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Introduction: Femoral deformities are highly prevalent in children with cerebral palsy (CP) and can have a severe impact on patients' gait abilities. While the mechanical stress regime within the distal femoral growth plate remains underexplored, understanding it is crucial given bone's adaptive response to mechanical stimuli. We quantified stresses at the distal femoral growth plate to deepen our understanding of the relationship between healthy and pathological gait patterns, internal loading, and femoral growth patterns., Methods: This study included three-dimensional motion capture data and magnetic resonance images of 13 typically developing children and twelve participants with cerebral palsy. Employing a multi-scale mechanobiological approach, integrating musculoskeletal simulations and subject-specific finite element analysis, we investigated the orientation of the distal femoral growth plate and the stresses within it. Limbs of participants with CP were grouped depending on their knee flexion kinematics during stance phase as this potentially changes the stresses induced by knee and patellofemoral joint contact forces., Results: Despite similar growth plate orientation across groups, significant differences were observed in the shape and distribution of growth values. Higher growth rates were noted in the anterior compartment in CP limbs with high knee flexion while CP limbs with normal knee flexion showed high similarity to the group of healthy participants., Discussion: Results indicate that the knee flexion angle during the stance phase is of high relevance for typical bone growth at the distal femur. The evaluated growth rates reveal plausible results, as long-term promoted growth in the anterior compartment leads to anterior bending of the femur which was confirmed for the group with high knee flexion through analyses of the femoral geometry. The framework for these multi-scale simulations has been made accessible on GitHub, empowering peers to conduct similar mechanobiological studies. Advancing our understanding of femoral bone development could ultimately support clinical decision-making., Competing Interests: Declaration of Competing Interest We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome. We, further, confirm that the manuscript has been read and approved by all named authors and that there are no other persons who satisfied the criteria for authorship but are not listed., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Slipped capital femoral epiphysis is a prevalent pediatric hip disorder. Recent studies suggest the spine's sagittal profile may influence the proximal femoral growth plate's slippage, an aspect not extensively explored. This study utilizes finite element analysis to investigate how various spinopelvic alignments affect shear stress and growth plate slip., Methods: A finite element model was developed from CT scans of a healthy adult male lumbar spine, pelvis, and femurs. The model was subjected to various sagittal alignments through reorientation. Simulations of two-leg stance, one-leg stance, walking heel strike, ascending stairs heel strike, and descending stairs heel strike were conducted. Parameters measured included hip joint contact area, stress, and maximum growth plate Tresca (shear) stress., Findings: Posterior pelvic tilt cases indicated larger shear stresses compared to the anterior pelvic tilt variants except in two leg stance. Two leg stance resulted in decreases in the posterior tilted pelvi variants hip contact and growth plate Tresca stress compared to anterior tilted pelvi, however a combination of posterior pelvic tilt and high pelvic incidence indicated larger shear stresses on the growth plate. One leg stance and heal strike resulted in higher shear stress on the growth plate in posterior pelvic tilt variants compared to anterior pelvic tilt, with a combination of posterior pelvic tilt and high pelvic incidence resulting in the largest shear., Interpretation: Our findings suggest that posterior pelvic tilt and high pelvic incidence may lead to increased shear stress at the growth plate. Activities performed in patients with these alignments may predispose to biomechanical loading that shears the growth plate, potentially leading to slip., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The purpose of this study was to investigate growth plate dynamics in surgical and loading murine models of osteoarthritis, to understand whether abnormalities in these dynamics are associated with osteoarthritis development. 8-week-old C57BL/6 male mice underwent destabilisation of medial meniscus (DMM) ( n = 8) surgery in right knee joints. Contralateral left knee joints had no intervention (controls). In 16-week-old C57BL/6 male mice ( n = 6), osteoarthritis was induced using non-invasive mechanical loading of right knee joints with peak force of 11N. Non-loaded left knee joints were internal controls. Chondrocyte transiency in tibial articular cartilage and growth plate was confirmed by histology and immunohistochemistry. Tibial subchondral bone parameters were measured using microCT and correlated to 3-dimensional (3D) growth plate bridging analysis. Higher expression of chondrocyte hypertrophy markers; Col10a1 and MMP13 were observed in tibial articular cartilage chondrocytes of DMM and loaded mice. In tibial growth plate, Col10a1 and MMP13 expressions were widely expressed in a significantly enlarged zone of proliferative and hypertrophic chondrocytes in DMM ( p =0.002 and p <0.0001, respectively) and loaded (both p <0.0001) tibiae of mice compared to their controls. 3D quantification revealed enriched growth plate bridging and higher bridge densities in medial compared to lateral tibiae of DMM and loaded knee joints of the mice. Growth plate dynamics were associated with increased subchondral bone volume fraction (BV/TV; %) in medial tibiae of DMM and loaded knee joints and epiphyseal trabecular bone volume fraction in medial tibiae of loaded knee joints. The results confirm articular cartilage chondrocyte transiency in a surgical and loaded murine models of osteoarthritis. Herein, we reveal spatial variation of growth plate bridging in surgical and loaded osteoarthritis models and how these may contribute to anatomical variation in vulnerability of osteoarthritis development., Competing Interests: The research leading to these results has received technical support from 3Dmagination Ltd, Didcot, UK. KM is co-founder and director of 3Dmagination Ltd in Oxfordshire, UK, a company which provides training and consultancy in 3D and 4D imaging. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Samvelyan, Madi, Törnqvist, Javaheri and Staines.)

Sandhoff disease (SD) is caused by decreased function of the enzyme β-N-acetylhexosaminidase, resulting in accumulation of GM2 ganglioside in tissues. Neural tissue is primarily affected and individuals with the infantile form of the disease generally do not survive beyond 4 years of age. Current treatments address neurometabolic deficits to improve lifespan, however, this extended lifespan allows clinical disease to become manifest in other tissues, including the musculoskeletal system. The impact of SD on bone and joint tissues has yet to be fully determined. In a feline model of infantile SD, animals were treated by intracranial injection of adeno-associated virus vectors to supply the central nervous system with corrective levels of hexosaminidase, resulting in a twofold to threefold increase in lifespan. As treated animals aged, signs of musculoskeletal disease were identified. The present study characterized bone and joint lesions from affected cats using micro-computed tomography and histology. All affected cats had similar lesions, whether or not they were treated. SD cats displayed a significant reduction in metaphyseal trabecular bone and markedly abnormal size and shape of epiphyses. Abnormalities increased in severity with age and appear to be due to alteration in the function of chondrocytes within epiphyseal cartilage, particularly the articular-epiphyseal complex. Older cats developed secondary osteoarthritic changes. The changes identified are similar to those seen in humans with mucopolysaccharidoses. Statement of clinical significance: the lesions identified will have significant implications on the quality of life of individuals whose lifespans are extended due to treatments for the primary neurological effects of SD., (© 2020 Orthopaedic Research Society. Published by Wiley Periodicals LLC.)

Background: Cessation of statural growth occurs with radiographic closure of the growth plates, radiographically defined as bone age (BA) 15 years in females and 17 in males., Methods: We determined the frequency of continued growth and compared the total height gain beyond the time of expected growth plate closure and the chronological age at achievement of final adult height in Crohn's disease (CD) vs ulcerative colitis (UC) and described height velocity curves in inflammatory bowel disease (IBD) compared with children in the National Health and Nutrition Examination Survey (NHANES). We identified all females older than chronological age (CA) 15 years and males older than CA 17 years with CD or UC in the ImproveCareNow registry who had height documented at ≥3 visits ≥6 months apart., Results: Three thousand seven patients (48% female; 76% CD) qualified. Of these patients, 80% manifested continued growth, more commonly in CD (81%) than UC (75%; P = 0.0002) and in females with CD (83%) than males with CD (79%; P = 0.012). Median height gain was greater in males with CD (1.6 cm) than in males with UC (1.3 cm; P = 0.0004), and in females with CD (1.8 cm) than in females with UC (1.5 cm; P = 0.025). Height velocity curves were shifted to the right in patients with IBD vs NHANES., Conclusions: Pediatric patients with IBD frequently continue to grow beyond the time of expected growth plate closure. Unexpectedly, a high proportion of patients with UC exhibited continued growth, indicating delayed BA is also common in UC. Growth, a dynamic marker of disease status, requires continued monitoring even after patients transition from pediatric to adult care., (© 2020 Crohn’s & Colitis Foundation. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: The purpose of this study was to characterize the incidence of growth disturbance following intra-articular distal radius fractures in skeletally immature patients and to assess early radiographic and functional outcomes., Methods: A retrospective investigation of pediatric patients with intra-articular distal radius fractures between 1997 and 2012 at a single institution was performed. Pathologic fractures and fractures in patients with closed physes were excluded. In total, 28 patients (24 males, 4 females), with a mean age of 13.8 years and mean follow-up of 31.7 months, met inclusion criteria. Fractures were categorized according to the Salter-Harris classification, and all radiographs were assessed for evidence of physeal disturbance. Information regarding treatment and early clinical results were obtained from a medical record review. Functional outcomes using the Disabilities of the Arm, Shoulder, and Hand (DASH) and Modified Mayo Wrist Score (MMWS) were collected. Fisher exact test was used to compare the incidence of physeal arrest in the study population to previously published rates of physeal arrest in extra-articular fractures involving the distal radius. Because the data were not parametrically distributed, the Mann-Whitney-Wilcoxon test was used to compare those who did and did not develop physeal arrest., Results: Of the 28 patients, 9 (32%) sustained Salter-Harris III fractures and 19 (68%) sustained Salter-Harris IV fractures. Growth disturbance occurred in 12 (43%) patients, comprised of 3 Salter-Harris III fractures and 9 Salter-Harris IV fractures; 7 of these patients underwent surgical intervention to address deformity. All 4 children age 10 years or younger had growth arrests that underwent subsequent procedures for a skeletal rebalancing of the wrist. No significant differences in DASH or MMWS were seen in the short term between patients who did or did not have physeal arrest., Conclusions: Intra-articular distal radius fractures in skeletally immature patients have a considerably higher rate of physeal growth arrest than extra-articular physeal fractures. Following acute management aimed at restoring and preserving anatomic physeal and articular alignment, follow-up radiographs should be obtained to evaluate for physeal arrest in skeletally immature children. Patients and families should be counseled regarding the high rate of growth disturbance and the potential need for deformity correction in the future, particularly in younger children., Level of Evidence: IV-case series.

