The physical examination is unreliable in determining the location of the distal fibular physis.

OBJECTIVES: Salter-Harris type 1 (SH1) fractures of the distal fibula are acute orthopedic injuries with tenderness over the physis without radiographic evidence of fracture. Our primary objective was to establish the accuracy of the physical examination performed by pediatric emergency medicine (PEM) physicians in determining the location of the distal fibular physis compared to a criterion standard of ultrasound. METHODS: This was a prospective, observational study at an urban academic pediatric emergency department of a convenience sample of children aged 4 to 10 years old between March 2019 and March 2020. A PEM physician or fellow examined the patient's distal fibula and marked the location of the physis with a marker. A study investigator scanned the distal fibula to establish the location of the physis on ultrasound and measured the distance between the clinician's estimated position and the actual sonographic position. We a priori defined a clinically accurate position as a distance of ≤5 mm. We compared the accuracy rate of physical examination to ultrasound landmarking using proportions with 95% confidence intervals (CI). RESULTS: We enrolled 71 patients, of whom 52 (73%) were male. The mean age was 6.7 years and the mean weight was 25.5 kg. Participating PEM physicians included 18 attending physicians and 2 fellows. The distal fibular physis was correctly identified in 24 patients, yielding an accuracy rate of 34% (95% CI 23%-46%). The mean distance between the physician's estimated position and the sonographic position was 7.4 mm (95% CI 6.4-8.4 mm). CONCLUSIONS: PEM physicians were unable to accurately identify the distal fibular physis on physical examination.

Selection for increased tibia length in mice alters skull shape through parallel changes in developmental mechanisms.

Bones in the vertebrate cranial base and limb skeleton grow by endochondral ossification, under the control of growth plates. Mechanisms of endochondral ossification are conserved across growth plates, which increases covariation in size and shape among bones, and in turn may lead to correlated changes in skeletal traits not under direct selection. We used micro-CT and geometric morphometrics to characterize shape changes in the cranium of the Longshanks mouse, which was selectively bred for longer tibiae. We show that Longshanks skulls became longer, flatter, and narrower in a stepwise process. Moreover, we show that these morphological changes likely resulted from developmental changes in the growth plates of the Longshanks cranial base, mirroring changes observed in its tibia. Thus, indirect and non-adaptive morphological changes can occur due to developmental overlap among distant skeletal elements, with important implications for interpreting the evolutionary history of vertebrate skeletal form.

Relationship of the Medial Patellofemoral Ligament Origin on the Distal Femur to the Distal Femoral Physis: A Systematic Review.

BACKGROUND: The relationship between the medial patellofemoral ligament (MPFL) and the distal femoral physis has been reported in multiple studies. PURPOSE: To determine the distance from the MPFL central origin on the distal femur to the medial distal femoral physis in skeletally immature participants. STUDY DESIGN: Systematic review. METHODS: A systematic review was performed according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Multiple databases were searched for studies investigating the anatomic origin of the MPFL on the distal femur and its relationship to the medial distal femoral physis in skeletally immature participants. Study methodological quality was analyzed with the Anatomical Quality Assessment tool, with studies categorized as low risk, high risk, or unclear risk of bias. Continuous variable data were reported as mean ± SD. Categorical variable data were reported as frequency with percentage. RESULTS: Seven articles were analyzed (298 femurs, 53.7% male patients; mean age, 11.7 ± 3.4 years). There was low risk of bias based on the Anatomical Quality Assessment tool. The distance from the MPFL origin to the distal femoral physis ranged from 3.7 mm proximal to the physis to 10.0 mm distal to the physis in individual studies. Six of 7 studies reported that the MPFL origin on the distal femur lies distal to the medial distal femoral physis in the majority of specimens. The MPFL originated distal to the medial distal femoral physis in 92.8% of participants at a mean distance of 6.9 ± 2.4 mm. CONCLUSION: The medial patellofemoral ligament originates distal to the medial distal femoral physis in the majority of cases at a mean proximal-to-distal distance of 7 mm distal to the physis. However, this is variable in the literature owing to study design and patient age and sex.

Trochlear Morphology Development: Study of Normal Pediatric Knee MRIs.

