Introduction: Metaphyseal inwaisting is a process that occurs during long bone growth and remodelling of epiphyses and results in a proportional increase in growth plate width (GPW) and a decrease in metaphyseal width (MW). The Metaphyseal Index (MI) compares GPW to MW, usually in the distal femur. However, due to bone-age assessments, the most commonly performed radiograph in children is that of the hand/forearm. Previous work showed that gymnasts have a more widened growth plate at the distal radius than normal children, but these studies did not quantify the morphological changes using the MI and pQCT measures. Previous studies have shown that the use of DXA hand/forearm images for the purposes of bone-age assessment were unreliable for children aged 11 and under. Aims: Examine distal radius morphology of 378 Normal subjects (155 male), 36 Gymnast subjects (15 male), 17 NF1 subjects (7 male) and 108 CDGP subjects (83male) to calculate the precision of MI, MW and GPW measurements, to determine a normal reference range for the MI in Normal subjects and use this to compare to the other 3 groups, and to compare longitudinal measurements. Also, to investigate whether DXA software upgrades have improved the ability to make TW3 bone-age assessments, to investigate how closely DXA compares with standard radiographs using 98 (38 male) DXA hand images and radiographs, and calculate the precision (CV%) of the GP and TW3 bone-age assessment methods. Methods: Anthropometric data, Tanner stage, posterior-anterior hand radiographs and pQCT scans of the non-dominant hand/forearm were obtained. MI was measured using a semi-automated computer-assisted method. Statistical analyses were used to compare males and females, and compare the Normal group to other groups. Also, DXA images and radiographs were assessed by the same assessor and the TW3 and GP bone-ageing methods were compared. A CV% was calculated for both comparisons. Results: The CV% of MI, MW and GPW = 1.05%, 0.92% and 1.28% respectively. MI of males and females was not statistically different in any group. The MI of Gymnasts was significantly lower than the Normal group (p = 0.008). The NF1 and CDGP groups were not significantly different from the Normal group. Longitudinal measurements indicated those with a low/high MI at the first visit were likely to have a low/high MI at the second visit, though occasionally the MI would decrease between visits. DXA bone age assessments proved to be reliable in subjects of all ages assessed in this study and showed a CV% only slightly higher than standard radiographs (CV = 2.95% DXA vs2.68% radiograph). The CV% of GP and TW3 methods = 2.68% & 1.61% respectively. Discussion: The CV% of MI, MW and GPW shows these methods to be very precise. The mean MI of gymnasts is significantly lower than in normal children due to a widening of the growth plate and not due to a reduction in metaphyseal width. Insufficient subject numbers and smaller age ranges, particularly in the Gymnast and NF1 groups may play a part in the non-significant differences between them and the Normal group. DXA CV% shows that DXA is almost interchangeable with standard radiographs. The TW3 and GP CVs% show that TW3 bone-age assessment is more precise than the GP method. This confirms the tight control that the MW and GPW have in proportion to each other. This is the first study to quantify changes in distal radius morphology in normal, athlete and disease groups, and create a range of normal reference values, which could be useful for future work in this area.