Background: Obesity in the prepuberal stage has been directly associated with slipped capital femoral epiphysis (SCFE). Serum insulin level increases in the prepuberal and adolescence stage, to a greater extent in the obese population. The main objective of this article was to analyze the relationship between insulin levels and SCFE., Methods: A case-control study was conducted between January 2018 and April 2019. The study group was formed with patients with SCFE and the control group with patients from the pediatric obesity clinic of our hospital selected during their initial evaluation. None were being treated for obesity. Anthropometric measurements of size, weight, waist circumference, and blood pressure were taken. Body mass index (BMI) and waist-height index of all patients were calculated. According to BMI for age, they were classified as normal, overweight, or obese. Serum determinations of glucose, insulin, glycated hemoglobin, lipid profile, and complete blood count were analyzed. Insulin resistance was diagnosed with Homeostatic Model Assessment (HOMA) >3. Insulin levels >13 U/mL for girls and >17 U/mL for boys were considered as hyperinsulinemia., Results: We studied 14 patients with SCFE and 23 in the control group. The mean age and BMI in both groups were similar. The elevation of serum insulin was significantly higher in the SCFE group (P=0.001) as was HOMA (P=0.005). Triglycerides and very-low-density lipoprotein were higher in the SCFE group (P=0.037 and 0.009, respectively). Glycemia, glycated hemoglobin, total cholesterol, high-density lipoprotein, low-density lipoprotein, and neutrophils showed no significant difference., Conclusions: Patients with SCFE showed elevated levels of insulin, HOMA, triglycerides, and very-low-density lipoprotein, even higher than the control group. Our study demonstrates a significant association between abnormally high serum insulin levels and SCFE. The known effects of insulin on growth cartilage may explain the physeal mechanical insufficiency to support the abnormally high or repetitive loads in accelerated growth stages that lead to SCFE., Level of Evidence: Level III-case-control, prognostic study.

Purpose: To assess the literature on indications, outcomes, and complications in pediatric patients undergoing all-epiphyseal (AE) anterior cruciate ligament reconstruction (ACLR)., Methods: PubMed, Medline, and Embase were searched for literature evaluating AE ACLR in pediatric patients. All included studies were assessed for quality using the Methodological Index for Non-Randomized Studies (MINORS). Descriptive statistics are presented where applicable., Results: Overall, 17 studies comprising 545 patients, with a mean age of 12.0 ± 1.2 (range 8-19) met the inclusion criteria. The graft choices in this systematic review included hamstring tendon autografts (75.4%, n = 403), quadriceps tendon autograft (6.2%, n = 33), Achilles tendon allograft (3.6%, n = 19) and posterior tibialis tendon allograft in one patient (0.2%, n = 1). Time of return-to-sport ranged from 8 to 22 months. Postoperative subjective IKDC scores were above 90 points. The rate of return-to-sport after AE ACLR was 93.2% (n = 219/235) and 77.9% (n = 142/183) of patients returned to sport at pre-injury level. The overall complication rate was 9.8% (n = 53/545) with the most common complication being ACL re-rupture (5.0%; n = 27/545). Only 1.5% (n = 8/545) of patients demonstrated growth disturbances., Conclusion: Overall, the AE ACLR technique can achieve good postoperative functional outcomes while notably minimizing the incidence of primary issue of physeal disruption and potential associated leg-length discrepancies. AE ACLR should be considered in pediatric patients with at least 2 years of skeletal growth remaining based on radiographic bone age to minimize the impact of growth-related complications., Level of Evidence: IV (Systematic Review of Level III and IV evidence).

Injuries are common in elite adolescent athletics, but few studies have addressed risk factors for injury. Growth and maturation are potential risk factors in this population; however, the current body of literature is both inconclusive and considered at high risk of bias. The aim of this study was therefore to examine whether growth rate, maturity status, and maturity tempo are associated with injury risk in an elite sports academy. Anthropometric, skeletal maturity and injury data collected prospectively over four seasons (117 athlete-seasons) were included in the analyses. Growth rate for stature was associated with greater risk of bone (incidence rate ratio (IRR): 1.5 per one standard deviation increase above the mean; 95% CI: 1.1-1.9) and growth plate injuries (IRR: 2.1; 1.5-3.1). Growth rate for leg length was associated with greater overall injury risk (IRR: 1.3; 1.0-1.7) as well as the risk of bone (IRR: 1.4; 1.0-1.9) and growth plate injuries (IRR: 2.1; 1.4-3.0). Athletes with greater skeletal maturity, expressed as skeletal age (IRR: 0.6 per year; 0.5-0.9) and percentage of predicted mature height (IRR: 0.8 per percent increase; 0.7-1.0), were less prone to growth plate injuries. Rate of change in skeletal age was associated with an increased risk of bone injuries (IRR: 1.5; 1.0-2.3). The results of this study suggest that rapid growth in stature and leg length, skeletal maturity status, and maturity tempo represent risk factors for certain injury types in adolescent athletics., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Outcome of the temporary epiphysiodesis procedure for limb length discrepancy (LLD) is commonly evaluated in the coronal plane. The purpose of this study was to investigate implant position and complications of the distal femur and patella in the sagittal plane after the temporary epiphysiodesis., Methods: We retrospectively reviewed 27 patients with LLD who underwent temporary epiphysiodesis of the distal femur using staples (11 patients) or eight-plates (16 patients) between 2007 and 2015. The mean age was 9.7 years (range, 6.3-13.8) at the time of epiphysiodesis. The implants were removed after a mean period of 2.6 years (range, 0.8-4.8) from the epiphysiodesis. Correction amount of LLD was measured on anteroposterior long leg standing radiographs. Implant position, extension deformity of the distal femur (>5° from epiphysiodesis to removal of implant) and patella baja (the epiphyseal line midpoint method < 1.0) were evaluated using lateral knee radiographs., Results: The average correction amount of LLD was 17.4 mm (range, 2-34). The average implant position was 43.1% (range, 35-55) from the anterior edge of the distal femoral epiphysis. At removal surgery, 16 patients (59%) had extension deformity of the distal femur and 14 patients (52%) showed patella baja. There were significant correlations between implant position and extension deformity (r = -0.51, p < 0.01) and as well as between correction amount of LLD and patella baja (r = -0.64, p < 0.01)., Conclusion: After temporary epiphysiodesis for the treatment of LLD, extension deformity of the distal femur and patella baja occurred frequently. Anterior placement of the implants is associated with extension deformity of the distal femur. The implant should be placed in the center of distal femoral physis, not the center of femoral shaft. Excessive correction of LLD should be avoided due to a risk of patella baja., (Copyright © 2019 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.)

Proximal femoral deformities can result from altered hip joint loading patterns during growth. The growth plate hyaline cartilage has low resistance to shear stress. Therefore, we hypothesized that the growth plate orients in a direction which minimizes the shear stress on its surface. A finite element model of the proximal femur was generated with a simplified flat growth plate. Hip joint forces were estimated for standing upright and standing in hip flexion. We also parametrically studied the effects of posteriorly and laterally directed loads. An algorithm was developed to predict the shape of the femoral growth plate in a plane of minimum shear (along the principal stress vectors). To characterize and compare the growth plate shapes, we represented the distance from the growth plate to a reference plane as a two-dimensional contour plot, providing information of shape and orientation across the entire surface. We also assessed the clinical measures of growth plate shape to compare our predicted growth plates with previous clinical studies data. The shape of the growth plate predicted for an upright standing load correlated closely with morphological properties of the growth plane of a typically developing child. The shape of the growth plate predicted for femoral hip flexion force was similar to the growth plate in subjects with cam morphology, a hip shape that has documented growth plate changes. The model proposed here allows for investigation of the relation between joint forces and growth plate shape, which will help predict the development of bony deformities.