INTRODUCTION: Trochlear dysplasia is a known risk factor for patellar dislocations yet normal trochlea development is not well described. This study will define the articular cartilage (AC) and subchondral trochlear morphology development in pediatric patients using magnetic resonance imaging (MRI) evaluation. METHODS: A retrospective knee MRI review included patients aged 3 to 16 years with nonpatellofemoral-related diagnoses. International classification of diseases-9/International classification of diseases-10 codes were used to identify eligible study patients. Measurements of the trochlea were made on the basis of previously established methods using the axial MRI just distal to the physis at the deepest portion of the trochlear groove. Three linear [lateral trochlear height (LTH), medial trochlear height (MTH), and central trochlear height (CTH)] and 3 angular [sulcus angle (SA), lateral trochlear slope (LTS), and medial trochlear slope (MTS)] were made at AC and subchondral bone (SCB). The 12 measurements were made independently by 2 study authors. Inter-rater reliability was assessed using an interclass correlation coefficient for absolute agreement to the average of the scores. Trochlea measurements were summarized across age quartiles defined as first quartile (age, 5.1 to 8.3 y), second quartile (8.3 to 11.5 y), third quartile (11.5 to 14.3 y), fourth quartile (14.3to 16.9 y). Associations between age and trochlea measures were assessed using linear regression with Huber-White-adjusted SEs to account for clustering from a small number of patients (N=16) with >1 MRI. RESULTS: In total, 246 knee MRIs from 230 patients were included in this study; 113 patients (51%) were female, whereas 117 (49%) were male. A total of 116 MRIs (47%) were of the left knee and 130 (53%) were right knee. The average patient age was 11.4±3.4 years. Inter-rater agreement was high across all measures with interclass correlation coefficient values >0.7. Mean values for measurements are presented by age quartiles. LTH, MTH, and CTH showed a linear increase with age (range, 2 to 2.6 cm/y; P<0.001). SA, LTS, MTS measured at AC showed no change with age (P>0.05); however, LTS and MTS measured at SCB showed significant increases with age (0.6 and 0.9 degrees/y; P<0.001), whereas SA showed a decrease with age (-1.4 degrees/y; P<0.001). There were no significant differences found in the age associations by laterality, left versus right. There were no sex differences in the age associations for SA, LTS (P>0.05); however, for MTH, LTH, and CTH, males were found to have a significantly greater growth rate (P<0.001). CONCLUSIONS: This study found an increase in AC and SCB MTH, LTH, and CTH over time, as well as an increase in SCB LTS and MTS, with a decrease in SA. However, AC of the LTS and SA remained constant, with no significant change throughout growth. This normative data indicate that the LTS and SA of AC are predictors of final trochlea shape in normal development. Final trochlear morphologic development is nearly complete around age 12 years, with no significant changes occurring thereafter.

Modified Serum ALP Values and Timing of Apparition of Knee Epiphyseal Ossification Centers in Preterm Infants with Cholestasis and Risk of Concomitant Metabolic Bone Disease of Prematurity.

The usefulness of serum alkaline phosphatase (ALP) and phosphorous in screening and monitoring of metabolic bone disease of prematurity (MBDP) still has some limitations, especially in preterm infants with concomitant conditions such as cholestasis. We aimed to assess a modification of serum ALP (M-ALP) as a biomarker for MBDP in preterm infants, and the use of ultrasound monitoring for the apparition of knee ossification centers as marker of bone mineralization. Biochemical and clinical registers were taken from 94 preterm newborns <32 weeks. A significant correlation existed between serum ALP and direct bilirubin (DB), expressed by the regression equation: M-ALP (IU/L) = 302.1 + 96.9 (DB (mg/dL)). The ratio ALP/M-ALP > 1 was demonstrated to be more specific (87.5%) in the diagnosis of MBDP than the cut-off value of serum ALP > 500 IU/L (62.5%). ALP/M-ALP > 1 showed 100% sensitivity and specificity for the diagnosis of MBDP, and a good correlation with specific bone ALP (B-ALP). Patients with the knee nucleus by post-menstrual week 37 had lower B-ALP compared to patients with no nucleus, and no patients with MBDP presented the nucleus by the 40th week. In the absence of reliable specific B-ALP, reinterpreting serum ALP values by M-ALP plus monitoring of knee ossification centers contribute to better management of MBDP in preterm infants with cholestasis.

