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Concept: Long bone

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Because of its close relationship to tetrapods, Eusthenopteron is an important taxon for understanding the establishment of the tetrapod body plan. Notably, it is one of the earliest sarcopterygians in which the humerus of the pectoral fin skeleton is preserved. The microanatomical and histological organization of this humerus provides important data for understanding the evolutionary steps that built up the distinctive architecture of tetrapod limb bones. Previous histological studies showed that Eusthenopteron’s long-bone organization was established through typical tetrapod ossification modalities. Based on a three-dimensional reconstruction of the inner microstructure of Eusthenopteron’s humerus, obtained from propagation phase-contrast X-ray synchrotron microtomography, we are now able to show that, despite ossification mechanisms and growth patterns similar to those of tetrapods, it also retains plesiomorphic characters such as a large medullary cavity, partly resulting from the perichondral ossification around a large cartilaginous bud as in actinopterygians. It also exhibits a distinctive tubular organization of bone-marrow processes. The connection between these processes and epiphyseal structures highlights their close functional relationship, suggesting that either bone marrow played a crucial role in the long-bone elongation processes or that trabecular bone resulting from the erosion of hypertrophied cartilage created a microenvironment for haematopoietic stem cell niches.

Concepts: Bone, Bone marrow, Skeletal system, Cartilage, Bird, Tetrapod, Long bone, Ichthyostega

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HT042, a new herbal prescription consisting of Astragalus membranaceus, Phlomis umbrosa and Eleutherococcus senticosus, is used in traditional Korean medicine to stimulate growth in children. This study was conducted to investigate the effects of HT042 on skeletal growth, insulin-like growth factor-1 (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3) levels, and oestrogenic activity in female rats. Female Sprague-Dawley rats were divided into control, recombinant human growth hormone (rhGH; 20 µg/kg/day), and HT042 (100 mg/kg/day) groups and treated for 3 weeks. Axial skeletal growth, femur length, and growth plate length were measured every 3 weeks. The serum IGF-1 and IGFBP-3 levels were analysed. Moreover, the oestrogenic activity of the herbal extracts in the immature and ovariectomized rats was tested. The nose-anus, nose-tail, femur and growth-plate lengths were increased significantly in the HT042 group. Both IGF-1 and IGFBP-3 were highly expressed in the hypertrophic zone of the growth plate. The serum IGF-1 levels were increased. Moreover, HT042 had no uterotrophic effects in the rats. Consequently, HT042 promoted longitudinal bone growth by stimulating cell proliferation in the epiphyseal plate and inducing the expression of IGF-1 without an oestrogenic response. HT042 may be helpful in stimulating growth in children with short stature. Copyright © 2012 John Wiley & Sons, Ltd.

Concepts: Immune system, Insulin-like growth factor 1, Growth hormone, Growth factors, Endochondral ossification, Insulin-like growth factor, Idiopathic short stature, Long bone

16

Chondrodystrophy in dogs is defined by dysplastic, shortened long bones and premature degeneration and calcification of intervertebral discs. Independent genome-wide association analyses for skeletal dysplasia (short limbs) within a single breed (PBonferroni = 0.01) and intervertebral disc disease (IVDD) across breeds (PBonferroni = 4.0 × 10(-10)) both identified a significant association to the same region on CFA12. Whole genome sequencing identified a highly expressed FGF4 retrogene within this shared region. The FGF4 retrogene segregated with limb length and had an odds ratio of 51.23 (95% CI = 46.69, 56.20) for IVDD. Long bone length in dogs is a unique example of multiple disease-causing retrocopies of the same parental gene in a mammalian species. FGF signaling abnormalities have been associated with skeletal dysplasia in humans, and our findings present opportunities for both selective elimination of a medically and financially devastating disease in dogs and further understanding of the ever-growing complexity of retrogene biology.