Growth retardation is a major feature of chronic kidney disease (CKD) of onset in infants or children and is associated with increased morbidity and mortality. Several factors have been shown to play a causal role in the growth impairment of CKD. All these factors interfere with growth by disturbing the normal physiology of the growth plate of long bones. To facilitate the understanding of the pathogenesis of growth impairment in CKD, this review discusses cellular and molecular alterations of the growth plate during uremia, including structural and dynamic changes of chondrocytes, alterations in their process of maturation and hypertrophy, and disturbances in the growth hormone signaling pathway.

The muscular dystrophy X-linked ( mdx ) mouse is commonly used as a mouse model of Duchenne muscular dystrophy (DMD). Its phenotype is, however, mild, and other mouse models have been explored. The mdx:Cmah -/- mouse carries a human-like mutation in the Cmah gene and has a severe muscle phenotype, but its growth and bone development are unknown. In this study, we compared male mdx , mdx:Utrn +/- , mdx:Cmah -/- and wild-type (WT) mice at 3, 5 and 7 weeks of age to determine the suitability of the mdx:Cmah -/- mouse as a model for assessing growth and skeletal development in DMD. The m dx:Cmah -/- mice were lighter than WT mice at 3 weeks, but heavier at 7 weeks, and showed an increased growth rate at 5 weeks. Cortical bone fraction as assessed by micro-computed tomography was greater in both mdx and mdx: C mah -/- mice versus WT mice at 7 weeks. Tissue mineral density was also higher in mdx:Cmah -/- mice at 3 and 7 weeks. Gene profiling of mdx:Cmah -/- bone identified increased expression of Igf1 , Igf1r and Vegfa Both the mdx and mdx:Cmah -/- mice showed an increased proportion of regulated bone marrow adipose tissue (BMAT) but a reduction in constitutive BMAT. The mdx:Cmah -/- mice show evidence of catch-up growth and more rapid bone development. This pattern does not mimic the typical DMD growth trajectory and therefore the utility of the mdx:Cmah -/- mouse for studying growth and skeletal development in DMD is limited. Further studies of this model may, however, shed light on the phenomenon of catch-up growth.This article has an associated First Person interview with the first author of the paper., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2020. Published by The Company of Biologists Ltd.)

Background: A vitamin A derivative, 13-cis-retinoic acid (isotretinoin), has been administered to treat several types of pediatric cancer and has improved survival rates in patients despite being known to induce premature epiphyseal closure. As the number of patients treated by 13-cis-retinoic acid increases, demands for salvage treatment after systemic retinoid therapy are emerging. However, few studies have described the surgical treatment of this disease., Case Presentation: We report a case with bilateral varus knee deformity due to premature epiphyseal closure that occurred during treatment with isotretinoin for neuroblastoma. The patient was successfully treated with correction osteotomy using a Taylor spatial frame in the right knee joint and femoral closed wedge osteotomy using a locking plate in left knee joint. Histopathological examination of the growth plate showed polar irregularity of chondrocytes and decreased cartilage matrix without apoptosis. In contrast, arthroscopic findings showed an intact joint surface. No recurrence of varus deformity was evident on follow-up at 1 year., Conclusions: To the best of our knowledge, this represents the first report of correction osteotomy for varus knee deformity due to premature epiphyseal closure that occurred during treatment with isotretinoin.

In our previous study, chondrocyte apoptosis in femoral head necrosis (FHN)-affected broilers was found to be associated with the endoplasmic reticulum stress (ERS) signaling pathway. In the present study, we further explored the role of ERS-induced chondrocyte apoptosis in FHN-affected broilers and the parallel test was carried out with articular chondrocytes cultivated in vitro. The broilers and chondrocytes were treated with methylprednisolone (MP). The main pathological changes in FHN-affected broilers included the proximal femoral head separated from its articular cartilage and growth plate lesions. MP-treated chondrocytes demonstrated morphology changes, cell viability reduction, secretory capacity dysfunction, and apoptosis. The mRNA expressions of pro-apoptotic genes controlled by ERS signaling pathway were up-regulated both in vivo and in vitro experiments. It showed that MP induced FHN in broilers, activated apoptosis-related genes on ERS signaling pathway, and affected the survival and apoptosis of chondrocytes, and bone growth., (© 2018 Poultry Science Association Inc.)

Background: Factors including obesity and morphologic parameters around the hip that increase physeal stress are associated with an increased risk of slipped capital femoral epiphysis (SCFE). Recent evidence suggests that superior epiphyseal extension may confer stability to the physis and help protect against SCFE. The purpose of this study is to investigate the relationship between epiphyseal extension and SCFE using an age-matched and sex-matched cohort study., Methods: We generated 2 separate cohorts for comparison: 89 patients with unilateral SCFE and 89 healthy subjects with no evidence of hip disease or deformity. We utilized the anterior-posterior and lateral films of the hip to measure the Southwick angle and the epiphyseal extension ratio (EER), defined as the ratio of extension of the capital femoral epiphysis down the femoral neck relative to the diameter of the femoral head. We then compared these measurements between cohorts and in subgroup analysis based on slip stability and whether subjects progressed to a contralateral slip., Results: The SCFE cohort demonstrated a decreased superior epiphyseal extension ratio compared with control (superior EER 0.71 vs. 0.68, P=0.002). There was also a significant downward trend in superior EER from the control subjects (0.71±0.07) to the stable slips (0.69±0.06) to the unstable slips (0.65±0.04) with an overall difference between the groups (P=0.001). Eighteen of 44 (41%) subjects with unilateral stable slips and at least 6 months of follow-up went on to develop SCFE of the contralateral limb. The subjects who developed contralateral slips were younger (11.6±1.2 vs. 12.7±1.4 y, P=0.008); however, there was no difference in superior or anterior epiphyseal extension (P=0.75 and 0.23, respectively). There was no significant linear correlation between Southwick angle and superior or anterior EER (r=0.13 and 0.17, respectively, P>0.05 for both)., Conclusions: Increasing capital femoral epiphyseal extension may confer physeal stability in the setting of SCFE. We propose that this epiphyseal extension reflects an adaptive response to limit physeal stress and reduce the risk for progression to SCFE., Level of Evidence: Level III-prognostic study.

Osteoarthritis (OA) is one of the most common degenerative disease which causes pain and disability of joint and brings heavy socioeconomic burden in the world. However, the pathogenesis of OA has not been fully understood. Articular cartilage degradation or loss was often regarded as the characteristic of osteoarthritis. But we believe that there may had a illusion that OA was simply considered to be a process of wear and tear because evidences have supported all joint tissues remodeling including cartilage, subchondral bone, synovium, ligament, fat pad, and etc, were engaged in OA, in particular the cartilage and subchondral bone. Many factors such as mechanics, inflammation and immunological abnormality could drive the joint tissues metabolic and disturb the steady state of cartilage and bone, which further devoted to a serial pathological manifestations, consisting of hypertrophy and apoptosis of articular chondrocytes, degradation of cartilage matrix, angiogenesis and calcification of hyaline cartilage, replication of tidemark, formation of osteophytes, degeneration of ligaments and, in the knee, the menisci, hypertrophy of the joint capsule and remodeling of subchondral bone along with increased permeability of the osteochondral interface. The thickening of calcified cartilage, the thinning of superficial hyaline cartilage and the remodeling of subchondral bone indicated that the cartilage degradation could be a procedure of enchondral ossification similar to the growth plate, of driven by a host of cytokines within the affected joint. Articular cartilage loses stable state from normal resting to a high turnover in the stimulation of abnormal mechanical stresses and cytokines would subsequently contributed to slowly sustained remodeling and calcification, which might be the key features of the initiation and development of OA. In this article, the development and structural comparison of articular cartilage and growth plate as well as the major pathologic features of OA will be discussed to explain that cartilage degeneration in OA might be a process of enchondral ossification similar to growth plate. This would provide a new perspective for understanding OA's pathogenesis and the treatment in the future., (Copyright © 2018. Published by Elsevier Ltd.)