Mutations in the COL10A1 gene cause metaphyseal chondrodysplasia type Schmid (MCDS) by triggering ER stress and unfolded protein response (UPR). MCDS is characterised by a mild short-limb dwarfism accompanied by expansion of the cartilage growth plate hypertrophic zone (HZ) and altered differentiation of hypertrophic chondrocytes (HCs). ATF6 is one of the UPR mediators, which exists in two isoforms, ATF6α and ATF6β. Activation and up-regulation of ATF6α was a prominent biochemical sign of ER stress in a mouse model of MCDS, COL10a1 p.N617K. Although ATF6β is induced and activated in response to ER stress in a similar fashion to ATF6α, the role and significance of ATF6β in the pathology of many ER stress-associated diseases including MCDS is unknown. Here we utilized a combination of in vitro and in vivo approaches to define the precise role of each isoform of ATF6 in MCDS.To investigate the functions of ATF6α and ATF6β in vitro, we developed a MCDS cell model system (expressing either the wild type collagen X or one of the following MCDS-causing mutant forms of the protein: p.N617K, G618V, Y598D, and NC1del10) in which the expression of either ATF6α or ATF6β was efficiently silenced using siRNAs. ATF6α knockdown in HeLa cells expressing different MCDS-causing mutations suppressed the increased expression of UPR-associated genes such as BiP leading to an elevated ER stress, based on increased XBP1 splicing and/or ATF4 protein. In contrast, ATF6β knockdown did not significantly affect the mutant collagen X-induced increased expression of UPR-associated genes. Furthermore, the ER stress levels were significantly reduced in the ATF6β knockdown MCDS mutant cells based on the lower levels of XBP1 splicing and/or ATF4 protein detected. We then crossed the ATF6α/β knockout mice models with COL10a1 p.N617K mouse model of MCDS to investigate the function of ATF6α and ATF6β in vivo. Ablation of ATF6α in MCDS mice further- reduced the endochondral bone growth rate, further expanded the growth plate hypertrophic zone, and disrupted differentiation of HCs. Therefore, ATF6α appeared to play a chondroprotective role in MCDS as its deficiency caused an increase in the severity of the disease. Of particular note, the level of ER stress was further increased in the absence of ATF6α in MCDS, based on enhanced activities of PERK and IRE1 signalling pathways in compensation for the ATF6α loss. Paradoxically, ablation of ATF6β in MCDS mice reduced the intracellular retention of collagen X protein, and alleviated the ER stress as judged by the attenuated activities of PERK and IRE1 signalling pathways. The reduced ER stress resulting from deficiency for ATF6β in MCDS mice restored the expression of collagen X mRNA towards normal and improved the differentiation of HCs, causing a mark decrease in the expansion of HZ. The results presented within this thesis greatly increased our understanding of the function of ATF6α and ATF6β and their interplay in the pathogenesis of MCDS. We demonstrated an indispensable beneficiary role for ATF6α but a detrimental role for its closely related isoform, ATF6β, in pathology of MCDS. We also showed that the role of ATF6β should not be ignored. These findings may be used to develop a potential therapeutic strategy for MCDS through targeting and enhancing ATF6α-dependent and/or attenuating/blocking of ATF6β-dependent signalling pathways.

The classic metaphyseal lesion (CML) is considered to be a strong indicator of physical abuse in infants. These fractures extend through the metaphysis of a long bone near the growth plate, disrupting the trabecular bone structure. The mechanism(s) behind this fracture type are not entirely understood. The present study investigated experimentally the possible loading conditions required to generate CMLs in pig models. Fifty hindlegs from stillborn pigs were tested in torsion using a mechanical testing machine and a digital torque wrench. Fractures to the metaphysis that resemble CMLs were produced during a combined loading event which applied torsion to the knee joint (distal femur, proximal tibia, and proximal fibula). A visual assessment of the physeal surface of each specimen was performed after testing, and classic metaphyseal lesions were identified by comparison with findings from Love et al. (2011). The only fractures seen in both the femora and tibiae were CMLs, with both bone types having 60% (30 of 50) total fractures. The frequency of total fractures on fibulae was less, with 42% (21 of 50). The frequency of CMLs in the fibulae, however, is lower than the frequency of total fractures (38%, n=50), as physeal fractures also presented in some of those bones. Thus, the CML was the most common type of fracture produced due to the torque applied to the bones during testing. When assessing the number of CMLs that occurred on each limb, nine limbs had only one CML present, while 28 limbs had one or more CMLs. Additionally, complete CMLs made up 51.9% (41 of 79) of the total number, while partial made up 48.1% (38 of 79). Out of the 150 bones tested, 79 (52.7%) showed fractures resembling CMLs in human infants. A fracture was 35% more likely to occur in a femur or a tibia than in a fibula, and multiple CMLs per specimen were more common than single CMLs. The physeal surfaces of the specimens recorded as having CMLs showed damage to the trabecular bone. Three physeal fractures were noted; one Type IV physeal fracture on a proximal tibia and one on a proximal fibula, and a Type II physeal fracture on a proximal fibula. No diaphyseal fractures of any kind were produced. Further investigation of these conditions is encouraged to gain more insight into the injury mechanism.

