Characterisation of Growth Plate Dynamics in Murine Models of Osteoarthritis.

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.

Rhizomelia and Impaired Linear Growth in a Girl with Juvenile Paget Disease: The Natural History of the Condition.

In ultra-rare bone diseases, information on growth during childhood is sparse. Juvenile Paget disease (JPD) is an ultra-rare disease, characterized by loss of function of osteoprotegerin (OPG). OPG inhibits osteoclast activation via the receptor activator of nuclear factor-κB (RANK) pathway. In JPD, overactive osteoclasts result in inflammatory-like bone disease due to grossly elevated bone resorption. Knowledge on the natural history of JPD, including final height and growth, is limited. Most affected children receive long-term antiresorptive treatment, mostly with bisphosphonates, to contain bone resorption, which may affect growth. In this study, we report the follow-up of height, growth velocity, and skeletal maturation in a 16-year-old female patient with JPD. The patient was treated with cyclic doses of pamidronate starting at 2.5 years of age and with 2 doses of denosumab at the age of 8 years, when pamidronate was paused. In the following years, a sustainable decline in a height z-score and a stunted pubertal growth spurt; despite appropriate maturation of the epiphyseal plates of the left hand, the proximal right humerus and both femora were observed. Whether this reflects the growth pattern in JPD or might be associated to the antiresorptive treatments is unclear, since there is very limited information available on the effect of bisphosphonates and denosumab on growth and the growth plate in pediatric patients. Studies are needed to understand the natural history of an ultra-rare bone disease and to assess the effects of antiresorptive treatment on the growing skeleton.

Growth Disturbance Following Intra-articular Distal Radius Fractures in the Skeletally Immature Patient.

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.

Abnormal epiphyseal development in a feline model of Sandhoff disease.

Sandhoff disease (SD) is caused by decreased function of the enzyme ß-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.

All-epiphyseal anterior cruciate ligament reconstruction produces good functional outcomes and low complication rates in pediatric patients: a systematic review.

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).

The Role of Hyperinsulinemia in Slipped Capital Femoral Epiphysis.

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.

Skeletal maturation and growth rates are related to bone and growth plate injuries in adolescent athletics.

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.

Continued Statural Growth in Older Adolescents and Young Adults With Crohn's Disease and Ulcerative Colitis Beyond the Time of Expected Growth Plate Closure.

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.

Growth plate alterations in chronic kidney disease.

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.

Sagittal plane deformity after temporary epiphysiodesis of the distal femur for correcting limb length discrepancy.

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.

Predicting growth plate orientation with altered hip loading: potential cause of cam morphology.

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.

A comparison of the bone and growth phenotype of mdx, mdx:Cmah-/- and mdx:Utrn+/- murine models with the C57BL/10 wild-type mouse.

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 mdx: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:Cmah-/- 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.

Correction osteotomy for bilateral varus knee deformity caused by premature epiphyseal closure induced by hypervitaminosis A: a case report.

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.

Capital Femoral Epiphyseal Extension May Confer Physeal Stability in Slipped Capital Femoral Epiphysis.

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.

Endoplasmic reticulum stress affected chondrocyte apoptosis in femoral head necrosis induced by glucocorticoid in broilers.

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.

Cartilage degradation in osteoarthritis: A process of osteochondral remodeling resembles the endochondral ossification in growth plate?

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.

Distraction-suppression effect on osteosarcoma.

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.

The Role of the Basement Plate in Physeal Bar Formation.

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.

Consequences Following Distal Femoral Growth Plate Violation in an Ovine Model With an Intramedullary Implant: A Pilot Study.

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.

Carbamazepine reduces disease severity in a mouse model of metaphyseal chondrodysplasia type Schmid caused by a premature stop codon (Y632X) in the Col10a1 gene.

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.