Concepts: DNA, Bone, Medicine, Cancer, Skeletal system, Biotechnology, Intervertebral disc, Long bone

11

Regulation of organ growth is a poorly understood process. In the long bones, the growth plates (GPs) drive elongation by generating a scaffold progressively replaced by bone. Although studies have focused on intrinsic GP regulation, classic and recent experiments suggest that local signals also modulate GP function. We devised a genetic mouse model to study extrinsic long bone growth modulation, in which injury is specifically induced in the left hindlimb, such that the right hindlimb serves as an internal control. Remarkably, when only mesenchyme cells surrounding postnatal GPs were killed, left bone growth was nevertheless reduced. GP signaling was impaired by altered paracrine signals from the knee joint, including activation of the injury response and, in neonates, dampened IGF1 production. Importantly, only the combined prevention of both responses rescued neonatal growth. Thus, we identified signals from the knee joint that modulate bone growth and could underlie establishment of body proportions.

Concepts: Bone, Bone marrow, Cartilage, Knee, Joint, Intramembranous ossification, Epiphyseal plate, Long bone

8

One of the major challenges that developing organs face is scaling, that is, the adjustment of physical proportions during the massive increase in size. Although organ scaling is fundamental for development and function, little is known about the mechanisms that regulate it. Bone superstructures are projections that typically serve for tendon and ligament insertion or articulation and, therefore, their position along the bone is crucial for musculoskeletal functionality. As bones are rigid structures that elongate only from their ends, it is unclear how superstructure positions are regulated during growth to end up in the right locations. Here, we document the process of longitudinal scaling in developing mouse long bones and uncover the mechanism that regulates it. To that end, we performed a computational analysis of hundreds of three-dimensional micro-CT images, using a newly developed method for recovering the morphogenetic sequence of developing bones. Strikingly, analysis revealed that the relative position of all superstructures along the bone is highly preserved during more than a 5-fold increase in length, indicating isometric scaling. It has been suggested that during development, bone superstructures are continuously reconstructed and relocated along the shaft, a process known as drift. Surprisingly, our results showed that most superstructures did not drift at all. Instead, we identified a novel mechanism for bone scaling, whereby each bone exhibits a specific and unique balance between proximal and distal growth rates, which accurately maintains the relative position of its superstructures. Moreover, we show mathematically that this mechanism minimizes the cumulative drift of all superstructures, thereby optimizing the scaling process. Our study reveals a general mechanism for the scaling of developing bones. More broadly, these findings suggest an evolutionary mechanism that facilitates variability in bone morphology by controlling the activity of individual epiphyseal plates.

Concepts: Bone, Organ, Anatomy, Biomechanics, Ligament, Epiphyseal plate, Long bone, Epiphysis

2

One of the roles of a forensic anthropologist is to assist medico-legal investigations in the identification of human skeletal remains. In some instances, only small fragments of bone may be present. In this study, a non-destructive novel technique is presented to distinguish between human and non-human long bones. This technique is based on the macroscopic and computed tomography (CT) analysis of nutrient foramina. The nutrient foramen of long bone diaphyses transmits the nutrient artery which provides much of the oxygen and nutrients to the bone. The nutrient foramen and its canal were analysed in six femora and humeri of human, sheep (Ovies aries) and pig (Sus scrofa) species. The location, position and direction of the nutrient foramina were measured macroscopically. The length of the canal, angle of the canal, circumference and area of the entrance of the foramen were measured from CT images. Macroscopic analysis revealed the femora nutrient foramina are more proximal, whereas humeri foramina are more distal. The human bones and sheep humerus conform to the perceived directionality, but the pig bones and sheep femur do not. Amongst the parameters measured in the CT analysis, the angle of the canal had a discriminatory power. This study shows the potential of this technique to be used independently or complementary to other methods in distinguishing between human and non-human bone in forensic anthropology.

Concepts: Bone, Bone marrow, Skeletal system, Femur, Pig, Long bone

1

Radial nerve palsy associated with fractures of the shaft of the humerus is the most common nerve lesion complicating fractures of long bones. However, the management of radial nerve injuries associated with humeral fractures is debatable. There was no consensus between observation and early exploration.