Osteosarcoma is the most common primary malignant bone tumor. It occurs mainly in children and adolescents. In patients with open growth plate, epiphyseal distraction is used to separate the uninvolved epiphysis from adjacent tumor. This helps preserve the growth potential and restore joint and limb function to a great extent. Interestingly, epiphyseal distraction also appears to inhibit the proliferation of osteosarcoma tumor cells and to increase sensitivity to chemotherapy. Tumor interstitial pressure (TIP) is often elevated in the microenvironment of most solid tumors, including osteosarcoma. Elevated TIP can promote the proliferation, invasion, and migration ability of osteosarcoma cells and also decrease the uptake and distribution of chemotherapeutic agents. Studies have confirmed that the sustained volumetric strain produced in distracted tissue decreases TIP; it stretches extracellular matrix, decreases interstitial density, and increases vessel diameter. We hypothesize that lowering of TIP during the period of epiphyseal distraction inhibits the proliferation and invasion of osteosarcoma cell and, at the same time, increases blood perfusion in the tumor and thus enhances uptake and distribution of chemotherapy agents. If the hypothesis is proved to be true, distraction of tumor segment could be a novel supplementary treatment for osteosarcoma by manipulation of TIP., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Mutations, mostly in the region of the COL10A1 gene encoding the C-terminal non-collagenous domain, cause the dwarfism metaphyseal chondrodysplasia type Schmid (MCDS). In most cases, the disease mechanism involves the misfolding of the mutant protein causing increased endoplasmic reticulum (ER) stress and an unfolded protein response (UPR). However, in an iliac crest biopsy, the COL10A1 p.Y632X mutation was found to produce instability of the mutant mRNA such that little mutant protein may be produced. To investigate the disease mechanism further, a gene-targeted mouse model of the Col10a1 p.Y632X mutation was generated. In this model, the mutant mRNA showed no instability, and in mice heterozygous for the mutation, mutant and wild-type mRNAs were present at equal concentrations. The protein was translated from the mutant allele and retained within the cell, triggering increased ER stress and a UPR. The mutation produced a relatively severe form of MCDS. Nevertheless, treatment of the mice with carbamazepine (CBZ), a drug which stimulates intracellular proteolysis and alleviates ER stress, effectively reduced the disease severity in this model of MCDS caused by a premature stop codon in the Col10a1 gene. Specifically, the drug reduced ER stress in the growth plate, restored growth plate architecture toward the wild-type state, significantly increased bone growth and within 2 weeks of treatment corrected the MCDS-induced hip distortion. These results indicate that CBZ is likely to be effective in ongoing clinical trials against all forms of MCDS whether caused by premature stop codons or substitutions.

Background: Physeal fractures and resultant physeal bars can pose significant problems in skeletal development for the injured growing child. Although now well-recognized, only a small body of experimental literature covering this problem is available. The goal of this study was to help further develop an understanding of the different regions of the physis and the way in which each region responds to injury/fracture., Methods: This Institutional Animal Care and Use Committee (IACUC)-approved study assessed bar formation using radiologic and histologic methods and measured leg lengths of skeletally immature rats. The right tibia was used as the control to measure leg length discrepancy (LLD), and the left tibia received either a fracture only (F), an epiphyseal scrape (ES), an epiphyseal drilling procedure (ED), or metaphyseal drilling (MD). Radiographs and LLD measurements were obtained at postoperative days 0, 21, and 56., Results: A significant LLD was present at day 56 in the ED group (P=0.01). Radiographic identification of bars showed significant evidence of bar formation for the ES and ED groups at 21 days and the ED group at 56 days (P<0.05). Histologic examination showed a high incidence of histologic physeal bar formation in the ES, ED, and MD groups at 21 and 56 days., Conclusions: Findings showed that the physis was able to continue to grow following an injury to the physis' hypertrophic region. MD produced little effects with few physeal bars and little LLD. By postoperative day 56, ED animals showed greater LLD than ES animals. Penetration of the basement plate was more likely to lead to bar formation/growth retardation than was ablation of the epiphyseal region of the physis (including resting cells)., Clinical Relevance: Data presented here provides insight into the importance of different regions of the physis and its repair/continued growth after physeal fracture. We suggest that a better understanding of the physiological cause of physeal arrest after physeal fracture will be important for the development of treatments to prevent physeal arrest or to treat physeal arrest after it occurs.

Background: Retrograde femoral nailing in skeletal immature patients would broaden the surgical options for fracture care and reconstructive procedures but involves violation of the open, active distal femoral physis with the potential for growth disturbance. The tolerance for putting a large diameter metal implant across the physis is largely unknown. The purpose of this pilot investigation was to define the upper limit of cross-sectional violation with a metal implant before causing premature growth arrest or inhibition using a sheep model., Methods: Eighteen sheep underwent placement of a retrograde, intramedullary implant at 3-months of age through an open distal femoral physis. The cross-sectional area of the physis was measured preoperatively and implants were selected that violated 3% to 8% of the cross-sectional area of the physis. Growth across the distal femoral physis was examined radiographically following surgery. Following euthanasia, both operative and no operative femurs were removed to compare differences in maximal lengths., Results: The distal femora grew an average of 10.6±2.2 mm radio graphically after implantation. When compared with control specimens, only operative specimens with 8% of physeal violation demonstrated significant growth discrepancy with operative femurs measuring <2.1 mm in length compared with the contralateral control femur. Histologic analysis did not demonstrate any significant physeal bars formation., Conclusion: Distal femoral growth continues across the physis when 3% to 7% of the cross-sectional area of the physis is violated using a retrograde intramedullary implant. Specimens with 8% of growth violation demonstrated significant growth inhibition. As such, retrograde nailing through the distal femoral physis appears safe up to 7%. On the basis of previous anatomic data in humans and average nail sizes, violations of >6% of the physis with pediatric retrograde nailing would be uncommon. These findings suggest that retrograde nailing may be a viable option and merits further study., Level of Evidence: Level IV-case series.

Osteoarthritis (OA) is a chronic disorder associated mainly with pain, limited range of motion, stiffness, low-grade systemic inflammation, and articular cartilage destruction. Recent studies have demonstrated the involvement of chondrocyte differentiation (hypertrophy) as one of the mechanisms in cartilage degradation in OA. This implicates the involvement of principal changes in the regulation of cellular function associated with profound alterations in chondrocyte energy metabolism in the course of cartilage resorption. Therefore, this review describes the major energy-generating pathways and their regulatory molecules used by the growth plate chondrocytes during endochondral ossification and by articular chondrocytes in OA. These regulatory molecules facilitate either the glycolytic pathway of energy generation, which controls cell proliferation, or mitochondrial oxidative phosphorylation promoted by AMPK and sirtuins and responsible for tissue regeneration. Consideration of the disturbances in energy metabolic pathways associated with OA might provide an approach to disclose the primary causes of the disease's development and progression. Medline/PubMed was searched for publications in English using key words: osteoarthritis, epiphyseal growth plate, articular cartilage, glycolysis, oxidative phosphorylation, and regulation of energy metabolism.

Scoliosis progression in skeletally immature patients depends on remaining growth. Relationships between vertebral growth plate histomorphometry, growth rates, and mechanical stresses have been reported in several animal studies. Hypertrophic zone heights and chondrocyte heights have been used to assess treatments that aim to modulate growth. The purpose of this study was to determine whether human vertebral physeal hypertrophic zone and cell heights differed between two groups: Severe scoliosis and autopsy controls. Severity was defined at time of surgical planning by curve magnitude and curve stiffness. Physeal samples were obtained from the convex side apex, and from the concave side when feasible. Histologic sections were prepared, and digital images were used to measure hypertrophic zone height, cell height, and cell width. Thirteen spinal deformity patients were included, mean curve magnitude 67° (±23). Etiologies were juvenile and adolescent idiopathic, congenital, neurofibromatosis, neuromuscular, and Marfan syndrome. Five age-matched autopsy specimens without scoliosis served as controls. Results were presented by etiology, then all convex scoliosis specimens were combined and compared to controls. Zone heights for scoliosis, convex side, and controls were 152 µm (±34) and 180 µm (±42) (p = 0.21), cell heights 8.5 µm (±1.1) and 12.8 µm (±1.2) (p < 0.0005), and cell widths 14.9 µm (±1.5) and 15.0 µm (±2.5), respectively. Human values were compared to published animal models and to a quantitative theory of a stress ̶ growth curve. This quantification of vertebral physeal structures in scoliosis may be expected to help assess theories of progression and potential treatments using growth modulation. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:2450-2459, 2018., (© 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)

When children around 2 years of age show leg bowing and diseases are ruled out based on radiographic findings without conducting blood tests, they are classified as "physiologic" genu varum. Since whether or not physiologic genu varum is associated with bone metabolism is unclear, this study was conducted to clarify the association between genu varum and bone metabolism in children. Thirty-five pediatric patients with genu varm who visited our out-patient clinic were enrolled. While two of the 35 children had nutritional rickets, showing abnormalities on both blood test (ALP, ≥1000 IU/L; iPTH, >65 pg/mL and 25(OH)D, ≤20 ng/mL) and radiographs (such as cupping, fraying or splaying), five of 35 children showed abnormalities on blood tests but not radiographs. While metaphyseal-diaphyseal angle (MDA) correlated with serum 25-hydroxy vitamin D (r = -0.35, p = 0.04) and magnesium (r = -0.36, p = 0.04), MDA and femorotibial angle (FTA) correlated with alkaline phosphatase (r = 0.43, p = 0.01 and r = 0.51, p = 0.006, respectively). A ridge regression analysis adjusted for age and body mass index indicated that ALP was associated with MDA and FTA. A logistic regression analysis adjusted for age and BMI indicated that higher ALP influenced an MDA >11°, which indicates the risk for the progression of genu varum (odds ratio 1.002, 95% confidence interval 1.0003-1.003, p = 0.021). The higher ALP (+100 IU), the higher risk of an MDA >11° (odds ratio 1.22). In conclusion, genu varum is associated with the alkaline phosphatase level regardless of the presence of radiographic abnormalities in the growth plate in children.

