Aberrant composition of chondroitin sulfates in the cartilage-type proteoglycan isolated from the iliac crest of patients with some lysosomal storage diseases

In order to investigate the involvement of cartilage proteoglycans in the pathogenesis of human congenital skeletal disorders, proteoglycans were extracted with 4 M guanidine HCl from the iliac crest cartilage of children with various skeletal diseases; lysosomal storage diseases (group I), osteochondrodysplasias (group II) and controls (group III). The cartilage-type proteoglycan (PG-H) was purified and its chondroitin sulfate moiety was analyzed by digestion with chondroitinase-ABC. In group II and group III, the relative amounts of the unsaturated disaccharide products changed in an age-related manner; decrease (from 50% to 30%) of delta Di-4S with a compensatory increase (from 40% to 60%) of delta Di-6S with increasing age from 0 to 15 years. On the other hand, some cases in group I showed aberrant composition of the disaccharide products; a lower content of delta Di-4S with a correspondingly higher content of delta Di-6S. Patients in group I have clinically similar skeletal disorders, and the extent of the compositional abnormality seems to reflect the severity of the skeletal disorder. Therefore, one may consider that the aberrant composition of the glycosaminoglycans in PG-H is involved in the pathogenesis of the skeletal disorder of lysosomal storage diseases.     

Palaeopathology of human remains from the Roman Imperial Age

The increasing attention of archaeological and anthropological research towards palaeopathological studies has allowed to focus the examination of many skeletal samples on this aspect and to evaluate the presence of many diseases afflicting ancient populations. This paper describes the most interesting diseases observed in skeletal samples from five necropolises found in urban and suburban areas of Rome during archaeological excavations in the last decades, and dating back to the Imperial Age. The diseases observed were grouped into the following categories: articular diseases, traumas, infections, metabolic or nutritional diseases, congenital diseases and tumors, and some examples are reported for each group. Although extensive epidemiological investigation in ancient skeletal records is impossible, palaeopathology allowed highlighting the spread of numerous illnesses, many of which can be related to the life and health conditions of the Roman population.     

Filamin B:The next hotspot in skeletal research?

Filamin B(FLNB)is a large dimeric actin-binding protein which crosslinks actin cytoskeleton filaments into a dynamic structure.Up to present,pathogenic mutations in FLNB are solely found to cause skeleta deformities,indicating the important role of FLNB in skeletal development.FLNB-related disorders are classifiedasspondylocarpotarsalsynostosis(SCT),Larsensyndrome(LS),atelosteogenesis(AO)boomerang dysplasia(BD),and isolated congenital talipes equinovarus,presenting with scoliosis,shortlimbed dwarfism,clubfoot,joint dislocation and other unique skeletal abnormalities.Several mecha?nisms of FLNB mutations causing skeletal malformations have been proposed,including delay of ossification in long bone growth plate,reduction of bone mineral density(BMD),dysregulation of muscle differentiation,ossification of intervertebral disc(IVD),disturbance of proliferation,differentiation and apoptosis in chondrocytes,impairment of angiogenesis,and hypomotility of osteoblast,chondrocyte and fibroblast.Interventions on FLNB-related diseases require prenatal surveillance by sonography,gene testing in high-risk carriers,andproper orthosis or orthopedic surgeries to correct malformations including scoliosis,cervical spine instability,large joint dislocation,and clubfoot.Gene and cell therapies for FLNB-related diseases are also promising but require further studies.     

Role of FGFs/FGFRs in skeletal development and bone regeneration

Fibroblast growth factor (FGF)/FGF (FGFR) signaling is an important pathway involved in skeletal development. Missense mutations in FGFs and FGFRs were found clinically to cause multiple congenital skeleton diseases including chondrodysplasia, craniosynostosis, syndromes with dysregulated phosphate metabolism. FGFs/FGFRs also have crucial roles in bone fracture repair and bone regeneration. Understanding the molecular mechanisms for the role of FGFs/FGFRs in the regulation of skeletal development, genetic skeletal diseases, and fracture healing will ultimately lead to better treatment of skeleton diseases caused by mutations of FGFs/FGFRs and fracture. This review summarizes the major findings on the role of FGF signaling in skeletal development, genetic skeletal diseases and bone healing, and discusses issues that remain to be resolved in applying FGF signaling‐related measures to promote bone healing. This review has also provided a perspective view on future work for exploring the roles and action mechanisms of FGF signaling in skeletal development, genetic skeletal diseases, and fracture healing. J. Cell. Physiol. 227: 3731–3743, 2012. © 2012 Wiley Periodicals, Inc.     