Background: Complex proximal humerus fractures with metaphyseal comminution remain challenging regarding reduction and stability. In most fracture patterns the hard bone of the bicipital groove remains intact. In this case series, we describe a novel technique of hybrid double plate osteosynthesis of complex proximal humerus fractures with metaphyseal comminution. Methods: In randomly chosen shoulder specimens and synthetic bones, pilot studies for evaluation of the feasibility of the technique were performed. Between 4/2010 and 1/2012 10 patients underwent hybrid double plate osteosynthesis. Seven patients (4 male, 3 female, mean age was 50 years (range 27–73)) were available for retrospective analysis. Based on plain radiographs (anterior-posterior and axial view), the fractures were classified according to the Orthopaedic Trauma Association classification (OTA) and by descriptive means (head-split variant (HS), diaphyseal extension or comminution (DE)). Results: Follow-up radiographs demonstrated complete fracture healing in six patients and one incomplete avascular necrosis. None of the patients sustained loss of reduction. Three patients where reoperated. The medium, not adapted, Constant score was 80 Points (58–94). Patients subjective satisfaction was graded mean 3 (range: 0–6) in the visual analog scoring system (VAS). Conclusion: The technique of hybrid double plate osteosynthesis using the bicipital groove as anatomic landmark may re-establish shoulder function after complex proximal humerus fractures in two dimensions. Firstly the anatomy is restored due to a proper reduction based on intraoperative landmarks. Secondly additional support by the second plate may provide a higher stability in complex fractures with metaphyseal comminution.

Dans le cadre de ce mémoire, les relations entre morphologie, locomotion et croissance chez les hominoïdes sont analysées sous l'angle des proportions métaphysaires et de leur acquisition. Plusieurs niveaux d'analyse — intermembre, supérieur et inférieur — sont abordés dans une perspective ontogénique. La masse corporelle et la direction des charges influencent la morphologie des surfaces articulaires et métaphysaires mais aussi leur développement. Les charges étant dépendantes du mode locomoteur et celui-ci se modifiant en fonction de l'âge, on tente de voir à quel(s) moment(s) les changements proportionnels ont lieu et pourquoi ils apparaissent. Des mesures linéaires ont été recueillies sur l'humérus, le radius, le fémur et le tibia sur un échantillon squelettique des espèces H. sapiens, P. troglodytes, G. gorilla et P. pygmaeus. À partir de ces mesures et du calcul de certains ratios, des comparaisons intra et interspécifiques ont été réalisées. Les différences les plus significatives entre les espèces se dévoilent au niveau intermembre et sont relatives aux différents pourcentages d'utilisation des membres supérieurs ou inférieurs. Au sein des espèces, les résultats révèlent une similarité dans les réactions des surfaces métaphysaires au niveau intermembre, supérieur et inférieur. Les changements proportionnels ont lieu entre les stades 0 et 1 pour H. sapiens (première marché indépendante), entre les stades 2 et 4 pour P. troglodytes (majorité du poids corporel soutenue par les membres inférieurs) et entre les stades 3 et 5 pour G. gorilla (taille adulte et quadrupédie très majoritaire). Pour P. pygmaeus aucun stade en particulier n'a été ciblé par les analyses et cela concorde avec l'homogénéité de ses modes de locomotion employés au cours de la vie. Les différences proportionnelles répondent à des changements locomoteurs majeurs. Australopithecus afarensis est intermédiaire entre H. sapiens et les grands singes pour de nombreuses comparaisons. Au niveau du genou, les plus jeunes individus A. afarensis ne montrent pas de morphologie bipède, similaire aux humains. / This thesis analyses the relationship between morphology, locomotion and growth in hominoids by studying metaphyseal proportions and development. Several levels of analysis — interlimb, upper and lower limbs — are discussed in an ontogenic perspective. Body mass and direction of loads affect the morphology of articular and metaphyseal surfaces but also their development. Taking into account the locomotion of a species and related loads during growth, we try to determine when proportions change, if at all, and why they appear. Australopithecus afarensis is one species for which the debate about its locomotion is still ongoing, study of the ontogeny of its proportions may shed light on the functions of its limbs during locomotion. Linear measurements were collected on the humerus, radius, ulna, femur and tibia of H. sapiens, P. troglodytes, G. gorilla and P. pygmaeus. From these measurements, ratios have been calculated to intra and inter limb proportions of hominoid appendicular skeleton for different age groups. Differences between species are most significant at the interlimb level and relative to the different relative percentage of upper and lower limbs use. Within species, results reveal a similarity for metaphyseal surfaces responses to loads at all levels of analyses. Proportional changes take place between dental stages 0 and 1 for H. sapiens (acquisition of bipedality), between stages 2 and 4 for P. troglodytes (majority of body weight supported by the lower limb) and between stages 3 and 5 for G. gorilla (knuckle-walking for 85 % of the time). For P. pygmaeus, no proportional change occur at any specific stage, which corresponds to the absence of changes in locomotor behavior from birth to adulthood in that species. From these data, it appears that proportional differences are responses to major changes in the mode of locomotion. Australopithecus afarensis is intermediate between H. sapiens and apes for many proportional comparisons while the knee joint, contrarily to expectation, is not like the bipedal humans.

