin against these conditions. © 2023 American Society for Bone and Mineral Research (ASBMR).

Molecular mechanisms of long bone growth and chondrocyte regulation: A narrative review

Long bone growth is a fundamental determinant of final height. Growth, metabolism, and differentiation of chondrocytes, which are the key cellular players in this process, are regulated by systemic hormones, local factors, and cellular signaling pathways. This review provides an overview of the structural aspects of the growth plate, factors influencing chondrocyte function, and their impact on longitudinal bone growth. Systemic factors, including growth hormone, sex hormones, thyroid hormone, glucocorticoids, leptin, and insulin significantly affect chondrocyte proliferation and hypertrophy. Local factors, including transcription factors such as SRY-box 9 protein (SOX9), Runt-related transcription factor 2 (RUNX2), and bone morphogenetic proteins (BMPs), along with signaling pathways such as the Wnt pathway, play critical roles in chondrocyte proliferation and differentiation. These factors regulate gene expression, cell differentiation, and extracellular matrix synthesis. Additionally, Indian hedgehog (Ihh) and C-type natriuretic peptide (CNP) are involved in the complex signaling network governing chondrocyte function. Understanding molecular mechanisms underlying normal growth plate function has provided valuable insights into the genetic defects that impact growth and foundation for the development of effective therapeutic strategies for individuals with growth disorders.

The Risk of Growth Disturbance Is Low After Pediatric Anterior Cruciate Ligament Reconstruction With a Femoral Growth Plate Sparing Technique

To evaluate radiological tibial and femoral length and axis growth disturbances, as well as clinical outcome in skeletal immature anterior cruciate ligament reconstruction (ACLR) patients treated with a femoral growth plate-sparing ACLR technique. Skeletally immature patients who underwent operation between 2013 to 2019 with ALCR using the femoral growth plate-sparing technique were investigated with follow-up after growth plate closure. The inclusion criteria were isolated ACL rupture in patients with open physis in the distal femur and proximal tibia seen at plain radiography. The minimum follow-up time was 29 months. Patients were evaluated with full extremity radiographs measuring limb length discrepancy and coronal knee alignment compared to contralateral leg, as well as clinical evaluation with Rolimeter measurements and the Knee Osteoarthritis Outcome Score (KOOS), the International Knee Documentation Committee subjective knee form (IKDC), and Tegner Activity Scale scores. Sixty-five patients were examined with radiography, and 52 patients were assessed with clinical examination. The mean follow-up time was 68 (range, 29-148) months. No limb-length discrepancy (-0.65 mm [confidence interval {CI},-2.21 to 0.92]) or angular deformity at tibia (-0.25° [CI,-0.78° to 0.28°]) was found. There was a small but statistically significant different angular deformity at the distal femur compared to the contralateral leg (-1.51° [CI,-2.31 to-0.72]) at follow-up. The side-to-side difference in knee laxity at follow-up was 2.4 mm. At follow-up the KOOS Sport, KOOS Quality of Life (QoL), IKDC, and Tegner scores were 80, 75, 86, and 5, respectively. Sixty-seven percent of the patients met the Patient Acceptable Symptom State, and 52% reported results exceeding the KOOS Sport MCID Level and 69% the KOOS QoL level. Femoral physis-sparing ALCR is associated with a low risk of alignment and length disturbances. The technique provides otherwise good subjective clinical outcome and knee stability. Level IV, therapeutic case series.

Dose-Effect of Proton and Photon Craniospinal Irradiation on Vertebral Growth in Pediatric Patients with Medulloblastoma