Epidemiological approach to the paleopathological diagnosis of leprosy

In paleopathology it is usually assumed that modern diagnostic criteria can be applied to infectious diseases in the past. However, as both the human species and populations of pathogenic microorganisms undergo evolutionary changes, this assumption is not always well-founded. To get valid estimates of the frequency (the point prevalence at death) of leprosy in skeletal samples, sensitivity, specificity, and sample frequency must be estimated simultaneously. It is shown that more than three symptoms must be evaluated in at least three samples in order to reach estimates with well-described properties. The method is applied to three skeletal samples from Medieval Denmark; the samples were scored for the presence of seven osteological conditions indicating leprosy. For the osteological conditions, sensitivity varied from 0.36-0.80, and specificity from 0.58-0.98. The frequency of leprosy in the three samples was: Odense (a lepers' institution), 0.98, 95% CI 0.64-1.00; Malm? (urban cemetery), 0.02, 95% CI 0.00-0.07; and Tirup (rural cemetery), 0.36, 95% CI 0.23-0.46. It is concluded that it is indeed possible to estimate disease frequencies without reference to modern standards, and that leprosy occurred with widely differing frequencies in different segments of the Medieval population in southern Scandinavia.     

Association between morbidity and skeletal biomarkers of biological aging

The Osseographic Scoring System (OSS) is a synthetic measure of skeletal aging that combines osteoporotic and osteoarthritic changes of the hand. The OSS is used to evaluate biological age in a population. The aim of the present study was to evaluate the association between certain chronic morbidities and the skeletal biomarker of biological aging. We performed a population-based study on a large sample of individuals who were receiving no medications to treat or prevent chronic morbidities [668 male (age 18-89 years) and 608 female (age 18-81 years) Chuvashians]. Morbidity data obtained from the individuals' medical records was sorted into 16 categories. A one-way ANOVA was used to elucidate the association between morbidity and age-adjusted OSS score. Statistically significant differences between means of OSS scores in affected vs. nonaffected individuals were found in the rheumatic diseases group. Ischemic heart disease, pulmonary diseases, traumatic brain injuries, and gynecological diseases also showed differences; however, after correction for multiple testing, the results were statistically nonsignificant. We conclude that individuals who suffer from the mentioned chronic morbidities will show a higher degree of skeletal aging. Further research is needed to clarify the biological mechanisms of association between certain types of morbidities and changes in skeletal aging.     

Malignant-Hyperthermia Susceptibility Is Associated with a Mutation of the a1-Subunit of the Human Dihydropyridine-Sensitive L-Type Voltage-Dependent Calcium-Channel Receptor in Skeletal Muscle

Malignant hyperthermia susceptibility (MHS) is characterized by genetic heterogeneity. However, except for the MHS1 locus, which corresponds to the skeletal muscle ryanodine receptor (RYR1) and for which several mutations have been described, no direct molecular evidence for a mutation in another gene has been reported so far. In this study we show that the CACNL1A3 gene encoding the alpha 1-subunit of the human skeletal muscle dihydropyridine-sensitive L-type voltage-dependent calcium channel (VDCC) represents a new MHS locus and is responsible for the disease in a large French family. Linkage analysis performed with an intragenic polymorphic microsatellite marker of the CACLN1A3 gene generated a two-point LOD score of 4.38 at a recombinant fraction of 0. Sequence analysis of the coding region of the CACLN1A3 gene showed the presence of an Arg-His substitution at residue 1086, resulting from the transition of A for G3333, which segregates perfectly with the MHS phenotype in the family. The mutation is localized in a very different part of the alpha 1-subunit of the human skeletal muscle VDCC, compared with previously reported mutations found in patients with hypokalemic periodic paralysis, and these two diseases might be discussed in terms of allelic diseases. This report is the first direct evidence that the skeletal muscle VDCC is involved in MHS, and it suggests a direct interaction between the skeletal muscle VDCC and the ryanodine receptor in the skeletal muscle sarcoplasmic reticulum.     