Ontogeny of the distal femoral metaphyseal surface and its relationship to locomotor behavior in hominoids.

OBJECTIVE: Distal femoral metaphyseal surface morphology is highly variable in extant mammals. This variation has previously been linked to differences in locomotor behavior. We perform the first systematic survey and description of the development of this morphology in extant hominoids. MATERIALS AND METHODS: We collected 3D surface laser scans of the femora of 179 human and great ape individuals throughout all subadult stages of development. We qualitatively and quantitatively describe metaphyseal surface morphology. RESULTS: We find that the metaphysis is topographically simple in all hominoids during the fetal and infant periods relative to later developmental periods, and in apes it develops significant complexity throughout development. Humans, by contrast, retain relatively flat metaphyseal surfaces throughout ontogeny. DISCUSSION: Major shifts in morphology appear to coincide with major shifts in locomotor behavior, suggesting that metaphyseal morphology is developmentally plastic and highly dependent on the biomechanical loadings at the knee joint. This is consistent with a large body of biomedical research, which demonstrates the primacy of mechanical forces in determining growth plate ossification patterns. Additionally, specific metaphyseal morphology appears highly correlated with specific locomotor modes, suggesting that metaphyseal surface morphology will be useful for reconstructing the locomotor behavior of fossil primate taxa.

Endochondral ossification and the evolution of limb proportions.

Mammals have remarkably diverse limb proportions hypothesized to have evolved adaptively in the context of locomotion and other behaviors. Mechanistically, evolutionary diversity in limb proportions is the result of differential limb bone growth. Longitudinal limb bone growth is driven by the process of endochondral ossification, under the control of the growth plates. In growth plates, chondrocytes undergo a tightly orchestrated life cycle of proliferation, matrix production, hypertrophy, and cell death/transdifferentiation. This life cycle is highly conserved, both among the long bones of an individual, and among homologous bones of distantly related taxa, leading to a finite number of complementary cell mechanisms that can generate heritable phenotype variation in limb bone size and shape. The most important of these mechanisms are chondrocyte population size in chondrogenesis and in individual growth plates, proliferation rates, and hypertrophic chondrocyte size. Comparative evidence in mammals and birds suggests the existence of developmental biases that favor evolutionary changes in some of these cellular mechanisms over others in driving limb allometry. Specifically, chondrocyte population size may evolve more readily in response to selection than hypertrophic chondrocyte size, and extreme hypertrophy may be a rarer evolutionary phenomenon associated with highly specialized modes of locomotion in mammals (e.g., powered flight, ricochetal bipedal hopping). Physical and physiological constraints at multiple levels of biological organization may also have influenced the cell developmental mechanisms that have evolved to produce the highly diverse limb proportions in extant mammals. This article is categorized under: Establishment of Spatial and Temporal Patterns > Regulation of Size, Proportion, and Timing Comparative Development and Evolution > Regulation of Organ Diversity Comparative Development and Evolution > Organ System Comparisons Between Species.

C-Type Natriuretic Peptide Restores Growth Impairment Under Enzyme Replacement in Mice With Mucopolysaccharidosis VII.

Growth impairment in mucopolysaccharidoses (MPSs) is an unresolved issue as it is resistant to enzyme replacement therapy (ERT) and growth hormone therapy. C-type natriuretic peptide (CNP) is a promising agent that has growth-promoting effects. Here we investigate the effects of CNP on growth impairment of MPSs using Gusbmps-2J mice, a model for MPS type VII, with combination therapy of CNP and ERT by hydrodynamic gene delivery. Although monotherapies were not sufficient to restore short statures of treated mice, combination therapy resulted in successful restoration. The synergistic effects of CNP and ERT were not only observed in skeletal growth but also in growth plates. ERT reduced cell swelling in the resting zone and increased cell number by accelerating proliferation or inhibiting apoptosis. CNP thickened the proliferative and hypertrophic zones. Regarding changes in the bone, ERT restored bone sclerosis through decreased bone formation and increased bone resorption, and CNP did not adversely affect this process. In addition, improvement of joint deformation by ERT was suggested by analyses of joint spaces and articular cartilage. CNP additively provided restoration of the short stature of MPS VII mice in combination with ERT, which improved abnormalities of growth plates and bone metabolism.