Dans le cadre de ce mémoire, les relations entre morphologie, locomotion et croissance chez les hominoïdes sont analysées sous l'angle des proportions métaphysaires et de leur acquisition. Plusieurs niveaux d'analyse — intermembre, supérieur et inférieur — sont abordés dans une perspective ontogénique. La masse corporelle et la direction des charges influencent la morphologie des surfaces articulaires et métaphysaires mais aussi leur développement. Les charges étant dépendantes du mode locomoteur et celui-ci se modifiant en fonction de l'âge, on tente de voir à quel(s) moment(s) les changements proportionnels ont lieu et pourquoi ils apparaissent. Des mesures linéaires ont été recueillies sur l'humérus, le radius, le fémur et le tibia sur un échantillon squelettique des espèces H. sapiens, P. troglodytes, G. gorilla et P. pygmaeus. À partir de ces mesures et du calcul de certains ratios, des comparaisons intra et interspécifiques ont été réalisées. Les différences les plus significatives entre les espèces se dévoilent au niveau intermembre et sont relatives aux différents pourcentages d'utilisation des membres supérieurs ou inférieurs. Au sein des espèces, les résultats révèlent une similarité dans les réactions des surfaces métaphysaires au niveau intermembre, supérieur et inférieur. Les changements proportionnels ont lieu entre les stades 0 et 1 pour H. sapiens (première marché indépendante), entre les stades 2 et 4 pour P. troglodytes (majorité du poids corporel soutenue par les membres inférieurs) et entre les stades 3 et 5 pour G. gorilla (taille adulte et quadrupédie très majoritaire). Pour P. pygmaeus aucun stade en particulier n'a été ciblé par les analyses et cela concorde avec l'homogénéité de ses modes de locomotion employés au cours de la vie. Les différences proportionnelles répondent à des changements locomoteurs majeurs. Australopithecus afarensis est intermédiaire entre H. sapiens et les grands singes pour de nombreuses comparaisons. Au niveau du genou, les plus jeunes individus A. afarensis ne montrent pas de morphologie bipède, similaire aux humains. / This thesis analyses the relationship between morphology, locomotion and growth in hominoids by studying metaphyseal proportions and development. Several levels of analysis — interlimb, upper and lower limbs — are discussed in an ontogenic perspective. Body mass and direction of loads affect the morphology of articular and metaphyseal surfaces but also their development. Taking into account the locomotion of a species and related loads during growth, we try to determine when proportions change, if at all, and why they appear. Australopithecus afarensis is one species for which the debate about its locomotion is still ongoing, study of the ontogeny of its proportions may shed light on the functions of its limbs during locomotion. Linear measurements were collected on the humerus, radius, ulna, femur and tibia of H. sapiens, P. troglodytes, G. gorilla and P. pygmaeus. From these measurements, ratios have been calculated to intra and inter limb proportions of hominoid appendicular skeleton for different age groups. Differences between species are most significant at the interlimb level and relative to the different relative percentage of upper and lower limbs use. Within species, results reveal a similarity for metaphyseal surfaces responses to loads at all levels of analyses. Proportional changes take place between dental stages 0 and 1 for H. sapiens (acquisition of bipedality), between stages 2 and 4 for P. troglodytes (majority of body weight supported by the lower limb) and between stages 3 and 5 for G. gorilla (knuckle-walking for 85 % of the time). For P. pygmaeus, no proportional change occur at any specific stage, which corresponds to the absence of changes in locomotor behavior from birth to adulthood in that species. From these data, it appears that proportional differences are responses to major changes in the mode of locomotion. Australopithecus afarensis is intermediate between H. sapiens and apes for many proportional comparisons while the knee joint, contrarily to expectation, is not like the bipedal humans.