Identification of a novel autoantigen UACA in patients with panuveitis

To identify the target autoantigens in Vogt-Koyanagi-Harada disease, we made use of an immunoscreening of a bovine uveal cDNA expression library with serum samples obtained from patients with Vogt-Koyanagi-Harada disease. We identified a novel bovine antigen and homologous human autoantigen and designated it as UACA (uveal autoantigen with coiled coil domains and ankyrin repeats). mRNA of human UACA is expressed most abundantly in skeletal muscles and in various human tissues, including choroid, retina, and epidermal melanocytes. IgG autoantibodies were quantitated in an ELISA, using recombinant C-terminal 18.0% fragment of human UACA. The prevalence of IgG anti-UACA autoantibodies in patients with panuveitis (Vogt-Koyanagi-Harada disease, Beh?et's disease, sarcoidosis) was significantly higher than that in healthy controls (19.6-28.1% vs 0%, P < 0.05) indicating that autoimmunity directed against UACA is a common phenomenon in these diseases.     

The Effects of Resveratrol,Metformin, Cold and Strength Training on the Level of Perilipin 5 in the Heart,Skeletal Muscle and Brown Adipose Tissues in Mouse

The high accumulation of lipid droplets in the cell is related to metabolic disorders, such as obesity. Perilipin 5 (Plin5), plays an important role in triglyceride hydrolysis in the lipid droplets. In this study, this protein has been evaluated in different tissues and conditions in mice. Fifty male mice were divided into 5 groups and treated for 45 days with Resveratrol, Metformin, strength training, and 4?°C cold. Brown adipose tissue (BAT), gastrocnemius skeletal muscle and heart were isolated for RNA extraction. The Plin5 gene expression was evaluated, using Real-Time PCR, and the plin5 was analyzed at the protein level, using western blot. In BAT, Resveratrol significantly reduced the plin5 protein level and gene expression (p?<?0.05). In heart tissue, Resveratrol and strength training, decreased (p?<?0.05) the plin5 expression, but Metformin increased the gene expression (p?<?0.05). In skeletal muscle, resveratrol, strength training, cold and Metformin significantly increased the plin5 expression at the gene and protein level (p?<?0.05). In BAT, Resveratrol has a greater effect in decreasing lipid deposits, compared with the strength training and cold; thus, it can play a better role in preventing lipid accumulation. In heart tissue, Resveratrol probably decreases insulin resistance, due to the increased expression of plin5 in skeletal muscle.     

Influence of size at birth on the endocrine profiles and expression of uncoupling proteins in subcutaneous adipose tissue, lung, and muscle of neonatal pigs

Epidemiological studies suggest that infants of low birth weight show poor neonatal growth and increased susceptibility to adult diseases such as diabetes and lung disease. Uncoupling protein 2 and 3 (UCP2 and UCP3) have been implicated in the development of such diseases; pigs provide an ideal model to examine the influence of birth weight due to the natural variance in piglet weight within a litter. This study examined whether birth weight influences the expression of UCP2 and UCP3 in adipose tissue, skeletal muscle, and lung. Piglets from 11 litters were ranked according to birth weight and three from each litter assigned to small (SFD), normal (NFD), or large for dates (LFD) groups. Blood samples and morphometric measurements were taken over the first 14 days of life, and tissue samples were taken on day 7 or 14. Plasma hormone and metabolite concentrations and the expression of UCP2 and UCP3 mRNA in adipose tissue, skeletal muscle, and lung were measured. UCP2 and UCP3 expression in adipose tissue was lower in the SFD compared with the LFD group on day 7. UCP3 expression in skeletal muscle was higher than that of adipose tissue. Lung UCP2 and skeletal muscle UCP3 mRNA expression were unaffected by size at birth. Regression analysis indicated that UCP3 expression was differentially associated with IGF-1, leptin, and insulin. In conclusion, low birth weight is associated with tissue-specific effects on UCP expression. It remains to be established whether these subsequently contribute to pathological conditions such as diabetes.     