The distal radial physis: Exploring normal anatomy on MRI enables interpretation of stress related changes in young gymnasts.

Rationale: Explore the MRI-appearance of the healthy distal radial physis and the distribution of stress-related changes in physeal thickness in young gymnasts to aid in the understanding of the pathophysiological process of stress-related physeal injury. Methods: Symptomatic gymnasts with clinically suspected overuse injury of the distal radial physis and age and gender-matched asymptomatic gymnasts and healthy non-gymnasts underwent an MRI-scan of the wrist. A cartilage-specific sequence was used to obtain three-dimensional reconstructions of the distal radial physis. Heat maps and line charts of these reconstructions visualised distribution of physeal thickness per study group and were used to explore differences between study groups. Symptomatic gymnasts displaying the most profound physeal widening (n = 10) were analysed separately. Results: Twenty-seven symptomatic - (skeletal age 12.9 ± 1.5 years), 16 asymptomatic - (skeletal age 12.8 ± 1.9 years) and 23 non-gymnasts (skeletal age 13.6 ± 1.9 years) were included for analysis. Physes of healthy non-gymnasts had a thin centre and increased in thickness towards the borders. Gymnasts demonstrated an increase in thickness of the entire physeal surface. In symptomatic gymnasts increase in physeal thickness was most prominent at the volar side when compared to asymptomatic gymnasts and non-gymnasts. Conclusion: The healthy distal radial physis is characterised by a thin centre surrounded by thicker borders. Stress applied to the wrist during gymnastics causes an overall increase in physeal thickness. Profound thickness increase is present at the volar side of the physis mainly in symptomatic gymnasts. These results can help unravel the pathophysiological mechanism of stress-related physeal injury in gymnasts and aid early injury identification.

Anatomic Dissection and CT Imaging of the Anterior Cruciate and Medial Collateral Ligament Footprint Anatomy in Skeletally Immature Cadaver Knees.

BACKGROUND: Anterior cruciate ligament (ACL) and medial collateral ligament (MCL) injuries in skeletally immature patients are increasingly recognized and surgically treated. However, the relationship between the footprint anatomy and the physes are not clearly defined. The purpose of this study was to identify the origin and insertion of the ACL and MCL, and define the footprint anatomy in relation to the physes in skeletally immature knees. METHODS: Twenty-nine skeletally immature knees from 16 human cadaver specimens were dissected and divided into 2 groups: group A (aged 2 to 5 y), and group B (aged 7 to 11 y). Metallic markers were placed to mark the femoral and tibial attachments of the ACL and MCL. Computed tomography scans were obtained for each specimen used to measure the distance from the center of the ligament footprints to the respective distal femoral and proximal tibial physes. RESULTS: The median distance from the ACL femoral epiphyseal origin to the distal femoral physis was 0.30 cm (interquartile range, 0.20 to 0.50 cm) and 0.70 cm (interquartile range, 0.45 to 0.90 cm) for groups A and B, respectively. The median distance from the ACL epiphyseal tibial insertion to the proximal tibial physis for groups A and B were 1.50 cm (interquartile range, 1.40 to 1.60 cm) and 1.80 cm (interquartile range, 1.60 to 1.85 cm), respectively. The median distance from the MCL femoral origin on the epiphysis to the distal femoral physis was 1.20 cm (interquartile range, 1.00 to 1.20 cm) and 0.85 cm (interquartile range, 0.63 to 1.00 cm) for groups A and B, respectively. The median distance from the MCL insertion on the tibial metaphysis to the tibial physis was 3.05 cm (interquartile range, 2.63 to 3.30 cm) and 4.80 cm (interquartile range, 3.90 to 5.10 cm) for groups A and B, respectively. CONCLUSION: Surgical reconstruction is a common treatment for ACL injury. Computed tomography scanning of pediatric tissue clearly defines the location of the ACL and MCL with respect to the femoral and tibial physes, and may guide surgeons for physeal respecting procedures. CLINICAL RELEVANCE: In addition to ACL reconstruction, recent basic science and clinical research suggest that ACL repair may be more commonly performed in the future. MCL repair and reconstruction is also occasionally required in skeletally immature patients. This information may be useful to help surgeons avoid or minimize physeal injury during ACL/MCL reconstructions and/or repair in skeletally immature patients.