Craniospinal irradiation (CSI) directly damages vertebral growth plates causing skeletal dysplasia leading to reduced height in pediatric long-term survivors. The objective of this study is to quantify the adjusted effect of CSI on standing and sitting height by radiation dose and modality in children. Two hundred sixty-five patients (M/F 169/96) were treated at a single institution on a clinical and molecular risk-directed trial for medulloblastoma (NCT01878617) using proton or photon therapy. Three CSI dose regimens were evaluated: 15 Gy (n = 31), 23.4 Gy (n = 103), ≥36 Gy (n = 131). Vertebral body dose was limited to 18-20 CGE for 23.4 Gy or 36 Gy proton therapy. All patients received post-CSI protocol-specified chemotherapy. Non-parametric tests were applied for baseline patient comparison. Changes in growth over time were calculated using random coefficients models using patient-specific intercepts and slopes. Dose-effects were modeled for ages 5, 10, and 18 years. Age at CSI and race were similar between the three dose levels. Females most often received 23.4 Gy and males ≥36 Gy (p = 0.001). Higher CSI doses were associated with photon therapy (p<0.001). Median follow-up was 3 years (range 0.1-7.1). Annual growth rate was significantly different between 15 Gy (3.66 cm/year) and the higher dose levels of 23.4 Gy (2.81 cm/year, p = 0.0389) and ≥36 Gy (2.46 cm/year, p = 0.0032). Lower annual growth rate in females (vs. males, p = 0.0331) was observed in models for those aged 5 (-0.17 cm/year), 10 (-0.35 cm/year), and 18 years (-0.62 cm/year). In multivariate analysis, modelled annual growth rate was dose-dependent at ages 5 and 10 years. The differences were, respectively, 1.68 cm/year between 15 and 23.4 Gy (p = 0.0005) and 0.98 cm/year between 23.4 and ≥36 Gy (p = 0.0002), and 1.13 cm/year between 15 and 23.4 Gy (p = 0.0002) and 0.68 cm/year between 23.4 and ≥36 Gy (p = 0.0003). Radiation modality did not impact standing height over time significantly. Annual sitting height growth was 2.34, 1.67 and 1.1 cm/year for the three dose levels (p<0.0001-0.001). In the multivariate model, a 5-year-old receiving 15 or 23.4 Gy had similar annual sitting height growth, but not when 23.4 Gy was compared to ≥36 Gy (0.83 cm/year, p<0.0001). In a separate model for a patient aged 10 years, there was a difference comparing all CSI regimens (0.81 cm/year, p<0.0001, 15 vs 23.4 Gy; 0.54 cm/year, p = 0.0002, 23.4 vs ≥36 Gy). Sitting height growth was affected by CSI dose at age 18 years, with a difference of 2.2 cm/year between 15 vs 23.4 Gy (p = 0.0013), and no difference between 23.4 and ≥36 Gy. Annual growth rates show a dose-response relationship, independent of treatment modality. A dose-response in sitting height growth rate is seen at any age, while the annual standing height growth rate was only affected by CSI dose in 5- and 10-year-olds. While all CSI doses had a significant impact on the annual standing height, sitting height growth rates approximated normal values for those treated with a low CSI dose.

Intraventricular SHH inhibition proves efficient in SHH medulloblastoma mouse model and prevents systemic side effects.

Medulloblastoma (MB) is the most common malignant brain tumor in children and requires intensive multimodal therapy. Long-term survival is still dissatisfying and, most importantly, survivors frequently suffer from severe treatment-associated morbidities. The sonic hedgehog pathway (SHH) in SHH MB provides a promising target for specific therapeutic agents. The small molecule Vismodegib allosterically inhibits SMO, the main upstream activator of SHH. Vismodegib has proven effective in the treatment of MB in mice and in clinical studies. However, due to irreversible premature epiphyseal growth plate fusions after systemic application to infant mice and children, its implementation to pediatric patients has been limited. Intraventricular Vismodegib application might provide a promising novel treatment strategy for pediatric medulloblastoma patients. Infant medulloblastoma-bearing Math1-cre::Ptch1Fl/Fl mice were treated with intraventricular Vismodegib in order to evaluate efficacy on tumor growth and systemic side effects. We show that intraventricular Vismodegib treatment of Math1-cre::Ptch1Fl/Fl mice leads to complete or partial tumor remission only 2 days after completed treatment. Intraventricular treatment also significantly improved symptom-free survival in a dose-dependent manner. At the same time, intraventricular application prevented systemic side effects in the form of anatomical or histological bone deformities. We conclude that intraventricular application of a SHH pathway inhibitor combines the advantages of a specific treatment agent with precise drug delivery and might evolve as a promising new way of targeted treatment for SHH MB patients.