The treatment of pediatric patients in trauma surgery is a special situation in every aspect. For deciding on the correct treatment of fractures of the lower leg and ankle joint, various parameters, such as residual growth rate, skeletal age and height of the patient are decisive. The differences between fractures in children and adolescents are the open epiphyseal plate and the resulting residual growth. The bones of young children have a higher healing tendency and a greater potential for correction than in adolescents. Especially in the lower leg and the ankle joint, the potential for correction is decisive for the healing of fractures and for possible development of growth disorders. The limits of tolerance concerning axial malalignments and the expected spontaneous potential for correction must play an essential role for further treatment with conservative or operative therapy. This article deals with the special features of pediatric fractures of the lower leg and ankle joint.

Objective: To investigate the effect of asymmetric tension on idiopathic scoliosis (IS) and to understand its pathogenic mechanism., Methods: The rodent model of scoliosis was established using Sprague-Dawley rats with left rib-tethering from T 6 to T 12 , tail and shoulder amputation, and high-cage feeding. Vertebrae epiphyseal cartilage plates were harvested from the convex and concave sides. To analyze differences on the convex and concave sides, finite element analysis was carried out to determine the mechanical stress. Protein expression on epiphyseal cartilage was evaluated by western blot. Micro-CT was taken to evaluate the bone quality of vertebral on both sides., Results: Scoliosis curves presented in X-ray radiographs of the rats. Finite element analysis was carried out on the axial and transverse tension of the spine. Stresses of the convex side were -170.14, -373.18, and -3832.32 MPa (X, Y, and Z axis, respectively), while the concave side showed stresses of 361.99, 605.55, and 3661.95 MPa. Collagen type II, collagen type X, Sox 9, RunX2, VEGF, and aggrecan were expressed significantly more on the convex side (P < 0.05). There was asymmetric expression of protein on the epiphyseal cartilage plate at molecular level. Compared with the convex side, the concave side had significantly lower value in the BV/TV and Tb.N, but higher value in the Tb.Sp (P < 0.05). There was asymmetry of bone quality in micro-architecture., Conclusions: In this study, asymmetric tension contributed to asymmetry in protein expression and bone quality on vertebral epiphyseal plates, ultimately resulting in asymmetry of anatomy. In addition, asymmetry of anatomy aggravated asymmetric tension. It is the first study to show that there is an asymmetrical vicious circle in IS., (© 2017 Chinese Orthopaedic Association and John Wiley & Sons Australia, Ltd.)

Injury to the growth plate is associated with growth disturbances, most notably premature cessation of growth. The goal of this study was to identify spatial changes in the structure and composition of the growth plate in response to injury to provide a foundation for developing therapies that minimize the consequences for skeletal development. We used contrast-enhanced microcomputed tomography (CECT) and histological analyses of a murine model of growth plate injury to quantify changes in the cartilaginous and osseous tissue of the growth plate. To distinguish between local and global changes, the growth plate was divided into regions of interest near to and far from the injury site. We noted increased thickness and CECT attenuation (a measure correlated with glycosaminoglycan (GAG) content) near the injury, and increased tissue mineral density (TMD) of bone bridges within the injury site, compared to outside the injury site and contralateral growth plates. Furthermore, we noted disruption of the normal zonal organization of the physis. The height of the hypertrophic zone was increased at the injury site, and the relative height of the proliferative zone was decreased across the entire injured growth plate. These results indicate that growth plate injury leads to localized disruption of cellular activity and of endochondral ossification. These local changes in tissue structure and composition may contribute to the observed retardation in femur growth. In particular, the changes in proliferative and hypertrophic zone heights seen following injury may impact growth and could be targeted when developing therapies for growth plate injury.

Adolescent idiopathic scoliosis (AIS) is now considered to be a multifactorial heterogeneous disease, with recent genomic studies supporting the role of intrinsic factors in contributing to the onset of disease pathology and curve progression. Understanding the key molecular signalling pathways by which these intrinsic factors mediate AIS pathology may facilitate the development of pharmacological therapeutics and the identification of predictive markers of progression. The heterogenic nature of AIS has implicated multiple tissue types in the disease pathophysiology, including spinal bone, intervertebral disc and paraspinal muscles. In this review, we highlight some of the mechanisms and intrinsic molecular regulators within these different tissue types and review the evidence for their involvement in AIS pathology.

Growth retardation is a major manifestation of chronic kidney disease (CKD) in pediatric patients. The involvement of the various pathogenic factors is difficult to evaluate in clinical studies. Here, we present an experimental model of adenine-induced CKD for the study of growth failure. Three groups (n = 10) of weaning female rats were studied: normal diet (control), 0.5% adenine diet (AD), and normal diet pair fed with AD (PF). After 21 days, serum urea nitrogen, creatinine, parathyroid hormone (PTH), weight and length gains, femur osseous front advance as an index of longitudinal growth rate, growth plate histomorphometry, chondrocyte proliferative activity, bone structure, aorta calcifications, and kidney histology were analyzed. Results are means ± SE. AD rats developed renal failure (serum urea nitrogen: 70 ± 6 mg/dl and creatinine: 0.6 ± 0.1 mg/dl) and secondary hyperparathyroidism (PTH: 480 ± 31 pg/ml). Growth retardation of AD rats was demonstrated by lower weight (AD rats: 63.3 ± 4.8 g, control rats: 112.6 ± 4.7 g, and PF rats: 60.0 ± 3.8 g) and length (AD rats: 7.2 ± 0.2 cm, control rats: 11.1 ± 0.3 cm, and PF rats: 8.1 ± 0.3 cm) gains as well as lower osseous front advances (AD rats: 141 ± 13 μm/day, control rats: 293 ± 16 μm/day, and PF rats: 251 ± 10 μm/day). The processes of chondrocyte maturation and proliferation were impaired in AD rats, as shown by lower growth plate terminal chondrocyte height (21.7 ± 2.3 vs. 26.2 ± 1.9 and 23.9 ± 1.3 μm in control and PF rats) and proliferative activity index (AD rats: 30 ± 2%, control rats: 38 ± 2%, and PF rats: 42 ± 3%). The bone primary spongiosa structure of AD rats was markedly disorganized. In conclusion, adenine-induced CKD in young rats is associated with growth retardation and disturbed endochondral ossification. This animal protocol may be a useful new experimental model to study growth in CKD., (Copyright © 2015 the American Physiological Society.)

Objective: To investigate the in vivo role of the IRE1/XBP1 unfolded protein response (UPR) signaling pathway in cartilage., Design: Xbp1(flox/flox).Col2a1-Cre mice (Xbp1(CartΔEx2)), in which XBP1 activity is ablated specifically from cartilage, were analyzed histomorphometrically by Alizarin red/Alcian blue skeletal preparations and X-rays to examine overall bone growth, histological stains to measure growth plate zone length, chondrocyte organization, and mineralization, and immunofluorescence for collagen II, collagen X, and IHH. Bromodeoxyuridine (BrdU) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) analyses were used to measure chondrocyte proliferation and cell death, respectively. Chondrocyte cultures and microdissected growth plate zones were analyzed for expression profiling of chondrocyte proliferation or endoplasmic reticulum (ER) stress markers by Quantitative PCR (qPCR), and of Xbp1 mRNA splicing by RT-PCR to monitor IRE1 activation., Results: Xbp1(CartΔEx2) displayed a chondrodysplasia involving dysregulated chondrocyte proliferation, growth plate hypertrophic zone shortening, and IRE1 hyperactivation in chondrocytes. Deposition of collagens II and X in the Xbp1(CartΔEx2) growth plate cartilage indicated that XBP1 is not required for matrix protein deposition or chondrocyte hypertrophy. Analyses of mid-gestation long bones revealed delayed ossification in Xbp1(CartΔEx2) embryos. The rate of chondrocyte cell death was not significantly altered, and only minimal alterations in the expression of key markers of chondrocyte proliferation were observed in the Xbp1(CartΔEx2) growth plate. IRE1 hyperactivation occurred in Xbp1(CartΔEx2) chondrocytes but was not sufficient to induce regulated IRE1-dependent decay (RIDD) or a classical UPR., Conclusion: Our work suggests roles for XBP1 in regulating chondrocyte proliferation and the timing of mineralization during endochondral ossification, findings which have implications for both skeletal development and disease., (Copyright © 2015 Osteoarthritis Research Society International. All rights reserved.)