Endothelial proteolytic activity and interaction with non-resorbing osteoclasts mediate bone elongation.

Growth plate cartilage contributes to the generation of a large variety of shapes and sizes of skeletal elements in the mammalian system. The removal of cartilage and how this process regulates bone shape are not well understood. Here we identify a non-bone-resorbing osteoclast subtype termed vessel-associated osteoclast (VAO). Endothelial cells at the bone/cartilage interface support VAOs through a RANKL-RANK signalling mechanism. In contrast to classical bone-associated osteoclasts, VAOs are dispensable for cartilage resorption and regulate anastomoses of type H vessels. Remarkably, proteinases including matrix metalloproteinase-9 (Mmp9) released from endothelial cells, not osteoclasts, are essential for resorbing cartilage to lead directional bone growth. Importantly, disrupting the orientation of angiogenic blood vessels by misdirecting them results in contorted bone shape. This study identifies proteolytic functions of endothelial cells in cartilage and provides a framework to explore tissue-lytic features of blood vessels in fracture healing, arthritis and cancer.

The effect of a high-calorie diet on bone growth is mediated by the insulin receptor.

Obese children grow faster than their normal-weight peers. Insulin resistance and hyperinsulinemia have been associated with obesity-related growth acceleration. To determine whether obesity-associated hyperinsulinemia promotes bone growth by activating the insulin receptor in the growth plate, we generated TamCartIRflox/flox mice. The injection of 4 doses of tamoxifen in these mice (beginning at postnatal day 5th with 2 days interval between injections) resulted in the Insulin Receptor (IR) gene excision exclusively in the cartilage. TamCartIRflox/flox tamoxifen-treated mice (KO mice) and their IRflox/flox control littermates (C mice) at 3 weeks of age were exposed to a standard or hypercaloric (high-fat) diet for 4 weeks. At the end of study, C and KO mice fed with a high-fat diet exhibited greater weight gain than the respective strains fed with a standard diet. Body and tibial growth and growth plate height of C mice fed with high-fat diet were greater than those of standard-diet-fed C mice; however, no difference was observed between KO mice fed with standard or high-fat diet with respect to body and tibial growth and growth plate height. Circulating levels of insulin, IGF-1 and leptin were significantly higher in C and KO mice exposed to high-fat diet compared to those in the same strain exposed to standard diet. Increased phosphorylation of Akt (one of the intracellular mediators of insulin action in bone) in the growth plate of C mice on high-fat diet (compared to those on standard diet) suggests that high-fat-mediated increased circulating insulin levels may directly affect growth plate function and bone growth. High-fat diet was not associated with any change of Akt phosphorylation in KO mice. In addition, in vitro studies in cultured primary chondrocytes revealed that Akt mediates the stimulatory effects of insulin on chondrocyte proliferation and differentiation. In conclusion, the activation of the insulin receptor in the growth plate of mice fed with a hypercaloric diet stimulates skeletal growth and growth plate chondrogenesis.

Cam morphology in young male football players mostly develops before proximal femoral growth plate closure: a prospective study with 5-yearfollow-up.

OBJECTIVES: Cam morphology is not completely understood. The aim of this study was threefold: (1) to investigate if cam morphology development is associated with growth plate status; (2) to examine whether cam morphology continues to develop after growth plate closure; and (3) to qualitatively describe cam morphology development over 5-year follow-up. METHODS: Academy male football players (n=49) participated in this prospective 5-year follow-up study (baseline 12-19 years old). Anteroposterior and frog-leg lateral views were obtained at baseline (142 hips), 2.5-year (126 hips) and 5-year follow-up (98 hips). Cam morphology on these time points was defined as: (A) visual scores of the anterior head-neck junction, classified as: (1) normal, (2) flattening, and (3) prominence; and (B) alpha angle ≥60°. Proximal femoral growth plates were classified as open or closed. Cam morphology development was defined as every increase in visual score and/or increase in alpha angle from <60° to ≥60°, between two time points. This resulted in 224 measurements for cam morphology development analysis. RESULTS: Cam morphology development was significantly associated with open growth plates based on visual score (OR: 10.03, 95% CI 3.49 to 28.84, p<0.001) and alpha angle (OR: 2.85, 95% CI 1.18 to 6.88, p=0.020). With both definitions combined, cam developed in 104 of 142 hips during follow-up. Of these 104 hips, cam developed in 86 hips (82.7%) with open growth plate and in 18 hips (17.3%) with a closed growth plate. Cam morphology developed from 12 to 13 years of age until growth plate closure around 18 years. CONCLUSION: Cam morphology of the hip is more likely to develop with an open growth plate.