Research Progress of Drinking Water and Trace Elements in KBD Area

Kaschin-beck disease (KBD) is an endemic, chronic, and deformable osteochondral disease characterized by multiple degenerations and deep cell necrosis of epiphysis, epiphysis, and articular cartilage. The disease mainly affects children and adolescents aged 5-15, is concentrated in northeast and southwest China, involving 15 provinces, and extends into southeastern Siberia and North Korea. Although the etiology and pathogenesis of KBD are still not very clear, in recent years, more breakthroughs have been made in the supplement and update of its biogeochemical theory, especially in the analysis of hydrochemical characteristics and the study of the role of selenium and iodine in the pathogenic factors of KBD. Therefore, the present research results on the environmental geographical factors of Kashin-beck disease are reviewed in this paper.

Embryonic cranial cartilage defects in the Fgfr3Y367C /+ mouse model of achondroplasia.

Achondroplasia, the most common chondrodysplasia in humans, is caused by one of two gain of function mutations localized in the transmembrane domain of fibroblast growth factor receptor 3 (FGFR3) leading to constitutive activation of FGFR3 and subsequent growth plate cartilage and bone defects. Phenotypic features of achondroplasia include macrocephaly with frontal bossing, midface hypoplasia, disproportionate shortening of the extremities, brachydactyly with trident configuration of the hand, and bowed legs. The condition is defined primarily on postnatal effects on bone and cartilage, and embryonic development of tissues in affected individuals is not well studied. Using the Fgfr3Y367C/+ mouse model of achondroplasia, we investigated the developing chondrocranium and Meckel's cartilage (MC) at embryonic days (E)14.5 and E16.5. Sparse hand annotations of chondrocranial and MC cartilages visualized in phosphotungstic acid enhanced three-dimensional (3D) micro-computed tomography (microCT) images were used to train our automatic deep learning-based 3D segmentation model and produce 3D isosurfaces of the chondrocranium and MC. Using 3D coordinates of landmarks measured on the 3D isosurfaces, we quantified differences in the chondrocranium and MC of Fgfr3Y367C/+ mice relative to those of their unaffected littermates. Statistically significant differences in morphology and growth of the chondrocranium and MC were found, indicating direct effects of this Fgfr3 mutation on embryonic cranial and pharyngeal cartilages, which in turn can secondarily affect cranial dermal bone development. Our results support the suggestion that early therapeutic intervention during cartilage formation may lessen the effects of this condition.

Anterior Cruciate Ligament Injury in Young Athletes

Abstract The incidence of anterior cruciate ligament (ACL) tears is increasing in youth, with rates higher in female athletes. The injury is usually noncontact; rather, a quick change of direction induces a “popping” sensation. The injury will be swollen, bruised, and painful, and there will be a limited range of motion and an inability to bear weight. The Lachman test, pivot test (used when patients are anesthetized), and anterior drawer test help diagnose ACL injuries. ACL injuries are categorized by severity as Grade I, II, or III sprains. Prompt first aid care can help reduce pain and swelling using the RICE method, an acronym for rest, ice, compression, and elevation. Medical treatment with stabilization braces might be enough to promote a return-to-normal function, but surgical options are usually required for Grade II and III injuries. Reconstructive surgeries can use an autograft or allograft, but consideration of the growth plates in children might delay the surgery. Postoperative therapy helps reduce edema and immobility. It is essential that injury prevention programs are implemented. Prevention programs and increased awareness of parents and coaches are called for with the population of youth athletes.