Bone sialoprotein (BSP) is an anionic phosphoprotein in the extracellular matrix of mineralized tissues, and a promoter of biomineralization and osteoblast development. Previous studies on the Bsp-deficient mouse (Bsp(-/-)) have demonstrated a significant bone and periodontal tissue phenotype in adulthood. However, the role of BSP during early long bone development is not known. To address this, early endochondral ossification in the Bsp(-/-) mouse was studied. Embryonic day 15.5 (E15.5) wild-type (WT) tibiae showed early stages of ossification that were absent in Bsp(-/-) mice. At E16.5, mineralization had commenced in the Bsp(-/-) mice, but staining for mineral was less intense and more dispersed compared with that in WT controls. Tibiae from Bsp(-/-) mice also demonstrated decreased mineralization and shortened length at postnatal day 0.5 (P0.5) compared to WT bones. There was no detectable difference in the number of tartrate-resistant acid phosphatase-positive foci at P0.5, although the P0.5 Bsp(-/-) tibiae had decreased Vegfα expression compared with WT tissue. Due to the shortened tibiae the growth plates were examined and determined to be of normal overall length. However, the length of the resting zone was increased in P0.5 Bsp(-/-) tibiae whereas that of the proliferative zone was decreased, with no change in the hypertrophic zone length of Bsp(-/-) mice. A reduction in cells positive for Ki-67, an S-phase cell-cycle marker, was noted in the proliferative zone. Decreased numbers of TUNEL-positive hypertrophic chondrocytes were also apparent in the Bsp(-/-) tibial growth plates, suggesting decreased apoptosis. Expression of the osteogenic markers Alp1, Col1a1, Sp7, Runx2, and Bglap was reduced in the endochondral bone of the neonatal Bsp(-/-) compared to WT tibiae. These results suggest that BSP is an important and multifaceted protein that regulates both chondrocyte proliferation and apoptosis as well as transition from cartilage to bone during development of endochondral bone., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Spondylolysis is a stress fracture of the pars interarticularis, which in some cases progresses to spondylolisthesis (forward slippage of the vertebral body). This slip progression is prevalent in children and occurs very rarely after spinal maturation. The pathomechanism and predilection for children remains controversial despite considerable clinical and basic research into the disorder over the last three decades. Here we review the pathomechanism of spondylolytic spondylolisthesis in children and adolescents, and specifically the Tokushima theory of growth plate slippage developed from our extensive research findings. Clinically, we have observed the slippage site near the growth plate on MRI; then, using fresh cadaveric spines, we found the weakest link against forward shear loading was the growth plate. We subsequently developed an immature rat model showing forward slippage after growth plate injury. Moreover, finite element analysis of the pediatric spine clearly showed increased mechanical stress at the growth plate in the spondylolytic pediatric spine model compared with the intact pediatric spine. Thus, spondylolysis progresses to spondylolisthesis (forward slippage) in children and adolescents with the growth plate as the site of the slippage. Repetitive mechanical loading on to the growth plate may serve to separate the growth plate and subsequently progress to spondylolisthesis.

Background: Radial neck fractures in children are rare, representing 5% of all elbow pediatric fractures. Most are minimally displaced or nondisplaced. Severely displaced or angulated radial neck fractures often have poor outcomes, even after open reduction, and case series reported in literature are limited. The aim of the study is to analyze the outcomes of patients with a completely displaced and angulated fracture who underwent open reduction when closed reduction failed., Methods: Between 2000 and 2009, 195 patients with radial neck fractures were treated in our institute. Twenty-four cases satisfied all the inclusion criteria and were evaluated clinically and radiologically at a mean follow-up of 7 years. At follow-up, the carrying angle in full elbow extension and the range of motion of the elbow and forearm were measured bilaterally. We recorded clinical results as good, fair, or poor according to the range of movement and the presence of pain. Radiographic evaluation documented the size of the radial head, the presence of avascular necrosis, premature physeal closure, and cubitus valgus., Results: Statistical analysis showed that fair and poor results are directly correlated with loss of pronation-supination (P = 0.001), reduction of elbow flexion-extension (P = 0.001), increase of elbow valgus angle (P = 0.002), necrosis of the radial head (P = 0.001), premature physeal closure (P = 0.01), and associated lesions (olecranon fracture with or without dislocation of the elbow) (P = 0.002)., Discussion: In our cases, residual radial head deformity due to premature closure of the growth plate and avascular necrosis were correlated with a functional deficit. Associated elbow injury was coupled with a negative prognosis. In our series, about 25% of patients had fair and 20% had poor results. Outcomes were good in 55% and felt to represent a better outcome than if the fracture remained nonanatomically reduced with residual angulation and/or displacement of the radial head. This study reports the largest series of these fractures with a combination of significant angulation and displacement of the fracture requiring open reduction. We feel that open reduction is indicated when the head of the radius is completely displaced and without contact with the rim of the metaphysis.

Purpose: To review radiographic changes in the proximal femurs of children of different ages during the course of treatment for nutritional rickets., Methods: Pelvic radiographs of 161 children aged ≤ 13 years with nutritional rickets were retrospectively reviewed. Patients were treated with dietary counselling and vitamin D and calcium supplementation. Patients were followed up at week 3 and thereafter at a 2-month interval until ulnar convexity was achieved. Sequential radiographs of the hips in children of different ages were reviewed for each growth plate in terms of (1) the direction of growth, (2) active areas, (3) contribution of growth, and (4) the structure of the epiphysis. Radiographs were superimposed for comparison by matching the triradiate cartilage and the ischial portion of the obturator foramen., Results: The direction of growth of the growth plates was from the physeal plate that is the longitudinal growth plate of the neck (LGP), the femoral neck isthmus (FNI), and the trochanteric growth plate (TGP) to the diaphyseal region, and from the perichondrium to the ossification centre in the proximal femoral epiphysis. Before the age of one year, the growth zone of the proximal femur was homogenous, with no differentiation between the LGP, FNI, and TGP. By the age of 2 years, the differentiation was more clearly established; the FNI was usually smaller than the TGP and LGP. By the age of 3 years, the FNI became prominent and the TGP remained small. By the age of 4 years, the ossification centre of the greater trochanter appeared, and the LGP extended medially as a medial overhang (MOH). During the children's growth, the LGP, FNI, or TGP remained active to a variable extent and were distinct until the age of 6 years. Gradually, the periphery of the LGP became less active than the centre of the LGP and gave rise to the 'eye sign'. The MOH generally ceased to be active beyond the age 9 years. By the age of 12 years, the TGP and FNI were minimally active and only the centre of the LGP remained active., Conclusion: The mineralisation process of healing rickets provides a useful biological marker for patterns of growth. Knowledge of the quantitative contribution of various growth plates of the proximal femur in childhood may increase the understanding of the pathomechanism of hip deformations.

Purpose: Premature physeal closure of the proximal femoral physis has been reported in Legg-Calve-Perthes Disease (LCPD). However, the timing of its occurrence had not yet been reported. We proposed (1) to determine the timing of premature physeal closure in unilateral LCPD with serial radiographic evaluation, and (2) to evaluate the relationship between the premature physeal closure and Herring classification, leg-length discrepancy (LLD), Stulberg classification, and trochanteric overgrowth., Methods: We performed a retrospective study with serial radiographs of 27 patients diagnosed with LCPD. The difference in the timing of physeal closure between the hips was calculated. The involved hip was classified according to Herring classification. The LLD and ATD index at latest follow up was measured. The mean values were calculated and statistical comparison of variables was done using the Fisher's exact test., Results: The mean difference of physeal closure at the involved hip compared to the uninvolved side was 3.5 years (range, two to five years). Hips demonstrating premature physeal closure were associated with Herring B/C and C (p = 0.01) and LLD >1 cm (p = 0.02). There is no correlation between Stulberg classification, trochanteric overgrowth and premature physeal closure (p = 0.06 and p = 0.19)., Conclusions: We may expect premature physeal closure of the proximal femoral physis in patients with LCPD to occur 3.5 years earlier than normal hips. Presence of premature physeal closure can be an adjunct diagnostic tool in the prognostication of LCPD outcomes. Future studies directed toward premature physeal closure in LCPD and associated growth disturbances are necessary.