A Pediatric Medial Epicondyle Fracture Cadaveric Study Comparing Standard AP Radiographic View With the Distal Humerus Axial View.

BACKGROUND: Controversy exists with regard to the amount of fracture displacement that warrants surgical fixation of medial epicondyle fractures. Inaccurate determination of degree of displacement on plain radiographs may account for the disputed management. Recently, a novel distal humerus axial radiograph technique has been developed to improve the accuracy of radiographs. The purposes of the study are 2-fold; to identify the anatomic orientation of the medial elbow epicondyle physis in children and to compare the accuracy of determining fracture displacement between axial radiographs and standard anterior-posterior (AP) radiographs in a cadaveric medial epicondyle fracture model. METHODS: Twelve pediatric elbow computed tomographic scans and 19 pediatric elbow magnetic resonance imaging scans were analyzed for the orientation of the medial elbow physis. After determining the correct orientation, 15 adult cadaveric medial epicondyle fracture models were created at displacements of 2, 5, 10 mm, and maximum displacement with elbow at 90 degrees of flexion. A linear mixed model regression analysis was used to compare displacement based on the axial versus the AP radiographic methods. RESULTS: The medial epicondyle physis was found to be a posterior structure angled distally at ~36 degrees (range, 10.7 to 49.6) and angled posteriorly at 45 degrees (range, 32.2 to 59). The AP radiograph significantly underestimated displacement relative to the axial radiograph at 5 mm [mean difference, -1.6; 95% confidence interval (CI), -2.9 to -0.3], at 10 mm (mean difference, -4.5; 95% CI, -5.8 to -3.2 mm), and at maximal displacement (mean, 15 mm; range, 13 to 20 mm) (mean difference, -7.1; 95% CI, -8.3 to -5.8). CONCLUSIONS: The medial epicondyle physis of the distal humerus is a posterior structure angled distally and posteriorly. When displacement was >5 mm, the distal humerus axial radiograph technique was significantly more accurate than the AP radiograph technique at determining actual fracture displacement in our adult cadaveric fracture models. Therefore, we recommend clinicians to include the axial radiograph view during the evaluation of patients with medial epicondyle fractures. CLINICAL RELEVANCE: This study provides further insight into the location and orientation of the medial humeral epicondyle physis, and further supports the improved accuracy of the distal humerus axial radiograph at detecting displacement in medial epicondyle fractures.

Long bone human anlage longitudinal and circumferential growth in the fetal period and comparison with the growth plate cartilage of the postnatal age.

The patterns of longitudinal and peripheral growth were analyzed in human autopod cartilage anlagen (fetal developmental stage 20th-22nd week) through morphometric assessment of chondrocyte parameter size, shape, alignment and orientation between peripheral and central sectors of the anlage transition zone defined by primary ossification center and the epiphyseal basis. The aim was to correlate the chondrocyte dynamics with the longitudinal and peripheral growth. A further comparison was carried out between the corresponding sectors of the postnatal (3-5 months old) growth plate cartilage documenting: (1) the different chondrocyte framework and the new peripheral mechanism; (2) the opposite direction of fetal periosteal ossification versus the Lacroix bone bark. Measurement of multiple parameters (% lac area, % total matrix area, total lac density and mean single lac area), which characterize the cartilage Anlage growth, suggested the following correlations with chondrocyte duplication rate: (a) slow duplication rate ≈ coupled, intralacunar chondrocytes (in central epiphysis); (b) repeated/frequent cell duplications ≈ clusters (in the basal epiphyseal layer); (c) clusters of chondrocytes before becoming hypertrophic were stacked up on the top of each other (both in the Anlage transition zone or in the columns of metaphyseal growth plate); (d) enhanced osteoclastic resorption of the Lacroix bone bark lower end, extended to the more external metaphyseal trabeculae counterbalancing the discrepancy between the epiphyseal and the diaphyseal circumferential growth.