A Combined Surgical Approach for Recurrent Patellar Dislocation in Adolescents With Patella Alta and Increased Tibial Tuberosity-Trochlear Groove Distance: Improved Clinical Outcomes but Decreased Posterior Tibial Slopes in Skeletally Immature Patients at Minimum 4-Year Follow-Up

Purpose(1) To report the clinical and radiological outcomes of a surgical technique combining anatomic medial patellofemoral ligament (MPFL) reconstruction and tibia tuberosity transfer in adolescents with patella alta and elevated tibial tuberosity-trochlear groove (TT-TG) distance, in the treatment of recurrent patellar dislocation (RPD); (2) To investigate the potential risks of growth arrest or developmental deformities associated with this combined technique. MethodsMedical records of patients underwent the combined surgery were reviewed from 2015 to 2019. This study included adolescents aged between 14 and 18 years with a Caton-Deschamps index (CDI) greater than 1.30 and TT-TG distance greater than 20mm, with a minimum follow-up of 4 years. Radiological examinations including lateral views and full-length posteroanterior standing radiographs were investigated to assess patella height by CDI, posterior tibia slope (PTS) angle, side-to-side difference (SSD) in bone length, and lower extremity alignment by hip-knee-ankle (HKA) angle; CT-scans and MRI profiles were investigated to evaluate TT-TG distance and staging of growth plate closure. Other evaluations included preoperative and postoperative physical examination, Kujala score, and Tegner activity score. The patients were stratified into 3 subgroups according to a MRI-based staging system of the growth plate closure, and each outcomes were analyzed. A cohort-specific minimal clinically important difference (MCID) estimation was performed using standard error of measurement. ResultsThe average age at the time of surgery was 16.1 years (range, 14.1-17.8). The average follow-up was 5.6 years (range, 4.0-7.6). No recurrent dislocation occurred, no clinically significant deformity or axis deviation was encountered. Postoperative patellar height by CDI was 1.00±0.11 (range, 0.81-1.15). No significant differences were found in pre- and postoperative HKA angle and SSD in femur/tibia length among all subgroups. A significantly decreased PTS angle was found in patients with open growth plates, from 10.2±1.7° preoperatively to 8.1±1.0° postoperatively (P=.015). The Kujala score and Tegner score both significantly improved, from 65.5±13.9 preoperatively to 90.4±7.2 postoperatively in Kujala score (P <0.001), and from 4.0±1.1 preoperatively to 4.7±1.3 postoperatively in Tegner score (P <0.001). Of the whole cohort, 63.1%, 100%, 47.1% and 94.1% patients achieved the MCID for PTS angle, CDI, Tegner score, and Kujala score respectively. ConclusionThis combined technique is safe and effective in treating RPD in skeletally mature adolescents with concurrent patella alta (CDI > 1.30) and TT-TG distance > 20mm, permitting patients to have improved knee function and low complication rates. Nonetheless, patients with open growth plates demonstrated a decrease in PTS, which might predispose the knee to recurvatum and osteoarthritis in the long-term. Study DesignRetrospective therapeutic case series; level of evidence, Ⅳ.

Chondrocyte targeting gold nanoparticles protect growth plate against inflammatory damage by maintaining cartilage balance

Cartilage destruction caused by inflammation is a clinical challenge. Many studies have investigated cartilage destruction in adults, but little research was conducted on children. In this study, the protective effect of gold nanoparticles (AuNPs) on the cartilage of children was realized by counteracting chondrocyte apoptosis and extracellular matrix (ECM) degradation in a young mouse model of lipopolysaccharide (LPS)-induced growth plate (GP) cartilage damage. Initially, engineered AuNPs can be efficiently absorbed by chondrocytes, approximately 20 times the amount absorbed by macrophages, resulting in a 29% ± 0.05% increase in chondrocyte viability. Then, AuNPs exposure significantly reduced the release of inflammatory cytokines and secretion of ECM degradation factors induced by LPS. Subsequently, AuNPs were applied to resist LPS-induced cartilage destruction in young mice. AuNPs inhibited the formation of gaps, without chondrocytes and extracellular matrix, between the proliferative and hypertrophy zones of the GP cartilage, and the gaps were noticeable in the LPS group. This finding can be attributed to the capability of AuNPs to reduce the LPS-induced apoptosis rate of mouse chondrocytes by 72.38% and the LPS-induced ECM degradation rate by 70.89%. Further analysis demonstrated that remission is partly due to AuNPs’ role in maintaining the balance of catabolic and anabolic factors in the ECM. Altogether, these findings indicate that AuNPs can partially protect the cartilage of children from inflammatory damage by suppressing chondrocyte apoptosis and ECM degradation.