This in vivo study aimed at investigating the effects of dynamic compression on the growth plate. Rats (28 days old) were divided into three dynamically loaded groups, compared with two groups (control, sham). A device was implanted on the 6th and 8th caudal vertebrae for 15 days. Controls (n = 4) did not undergo surgery. Shams (n = 4) were operated but not loaded. Dynamic groups had sinusoidal compression with a mean value of 0.2 MPa: 1.0 Hz and ± 0.06 MPa (group a, n = 4); 0.1 Hz and ± 0.2 MPa (group b, n = 4); 1.0 Hz and ± 0.14 MPa (group c, n = 3). Growth rates (µm/day) of dynamic groups (a) and (b) were lower than shams (p < 0.01). Growth plate heights, hypertrophic cell heights and proliferative cell counts per column did not change in dynamic (a) and (b) groups compared with shams (p > 0.01). Rats from dynamic group (c) had repeated inflammations damaging tissues; consequently, their analysis was unachievable. Increasing magnitude or frequency leads to growth reduction without histomorphometric changes. However, the combined augmentation of magnitude and frequency alter drastically growth plate integrity. Appropriate loading parameters could be leveraged for developing novel growth modulation implants to treat skeletal deformities., (© 2014 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)

Injuries to the growth plate cartilage often lead to bony repair, resulting in bone growth defects such as limb length discrepancy and angulation deformity in children. Currently utilised corrective surgeries are highly invasive and limited in their effectiveness, and there are no known biological therapies to induce cartilage regeneration and prevent the undesirable bony repair. In the last 2 decades, studies have investigated the cellular and molecular events that lead to bony repair at the injured growth plate including the identification of the four phases of injury repair responses (inflammatory, fibrogenic, osteogenic and remodelling), the important role of inflammatory cytokine tumour necrosis factor alpha in regulating downstream repair responses, the role of chemotactic and mitogenic platelet-derived growth factor in the fibrogenic response, the involvement and roles of bone morphogenic protein and Wnt/B-catenin signalling pathways, as well as vascular endothelial growth factor-based angiogenesis during the osteogenic response. These new findings could potentially lead to identification of new targets for developing a future biological therapy. In addition, recent advances in cartilage tissue engineering highlight the promising potential for utilising multipotent mesenchymal stem cells (MSCs) for inducing regeneration of injured growth plate cartilage. This review aims to summarise current understanding of the mechanisms for growth plate injury repair and discuss some progress, potential and challenges of MSC-based therapies to induce growth plate cartilage regeneration in combination with chemotactic and chondrogenic growth factors and supporting scaffolds., (© 2014 Society for Endocrinology.)

Purpose: To evaluate the effects of ovariectomy and the hyperprolactinemia procedure in the tibial epiphyseal growth plate of female mice., Methods: In this study, the epiphyseal growth plate of ovariectomized (OVX) and/or rendered hyperprolactinemic female mice by 50 days of treatment with 200 μg metoclopramide (M) was evaluated morphologically, morphometrically and immuno-histochemically. Forty female and adult mice were divided into four groups according to treatment: V group--animals treated with saline solution; H group--hyperprolactinemic animals; Ovx/V group--ovariectomized animals and treated with saline solution; Ovx/H group--hyperprolactinemic and ovariectomized animals. After the treatment period, the animals were sacrificed, tibia was removed and fixed in 10% buffered formalin and decalcified in 10% formic acid. The material was immersed in paraffin and subjected to histological processing in paraffin. The sections were stained with Masson's trichrome and immunohistochemistry was carried out for the pro-apoptotic protein BCL-2. The images for the morphological and morphometric study were analyzed with the imaging program AxioVision 4.8 (Carl-Zeiss(r), Germany)., Results: The combination of hyperprolactinemia and the ovariectomy procedure decreased the number of resting chondrocytes 1.5-fold, the number of proliferative chondrocytes 1.8-fold; the percentage of resting cartilage 2.4-fold and the percentage of trabecular bone 2.1-fold, compared with respective control animals., Conclusion: The procedure of ovariectomy combined with the metoclopramide-induced hyperprolactinemia in female mice has showed marked bone degeneration due to significant decrease of cell proliferation in the epiphyseal growth plate and bone formation.

Skeletons are formed through two distinct developmental actions, intramembranous ossification and endochondral ossification. During embryonic development, most bone is formed by endochondral ossification. The growth plate is the developmental center for endochondral ossification. Multiple signaling pathways participate in the regulation of endochondral ossification. Fibroblast growth factor (FGF)/FGF receptor (FGFR) signaling has been found to play a vital role in the development and maintenance of growth plates. Missense mutations in FGFs and FGFRs can cause multiple genetic skeletal diseases with disordered endochondral ossification. Clarifying the molecular mechanisms of FGFs/FGFRs signaling in skeletal development and genetic skeletal diseases will have implications for the development of therapies for FGF-signaling-related skeletal dysplasias and growth plate injuries. In this review, we summarize the recent advances in elucidating the role of FGFs/FGFRs signaling in growth plate development, genetic skeletal disorders, and the promising therapies for those genetic skeletal diseases resulting from FGFs/FGFRs dysfunction. Finally, we also examine the potential important research in this field in the future., (© 2014 Society for Endocrinology.)

Objective: Activation of the Liver X Receptor (LXR) has recently been identified as a therapeutic strategy for osteoarthritis (OA). Human OA articular cartilage explants show decreased LXR expression, and LXRβ-null mice display OA-like symptoms. LXR agonist administration to OA articular cartilage explants suppresses proteoglycan degradation and restores LXR-activated transcription. We aimed to investigate the effect of LXR activation on chondrocyte differentiation to elucidate the molecular mechanisms behind its protection against OA., Method: The specific LXR agonist, GW3965, was used to examine the effect of LXR activation on chondrocyte differentiation. Tibia organ cultures were used to examine the effect of LXR activation on bone growth and growth plate morphology, followed by immunohistochemical analysis. In ATDC5 and micromass cultures, chondrocyte differentiation was examined through cellular staining and proliferation assays. Various chondrogenic markers were analyzed by real-time reverse-transcription polymerase chain reaction (qRT-PCR) in micromass RNA., Results: Chondrocyte hypertrophy was suppressed by GW3965 treatment, as shown by decreased hypertrophic zone length in the tibial growth plate, decreased alkaline phosphatase staining in ATDC5 and micromass cultures, and down regulation of Col10a1, Mmp13 and Runx2 expression. Increased proliferation in treated ATDC5 cells and up-regulation of Col2a1 expression in treated micromass cultures suggest hypertrophy is suppressed secondary to prolonged proliferation. Decreased p57 levels in treated growth plates suggest this to be due to cell-cycle exit delay., Conclusion: Our findings regarding LXR's role in cartilage development provide insight into how LXR activation prevents cartilage breakdown, further solidifying its potential as a therapeutic target of OA., (Copyright © 2014 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Objectives: To evaluate the effects of low-magnitude high-frequency vibration (LMHFV) on degenerated articular cartilage and subchondral bone in anterior cruciate ligament transection (ACLT) induced osteoarthritis (OA) rat model., Methods: 6 months old female Sprague-Dawley rats received ACLT on right knee and randomly divided into treatment and control groups. OA developed 12 weeks after surgery. LMHFV (35 Hz, 0.3 g) treatment was given 20 min/day and 5 days/week. After 6, 12 and 18 weeks, six rats of each group were sacrificed at each time point and the right knees were harvested. OA grading score, distal femur cartilage volume (CV), subchondral bone morphology, elastic modulus of cartilage and functional changes between groups were analyzed., Results: Increased cartilage degradation (higher OA grading score) and worse functional results (lower duty cycle, regular index and higher limb idleness index) were observed after LMHFV treatment (P = 0.011, 0.020, 0.012 and 0.005, respectively). CV increased after LMHFV treatment (P = 0.019). Subchondral bone density increased with OA progress (P < 0.01). Increased BV/TV, Tb.N and decreased Tb.Sp were observed in distal femur epiphysis in LMHFV treatment group (P = 0.006, 0.018 and 0.011, respectively)., Conclusion: LMHFV accelerated cartilage degeneration and caused further functional deterioration of OA affected limb in ACLT-induced OA rat model. In contrast, LMHFV promoted bone formation in OA affected distal femur epiphysis, but did not reverse OA progression., (Copyright © 2014 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Objective: To explore the relationship between subchondral bone reconstruction and articular cartilage regeneration in a rabbit model of spontaneous osteochondral repair., Methods: Twenty-four 6-month-old New Zealand white rabbits were included. The osteochondral defects (4 mm in diameter and 3 mm in depth) were created in the trochlear groove of the unilateral femur, which penetrated the subchondral bone without any treatment. The rabbits were sacrificed at 1, 4, 12, and 24 weeks. after operation, respectively. The specimens were obtained for macroscopic, histological, and immunohistochemical observations. According to the International Cartilage Repair Society (ICRS) histological scoring, the effect of cartilage repair was assessed. The histomorphometrical parameters of subchondral bone were analyzed by micro-CT scan and reconstruction, and the relationship between cartilage repair and the histomorphometrical parameters of the subchondral bone were also analyzed., Results: Osteochondral defects could be repaired spontaneously in rabbit model. With time, defect was gradually filled with repaired tissue, subchondral bone plate under the defect region gradually migrated upward. Bone mineral density, bone volume fraction, tissue mineralized density, trabecula number, and trabecula thickness were increased, while trabecula spacing was decreased. Significant difference was found in the other parameters between different time points (P < 0.05) except for trabecula thickness between at 4 and 12 weeks after operation (P > 0.05). Histological examination showed that fibrous repair was predominant with rare hyaline cartilage. With time, ICRS scores increased gradually, showing significant differences between other time points (P < 0.05) except for between at 4 and 12 weeks after operation (P > 0.05). Among the histomorphometrical parameters of subchondral bone, the trabecula spacing was negatively correlated with ICRS score (r = -0.584, P = 0.039), and the other histomorphometrical parameters were positively correlated with ICRS score (r = 0.680-0.891)., Conclusion: There is relevant correlation as well as independent process between cartilage regeneration and subchondral bone reconstruction in the rabbit model of spontaneous osteochondral repair, and fast subchondral bone remodeling may adversely affect articular cartilage repair.