骨骼肌中肌浆网/内质网钙ATP酶的功能及其作用机制

骨骼肌是机体生命活动和能量代谢的重要场所,其代谢紊乱会诱发一系列肌肉疾病。Ca²⁺作为肌肉收缩过程的重要调节器,在骨骼肌的功能行使中发挥重要作用。骨骼肌细胞中Ca²⁺浓度主要受肌浆网/内质网钙ATP酶(sarcoplasmic/endoplasmic reticulum Ca²⁺ATPase, SERCA)的调节。SERCA利用ATP水解产生的能量介导胞质Ca²⁺进入肌浆网内腔,维持胞质Ca²⁺平衡。SERCA功能的失调会引发一系列骨骼肌疾病,而SERCA活性受部分肌浆网蛋白质的调控,跨膜蛋白质PLN、SLN、MRLN、DWORF和sAnk1以及胞质蛋白质THADA和SAR,其通过磷酸化,进而调控SERCA的功能。本文对骨骼肌中SERCA的功能、调控SERCA的相关功能蛋白质的结构及其作用机制进行了总结,以期为骨骼肌相关疾病的治疗提供最新的思路和方法。     

Epiphyseal union and dental eruption in Macaca mulatta

Age of dental eruption and epiphyseal fusion is estimated for the permanent dentition and long bone epiphyses of rhesus macaques (Macaca mulatta), with 299 skeletons of individuals with known age of death, from the Cayo Santiago skeletal collection. Epiphyses at a given joint tend to fuse at the same time. While males and females tend to have the same pattern of epiphyseal fusion, females' epiphyses fuse earlier than those of males, espeically at the elbow and knee joints. The order of epiphyseal fusion in rhesus macaques follows the general primate pattern. Times of dental eruption for males and females are generally the same, except for the relatively late eruption of the canine in the males. The order of eruption follows a common primate pattern (dm2?M1?I1?I2?M2?(P3,P4)?C?M3). Multiple regressions were calculated in order to allow determination of developmental state, or predictions of chronological age, from epiphyseal fusion and/or dental eruption scores in juvenile rhesus macaques. Standard deviations of residuals from these regressions indicate considerable variation in developmental state among aminals of the same chronological age. The lack of correlation between residuals from the separate skeletal and dental regressions, indicates that skeletal and dental development are largely independent.     

Development of calcareous skeletal elements in invertebrates

Most metazoans require skeletal support systems. While the formation of bones and teeth in vertebrates has been well studied, endo- and exoskeleton development of non-vertebrates, especially calcification during terminal differentiation, has been neglected. Biomineralization of skeletons in invertebrates presents interesting research opportunities. We undertake here to survey some of the better understood examples of skeletal development in selected invertebrates. The differentiation of the skeletal spicules of euechinoid larvae and other non-vertebrate deuterostomes, the shells of molluscs, and the calcification of crustacean carapaces are surveyed. The diversity of these different kinds of animals and our present limited understanding make it difficult to identify unifying themes, but there certainly are unifying questions: How is the mineral precursor secreted? What is the nature of the interaction of mineral with the matrix proteins of the skeleton? Is there any conservation of protein domains in matrix proteins found in skeletal elements from different phyla? Are there common strategies in the development of organs that form mineralized structures?     

Osteoporosis and Dental Osteopenia in the Elderly1

Osteoporosis is a common, morbid, and expensive disease of the elderly skeleton, particularly in the postmenopausal female, resulting in fractures of the spine, hip, and wrist. Dental osteopenia (inadequate bone mass, particularly of the mandible) is also a condition of significant morbidity for the elderly, associated with loss of teeth and poorly fitting dentures. Questions of immediate concern regarding these disorders are: (1) Are techniques available for quantitating mandibular bone mass? (2) Is dental osteopenia a localized manifestation of a generalized skeletal osteoporosis, with similar etiologies and risk factors, or is it an entirely separate disease process, due primarily to periodontal disease with its associated causal factors? (3) Are therapeutic measures noted to be of benefit in osteoporosis also of benefit in dental osteopenia? Recent studies from our laboratories address these questions and indicate efficiency of the mandibular microdensitometry technique for measuring mandibular bone mass. Also, these studies suggest that dental osteopenia is part of a generalized skeletal osteoporosis of the elderly female, and that therapy for osteoporosis would possibly be of value in the treatment of dental osteopenia.     