Background: Complex proximal humerus fractures with metaphyseal comminution remain challenging regarding reduction and stability. In most fracture patterns the hard bone of the bicipital groove remains intact. In this case series, we describe a novel technique of hybrid double plate osteosynthesis of complex proximal humerus fractures with metaphyseal comminution. Methods: In randomly chosen shoulder specimens and synthetic bones, pilot studies for evaluation of the feasibility of the technique were performed. Between 4/2010 and 1/2012 10 patients underwent hybrid double plate osteosynthesis. Seven patients (4 male, 3 female, mean age was 50 years (range 27–73)) were available for retrospective analysis. Based on plain radiographs (anterior-posterior and axial view), the fractures were classified according to the Orthopaedic Trauma Association classification (OTA) and by descriptive means (head-split variant (HS), diaphyseal extension or comminution (DE)). Results: Follow-up radiographs demonstrated complete fracture healing in six patients and one incomplete avascular necrosis. None of the patients sustained loss of reduction. Three patients where reoperated. The medium, not adapted, Constant score was 80 Points (58–94). Patients subjective satisfaction was graded mean 3 (range: 0–6) in the visual analog scoring system (VAS). Conclusion: The technique of hybrid double plate osteosynthesis using the bicipital groove as anatomic landmark may re-establish shoulder function after complex proximal humerus fractures in two dimensions. Firstly the anatomy is restored due to a proper reduction based on intraoperative landmarks. Secondly additional support by the second plate may provide a higher stability in complex fractures with metaphyseal comminution.

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No description available.

Die Homöostase des Knochengewebes wird durch das balancierte Zusammenspiel von Ossifikation und Resorption gewährleistet. Eine in Relation zur Resorption zu starke Ossifikation führt zur Modellierungsstörung, Hyperostose und Sklerose. Knochenerkrankungen mit diesen Merkmalen werden als Sklerosierende Skelettdysplasien erfasst. Gegenstand der vorliegenden Arbeit sind fünf Skelettdysplasien aus dem Formenkreis der Sklerosierenden Skelettdysplasien: (1) Craniometaphysäre Dysplasie, autosomal dominante Form (MIM #123000); (2) Metaphysäre Dysplasie, Typ Braun-Tinschert (MIM *605946); (3) Caffey-Syndrom (MIM *114000); (4) McCune-Albright-Syndrom (MIM #174800); (5) Melorheostose (MIM 155950). Diese werden auf unterschiedlichen pathogenetischen Ebenen charakterisiert, die den Etappen des Weges entsprechen, der mit der Analyse des Phänotyps beginnt und zu einer Aufklärung des Basisdefektes führt. Die Arbeit gliedert sich ein in die Reihe von Bemühungen, zum molekularen Verständnis von Erkrankungen des Skelettsystems beizutragen. / Homeostasis of bone tissue is maintained by the balanced process of bone formation and resorption. Increased ossification in relation to resorption gives rise to conditions with modelling defects, hyperostosis and sclerosis. Skeletal diseases with these signs are classified as sclerosing bone dysplasias. The work presented here focuses on five skeletal dysplasias from the group of sclerosing bone dysplasias: (1) Craniometaphyseal dysplasia, autosomal dominant form (MIM #123000); (2) Metaphyseal dysplasia, Braun-Tinschert type (MIM *605946); (3) Caffey syndrome (MIM *114000); (4) McCune-Albright syndrome (MIM #174800); (5) Melorheostosis (MIM 155950). They were investigated at different pathogenetic levels that represent different steps on the path from phenotypic characterisation to clarification of the respective basic molecular defect. This work has contributed to our understanding of the molecular basis of skeletal diseases.