Local BMP2 hydrogel therapy for robust bone regeneration in a porcine model of Legg-Calvé-Perthes disease

Legg-Calvé-Perthes disease is juvenile idiopathic osteonecrosis of the femoral head (ONFH) that has no effective clinical treatment. Previously, local injection of bone morphogenetic protein-2 (BMP2) for ONFH treatment showed a heterogeneous bone repair and a high incidence of heterotopic ossification (HO) due to the BMP2 leakage. Here, we developed a BMP2-hydrogel treatment via a transphyseal bone wash and subsequential injection of BMP2-loaded hydrogel. In vitro studies showed that a hydrogel of gelatin-heparin-tyramine retained the BMP2 for four weeks. The injection of the hydrogel can efficiently prevent leakage. With the bone wash, the injected hydrogel had a broad distribution in the head. In vivo studies on pigs revealed that the BMP2-hydrogel treatment produced a homogeneous bone regeneration without HO. It preserved the subchondral contour and restored the subchondral endochondral ossification, although it increased growth plate fusions. In summary, the study demonstrated a promising BMP2-hydrogel treatment for ONFH treatment, especially for teenagers.

Muscle forces acting on the greater trochanter lead to a dorsal warping of the apophyseal growth plate.

The apophyseal growth plate of the greater trochanter, unlike most other growth plates of the human body, exhibits a curved morphology that results in a divergent pattern resembling an open crocodile mouth on plain antero-posterior radiographs. To quantify the angular alignment of the growth plate and to draw conclusions about the function of the muscles surrounding it, we analyzed 57 MRI images of 51 children and adolescents aged 3-17 years and of six adults aged 18-52 years. We measured the angulation of the plate relative to the horizontal plane (AY angle) and the trajectories of the muscles attaching to the greater trochanter of the proximal femur. From anterior to posterior, the AY angle shows a decrease of 33.44°. In the anterior third, the cartilage is angled at a mean of 51.64°, and in the posterior third, the mean angulation is 18.6°. This indicates that the cartilage in the anterior region of the greater trochanteric apophysis is subject to more vertically oriented force vectors compared to the posterior region, as the growth plates align perpendicular to the force vectors acting on them. Combining the measured muscle trajectories with the physiological cross-sectional areas (PCSA) available from the literature revealed that, in addition to the known internal and external lateral traction ligament systems, a third, dorsally located traction ligament system exists that may be responsible for the dorsal deformation of the AY angle.

Anterior Talo-Fibular Ligament Reconstruction With InternalBrace™ for Chronic Lateral Ankle Instability in Pediatric Patients.

Ankle injuries and instability in a pediatric age group are common problems and often underreported. The injuries can range from a relatively benign ankle sprain to pain-limiting ankle instability that can inhibit the child from participating in sporting activities. However, conservative management and physiotherapy are the mainstay of treatment; a small group of patients present with persistent instability and benefit from surgical intervention in lateral ligament reconstruction. Our study looked at pediatric patients who had instability following failed conservative management. Retrospective analysis of 14 patients with Chronic lateral Ankle instability (CLAI) who underwent Modified Brostrom-Gould repair( MBG) with or without Internal brace augmentation between January 2015 and October 2020. Patients were evaluated for the visual analogue scale (VAS), Manchester-oxford foot questionnaire (MOxFQ), subjective satisfaction, and return to preinjury activity level. Pain score improved from 8 (average 5-9) to 1 (average 0-3) following surgery. Functional assessment was made by assessing the Manchester Oxford questionnaire pre-and postoperatively. MOxFQ scores improved from 64 (8 SD) to 7 (15 SD). Thirteen of fourteen patients returned to normal sporting activities at the final follow-up. Modified Brostrom-Gould with InternalBrace™ augmentation is an excellent procedure for chronic lateral ligament injuries in the Paediatric population. It can be safely performed if we respect the anatomy and the physeal growth plate. It allows faster rehabilitation and return to preinjury activity level.