Use of the Greulich-Pyle "Atlas of Skeletal Development of the Hand and Wrist" in a clinical context

Assessments of the relative maturity of individual children have been widely used to improve estimations of future growth as well as in evaluations of physiological disorders. Skeletal age (Hand) has been the most commonly used method for these estimations. In the clinical use of skeletal ages, certain problems are inherent regardless of which standard is selected. One of these is the method of reporting so that the cliniciam may learn of the normal variation at each age as well as the operational error of the specific assessor. Another problem lies in the proper clinical interpretation to be put upon significantly variant skeletal age readings in infancy, in childhood, or in adolescence. A third problem arises in limiting the use of skeletal ages which are read from areas which are involved with osseous pathology. And fourthly, a child's level of maturity is not static throughout his growing years; even with no change in therapeutic regime, marked shifts in relative maturity have been often noted. The wealth of experience which has now been acquired with the Greulich-Pyle standard is not the least of the advantages in using the Hand for the assessment of skeletal age. The 30 centers in this small area of the body, however, may be harmonious in development or may vary in “maturity” by as much as three years in a single hand. The problems then are: Which centers best represent the individual child? Which centers are most closely related to growth? Is growth in the hand and accurate index of the growth in other areas of the body? In total stature? The clinical assessment of future growth may best be made from a consideration of the whole child: his size, his physical characteristics, and his skeletal age, as well as the pattern of change-with-age in each of these. These problems will be discussed with illustrations drawn from the longitudinal Growth Study at this institution.     

Muscle function and dysfunction in health and disease

Skeletal muscles of the trunk and limbs developmentally originate from the cells of the dermomyotomal compartment of the somite. A wealth of knowledge has been accumulated with regard to understanding the molecular regulation of embryonic skeletal myogenesis. Myogenic induction is controlled through a complex series of spatiotemporal dependent signaling cascades. Secreted signaling molecules from surrounding structures not only initiate the myogenic program, but also influence proliferation and differentiation decisions. The proper coordination of these molecular events is thus critical for the formation of physiologically functional skeletal muscles. Hereditary congenital skeletal muscle defects arise due to genetics lesions in myogenic specific components. Understanding the mechanistic routes of congenital skeletal muscle disease therefore requires a comprehensive knowledge of the developmental system. Ultimately, the application of this knowledge will improve the diagnostic and therapeutic methodologies for such diseases. The aim of this review is to overview our current understanding of skeletal muscle development and associated human congenital diseases.     

Maternal protein restriction induce skeletal muscle changes without altering the MRFs MyoD and myogenin expression in offspring

Stimuli during pregnancy, such as protein restriction, can affect morphophysiological parameters in the offspring with consequences in adulthood. The phenomenon known as fetal programming can cause short- and long-term changes in the skeletal muscle phenotype. We investigated the morphology and the myogenic regulatory factors (MRFs) MyoD and myogenin expression in soleus, SOL; oxidative and slow twitching and in extensor digitorum longus, EDL; glycolytic and fast twitching muscles in the offspring of dams subjected to protein restriction during pregnancy. Four groups of male Wistar offspring rats were studied. Offspring from dams fed a low-protein diet (6?% protein, LP) and normal protein diet (17?% protein, NP) were euthanized at 30 and 112?days old, and their muscles were removed and kept at ?80?°C. Muscles histological sections (8?μm) were submitted to a myofibrillar adenosine triphosphatase histochemistry reaction for morphometric analysis. Gene and protein expression levels of MyoD and myogenin were determined by RT-qPCR and western blotting. The major findings observed were distinct patterns of morphological changes in SOL and EDL muscles in LP offspring at 30 and 112?days old without changes in MRFs MyoD and myogenin expression. Our results indicate that maternal protein restriction followed by normal diet after birth induced morphological changes in muscles with distinct morphofunctional characteristics over the long term, but did not alter the MRFs MyoD and myogenin expression. Further studies are necessary to better understand the mechanisms underlying the maternal protein restriction response on skeletal muscle.