Concepts: Humerus, Ulnar nerve, Planning, Plan, Brachioradialis, Long bone, Radial neuropathy, Long bones

0

Researchers are gaining an increasing understanding of host-gut microbiota interactions, but studies of the role of gut microbiota in linear growth are scarce. The aim of this study was to investigate the effect of food restriction and refeeding with different diets on gut microbiota composition in fast-growing rats. Young male Sprague-Dawley rats were fed regular rat chow ad libitum (control group) or subjected to 40% food restriction for 36 days followed by continued restriction or ad libitum refeeding for 24 days. Three different diets were used for refeeding: regular vegetarian protein chow or chow in which the sole source of protein was casein or whey. In the control group, the composition of the microbiota remained stable. Food restriction for 60 days led to a significant change in the gut microbiota at the phylum level, with a reduction in the abundance of Firmicutes and an increase in Bacteroidetes and Proteobacteria. Rats refed with the vegetarian protein diet had a different microbiota composition than rats refed the casein- or whey-based diet. Similarities in the bacterial population were found between rats refed vegetarian protein or a whey-based diet and control rats, and between rats refed a casein-based diet and rats on continued restriction. There was a significant strong correlation between the gut microbiota and growth parameters: humerus length, epiphyseal growth plate height, and levels of insulin-like growth factor 1 and leptin. In conclusion, the type of protein in the diet significantly affects the gut microbiota and, thereby, may affect animal’s health.

Concepts: Bacteria, Gut flora, Nutrition, Escherichia coli, Epiphyseal plate, Long bone, Epiphysis

0

Repetitive stress fracture of the middle phalanx epiphysis is an injury specific to elite adolescent sport climbers. As sport climbing becomes increasingly popular in younger age groups, an increased number of these injuries have been reported in recent years. To date, treatment of these fractures has been nonsurgical, with strict rest and physiotherapy prescribed until fracture union. However, when these patients present in a delayed fashion with an established nonunion, nonsurgical treatment may fail, leading to disabling chronic pain and/or digital deformity in some cases. In this article, we present 2 cases of surgical treatment for finger middle phalanx repetitive stress epiphyseal fracture nonunion, using a percutaneous spot drilling epiphysiodesis technique.

Concepts: Bone fracture, Injury, Finger, Hand, Epiphyseal plate, Long bone, Rock climbing, Glossary of climbing terms

0

Fetuin-A / α2-Heremans-Schmid-glycoprotein (gene name Ahsg) is a systemic inhibitor of ectopic calcification. Due to its high affinity for calcium phosphate, fetuin-A is highly abundant in mineralized bone matrix. Foreshortened femora in fetuin-A-deficient Ahsg-/- mice indicated a role for fetuin-A in bone formation. We studied early postnatal bone development in fetuin-A-deficient mice and discovered that femora from Ahsg-/- mice exhibited severely displaced distal epiphyses and deformed growth plates, similar to the human disease slipped capital femoral epiphysis (SCFE). The growth plate slippage occurred in 70% of Ahsg-/- mice of both sexes around three weeks postnatal. At this time point, mice weaned and rapidly gained weight and mobility. Epiphysis slippage never occurred in wildtype and heterozygous Ahsg+/- mice. Homozygous fetuin-A-deficient Ahsg-/- mice and, to a lesser degree, heterozygous Ahsg+/- mice showed lesions separating the proliferative zone from the hypertrophic zone of the growth plate. The hypertrophic growth plate cartilage in long bones from Ahsg-/- mice was significantly elongated and V-shaped until three weeks of age and thus prior to the slippage. Genome-wide transcriptome analysis of laser-dissected distal femoral growth plates from 13-day-old Ahsg-/- mice revealed a JAK-STAT-mediated inflammatory response including a 550-fold induction of the chemokine Cxcl9. At this stage, vascularization of the elongated growth plates was impaired, which was visualized by immunofluorescence staining. Thus, fetuin-A-deficient mice may serve as a rodent model of growth plate pathologies including SCFE and inflammatory cartilage degradation.

Concepts: Inflammation, Bone, Skeletal system, Cartilage, Femur, Epiphyseal plate, Long bone, Epiphysis