Growth plate injuries often result in undesirable bony repair causing bone growth defects, for which the underlying mechanisms are unclear. Whilst the key importance of pro-angiogenic vascular endothelial growth factor (VEGF) is well-known in bone development and fracture repair, its role during growth plate bony repair remains unexplored. Using a rat tibial growth plate injury repair model with anti-VEGF antibody, Bevacizumab, as a single i.p. injection (2.5 mg/kg) after injury, this study examined the roles of VEGF-driven angiogenesis during growth plate bony repair. Histology analyses observed isolectin-B4-positive endothelial cells and blood vessel-like structures within the injury site on days 6 and 14, with anti-VEGF treatment significantly decreasing blood-vessel-like structures within the injury site (P<0.05). Compared with untreated controls, anti-VEGF treatment resulted in an increase in undifferentiated mesenchymal repair tissue, but decreased bony tissue at the injury site at day 14 (P<0.01). Consistently, microcomputed tomography analysis of the injury site showed significantly decreased bony repair tissue after treatment (P<0.01). RT-PCR analyses revealed a significant decrease in osteocalcin (P<0.01) and a decreasing trend in Runx2 expression at the injury site following treatment. Furthermore, growth plate injury-induced reduced tibial lengthening was more pronounced in anti-VEGF-treated injured rats on day 60, consistent with the observation of a significantly increased height of the hypertrophic zone adjacent to the growth plate injury site (P<0.05). These results indicate that VEGF is important for angiogenesis and formation of bony repair tissue at the growth plate injury site as well as for endochondral bone lengthening function of the uninjured growth plate.

The common denominator for all types of rickets is hypophosphatemia, leading to inadequate supply of the mineral to the growing bone. Hypophosphatemia can result from insufficient uptake of the mineral from the gut or its disproportionate losses in the kidney, the latter being caused by either tubular abnormalities per se or the effect on the tubule of circulating factors like fibroblast growth factor-23 and parathyroid hormone (PTH). High serum levels of the latter result in most cases from abnormalities in vitamin D metabolism which lead to decreased calcium absorption in the gut and hypocalcemia, triggering PTH secretion. Rickets is a disorder of the growth plate and hence pediatric by definition. However, it is important to recognize that the effect of hypophosphatemia on other parts of the skeleton results in osteomalacia in both children and adults. This review addresses the etiology, pathophysiologic mechanisms, clinical manifestations and treatment of entities associated with hypophosphatemic rickets due to perturbations in renal tubular function.

Objective: Little is known of how to routinely elicit hyaline cartilage repair tissue in middle-aged patients. We tested the hypothesis that in skeletally aged rabbit knees, microdrill holes can be stimulated to remodel the bone plate and induce a more integrated, voluminous and hyaline cartilage repair tissue when treated by subchondral chitosan/blood implants., Design: New Zealand White rabbits (13 or 32 months old, N = 7) received two 1.5 mm diameter, 2 mm depth drill holes in each knee, either left to bleed as surgical controls or press-fit with a 10 kDa (distal hole: 10K) or 40 kDa (proximal hole: 40K) chitosan/blood implant with fluorescent chitosan tracer. Post-operative knee effusion was documented. Repair tissues at day 0 (N = 1) and day 70 post-surgery (N = 6) were analyzed by micro-computed tomography, and by histological scoring and histomorphometry (SafO, Col-2, and Col-1) at day 70., Results: All chitosan implants were completely cleared after 70 days, without increasing transient post-operative knee effusion compared to controls. Proximal control holes had worse osteochondral repair than distal holes. Both implant formulations induced bone remodeling and improved lateral integration of the bone plate at the hole edge. The 40K implant inhibited further bone repair inside 50% of the proximal holes, while the 10K implant specifically induced a "wound bloom" reaction, characterized by decreased bone plate density in a limited zone beyond the initial hole edge, and increased woven bone (WB) plate repair inside the initial hole (P = 0.016), which was accompanied by a more voluminous and hyaline cartilage repair (P < 0.05 vs control defects)., Conclusion: In a challenging aged rabbit model, bone marrow-derived hyaline cartilage repair can be promoted by treating acute drill holes with a biodegradable subchondral implant that elicits bone plate resorption followed by anabolic WB repair within a 70-day repair period., (Copyright © 2013 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Significant changes have occurred recently in fixation methods following fracture or osteotomy in children and teenagers. Children have benefited the most from these advances. A child's growth is anatomically and physiologically ensured by the growth plate and periosteum. The need to keep the periosteum intact during trauma cases has led to the introduction of flexible intramedullary nailing. We will review the basic principles of this safe, universally adopted technique, and also describe available material, length and diameter options. The problems and the limitations of this method will be discussed extensively. In orthopedics, the desire to preserve the periosteum has led to the use of locking compression plates. Because of their low profile and high stability, they allow the micromovements essential for bone union. These new methods reduce the immobilization period and allow autonomy to be regained more quickly, which is especially important in children with neurological impairment. The need to preserve the growth plate, which is well known in pediatric surgery, is reviewed with the goal of summarizing current experimental data on standard fracture and osteotomy fixation methods. Adjustable block stop wires provide better control over compression. These provide an alternate means of fixation between K-wires and screws (now cannulated) and have contributed to the development of minimally invasive surgical techniques. The aim of this lecture is to provide a rationale for the distinct technical features of pediatric surgery, while emphasizing the close relationship between the physiology of growth, bone healing and technical advances., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

Fractures of the growth plate region were performed with cadaver specimens obtained from the ovine distal femur and proximal tibia. Specimens of 6 different ages, ranging from 1 week to 4 years, were investigated in order to determine changes in the fracture characteristics. Mechanical properties (crack resistance and notch tensile strength), supported by microscopy of the distal tibia (thickness of growth plate and its zones, trabecular bone volume ratio) were determined. The crack propagated through different regions depending on age, which was observed both in microscopy and mechanical tests. In specimens of younger animals the fracture typically went through trabecular bone, often parallel to the growth plate, and only sometimes through the growth plate cartilage. Specimens of older animals fractured directly through the growth plate cartilage, while trabecular bone was not affected at all. Adult specimens had significantly higher mechanical values than the young ones. The results reveal the underlying mechanical properties that induce different fracture patterns of the epiphyseal growth plate at different stages of growth. The possibility of fractures through trabecular bone parallel to the growth plate in newborns and infants should be considered when clinical radiographs of paediatric fractures are analysed and classified., (© 2013 Elsevier Ltd. All rights reserved.)

As a potential means of comparing hypothyroidism in humans, this work intended to establish a defined hypothyroid state in immature miniature swine and evaluate specific molecular, cellular, and extracellular responses of their growth plates. Two male, 11-week-old Sinclair miniature swine were given 6-propyl-2-thiouracil (PTU) in their water and two other like animals (controls) were provided water without PTU. Blood levels of thyroid stimulating hormone (TSH), triiodothyronine (T3), and thyroxin (T4) were monitored weekly. At 25 weeks of age, the hind limb proximal femoral physes were harvested and divided into portions for histology and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analysis. Compared to controls, swine administered PTU exhibited increased TSH and decreased T3 and T4 serum levels during the study period, features consistent with a hypothyroid state. Compared to controls, hypothyroid swine exhibited structurally altered physes and demonstrated significantly decreased gene expression of aggrecan (p < 0.05) and type X collagen (p ≤ 0.1). This is the first hypothyroid model established in miniature swine and represents a potentially important advance for understanding the condition in humans, in which, like this swine model, there are changes critical to growth plate molecular biology, biochemistry and structure., (© 2013 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)