Epiphyseal growth plate architecture is unaffected by early postnatal activation of the expression of R992C collagen II mutant.

Spondyloepiphyseal dysplasia (SED) exemplifies a group of heritable diseases caused by mutations in collagenous proteins of the skeletal system. Its main feature is altered skeletal growth. Pathomechanisms of SED include: changes in the stability of collagen II molecules, inability to form proper collagen fibrils, excessive intracellular retention of mutant molecules, and endoplasmic reticulum stress. The complexity of this pathomechanism presents a challenge for designing therapies for SED. Our earlier research tested whether such therapies only succeed when applied during a limited window of development. Here, employing an inducible mouse model of SED caused by the R992C mutation in collagen II, we corroborate our earlier observations that a therapy must be applied at the prenatal or early postnatal stages of skeletal growth in order to be successful. Moreover, we demonstrate that blocking the expression of the R992C collagen II mutant at the early prenatal stages leads to long-term positive effects. Although, we could not precisely mark the start of the expression of the mutant, these effects are not significantly changed by switching on the mutant production at the early postnatal stages. By demonstrating the need for early therapeutic interventions, our study provides, for the first time, empirically-based directions for designing effective therapies for SED and, quite likely, for other skeletal dysplasias caused by mutations in key macromolecules of the skeletal system.

The tibial growth plate as a predictor of the original tibial plateau joint line as a reference for kinematically aligned total knee arthroplasty.

BACKGROUND: Restoration of the natural joint line is a cornerstone for kinematically aligned total knee arthroplasty (TKA). The purpose of this study was to investigate the relative orientation of the tibial growth plate (GP) with respect to the tibial plateau (TP) for possible application in predicting natural joint line for knees with highly advanced osteoarthritis patient at the time of kinematically aligned TKA. METHODS: Images from computed tomography (CT) of 27 normal knees (9 males, 18 females; mean age, 31.6 years) were studied. Geometry of the GP was extracted from CT images, and its moment-of-inertia axes were calculated for the whole GP and the medial and lateral halves. Angular orientations of each GP axis with respect to the TP plane were measured in anatomical coordinates. RESULTS: The TP and GP planes were oriented in 2.3 ± 1.8° of varus and 1.1 ± 1.9° of valgus relative to the tibial mechanical axis, respectively. With respect to the TP plane, the whole GP plane was inclined in 3.4 ± 1.5° of valgus. Orientation of the GP plane differed drastically between medial and lateral halves. The medial GP was in 4.9 ± 2.9° of varus and 1.8 ± 2.5° of anterior inclination, and the lateral half was in 10.4 ± 2.4° of valgus and 18.6 ± 4.0° of anterior inclination relative to the TP. CONCLUSIONS: Angular orientation of the original TP plane can be predicted in reference to the GP plane and may provide reasonable guidance for the target bone resection angle of the tibia in kinematically aligned TKA.

The influence of biodegradable magnesium implants on the growth plate.

Mg-based biodegradable materials are considered promising candidates in the paediatric field due to their favourable mechanical and biological properties and their biodegrading potential that makes a second surgery for implant removal unnecessary. In many cases the surgical fixation technique requires a crossing of the growth plate by the implant in order to achieve an adequate fragment replacement or fracture stabilisation. This study investigates the kinetics of slowly and rapidly degrading Mg alloys in a transphyseal rat model, and also reports on their dynamics in the context of the physis and consecutive bone growth. Twenty-six male Sprague-Dawley rats received either a rapidly degrading (ZX50; n = 13) or a slowly degrading (WZ21; n = 13) Mg alloy, implanted transphyseal into the distal femur. The contralateral leg was drilled in the same manner and served as a direct sham specimen. Degradation behaviour, gas formation, and leg length were measured by continuous in vivo micro CT for up to 52 weeks, and additional high-resolution µCT (HRS) scans and histomorphological analyses of the growth plate were performed. The growth plate was locally destroyed and bone growth was significantly diminished by the fast degradation of ZX50 implants and the accompanying release of large amounts of hydrogen gas. In contrast, WZ21 implants showed homogenous and moderate degradation performance, and the effect on bone growth did not differ significantly from a single drill-hole defect. STATEMENT OF SIGNIFICANCE: This study is the first that reports on the effects of degrading magnesium implants on the growth plate in a living animal model. The results show that high evolution of hydrogen gas due to rapid Mg degradation can damage the growth plate substantially. Slow degradation, however, such as seen for WZ21 alloys, does not affect the growth plate more than drilling alone, thus meeting one important prerequisite for deployment in paediatric osteosynthesis.

Variation in the Medial Patellofemoral Ligament Origin in the Skeletally Immature Knee: An Anatomic Study.

BACKGROUND: The medial patellofemoral ligament (MPFL) is frequently reconstructed to treat recurrent patellar instability. The femoral origin of the MPFL is well described in adults but not in the skeletally immature knee. PURPOSE: To identify a radiographic landmark for the femoral MPFL attachment in the skeletally immature knee and study its relationship to the distal femoral physis. STUDY DESIGN: Descriptive laboratory study. METHODS: Thirty-six cadaveric specimens between 2 and 11 years old were dissected and examined (29 male and 7 female). Metallic markers were placed at the proximal and distal borders of the MPFL femoral origin footprint. Computed tomography scans with 0.625-mm slices in the axial, coronal, and sagittal planes were used to measure the maximum ossified height and ossified depth. The measurements were used to describe the position of the midpoint MPFL attachment with respect to the posterior-anterior and distal-proximal dimensions of the femoral condyle on the sagittal view and to describe the distance from the physis to the femoral origin of the MPFL. RESULTS: In 23 of 36 specimens, the femoral origin of the MPFL was distal to the physis. Thirteen of the 36 specimens had an MPFL origin at or proximal to the physis, with a more proximal MPFL origin consistently seen in older specimens. The distance of the MPFL origin to the physis ranged from 15.1 mm distal to the physis to 8.3 mm proximal to the physis. The mean midpoint of the MPFL femoral origin was located 3.0 ± 5.5 mm distal to the physis for all specimens. For specimens aged <7 years, the mean MPFL origin was 4.7 mm distal to the physis, and for specimens aged ≥7 years, the mean MPFL origin was 0.8 mm proximal to the femoral physis. The MPFL origin was more proximal and anterior for those aged ≥7 years and more distal and posterior for those aged <7 years. CONCLUSION: Surgical reconstruction of the MPFL is a common treatment to restore patellar stability. There appears to be significant variability in the origin of the MPFL in skeletally immature specimens. This study demonstrated that the MPFL origin was more proximal and anterior with respect to the physis in the older age group. The MPFL origin footprint may be customized for different age groups. CLINICAL RELEVANCE: This information shows anatomic variation of the MPFL origin with age, with older specimens having a footprint that was more proximal and anterior than younger specimens. Customization of the surgical technique might be considered based on patient age.

Effects of bisphosphonates on osteogenesis and osteoclastogenesis signaling during the endochondral ossification of growing rats.

Osteoclasts and chondroclasts are necessary, during endochondral ossification, for the resorption of primary bone and calcified cartilage septa, respectively. The bisphosphonates inhibit mineralized tissue resorption by various mechanisms according to the different types of this drug, which can affect bone remodeling during skeletal growth. The objective of the present study is to analyze the way that alendronate (ALN) and etidronate (ETN) can affect osteoclastogenesis and bone formation during endochondral ossification of the long bones of growing rats. Newborn Wistar rats were treated daily with ETN, ALN, or sterile saline solution (control) for 21 days. Their femur and tibiae epiphyses were radiographed and analyzed by light, scanning and transmission electron microscopy. The expression of genes related to osteogenesis and to osteoclast differentiation and activity were analyzed by real-time quantitative polymerase chain reaction. The ETN group presented reduced body weight, disorganized growth plate and an extended area of cartilage in the ossification zone with little bone matrix; in the ALN group, this area was not altered. The ALN presented latent TRAP-positive cells, whereas in the ETN group, they were activated. The expression of NFκB1 and 2, OPG, Spp1 and Runx2 in the ossification zone was reduced by both bisphosphonates. RANKL expression was reduced by ETN, whereas ALN decreased the expression of RANK. The results also indicated that, in addition to the anti-resorptive effect of the drugs, disturbances in bone deposition occurred concomitantly with the reduced expression of osteogenesis-related genes.