Prediction of bone adaptation in the ulnar-osteotomized sheep's forelimb using an anatomical finite element model

A method for the prediction of the time-course of bone adaptation based on an alternative hypothesis of strength optimization has been previously investigated and developed by Prendergast and Taylor¹. This paper extends our work in the study of the effectiveness of this bone adaptation model in predicting similar bone remodelling to that observed in animal experiments. In particular the experimental work which has been modelled is that of Lanyon, Goodship, Pye and McFie². An anatomical finite element model of the sheep's forelimb has been generated for this purpose and is used to estimate stresses in the bone structure for the normal and osteotomized condition. The propensity for remodelling of the altered bone structure is predicted using the proposed remodelling law for the new stress field in the bone structure. The preliminary results indicate an initial bone adaptation pattern similar to that observed experimentally without the necessity to use arbitrarily different constants for the endosteal and periosteal surfaces. We therefore suggest that the remodelling law based on damage and repair gives a better predictive model of bone adaptation than previous models.     

Evaluation of circulating sRAGE in osteoporosis according to BMI,adipokines and fracture risk: a pilot observational study

Background

Osteoporosis is a systemic metabolic disease based on age-dependent imbalance between the rates of bone formation and bone resorption. Recent studies on the pathogenesis of this disease identified that bone remodelling impairment, at the base of osteoporotic bone fragility, could be related to protein glycation, in association to oxidative stress. The glycation reactions lead to the generation of glycation end products (AGEs) which, in turn, accumulates into bone, where they binds to the receptor for AGE (RAGE). The aim of this study is to investigate the potential role of circulating sRAGE in osteoporosis, in particular evaluating the correlation of sRAGE with the fracture risk, in association with bone mineral density, the fracture risk marker FGF23, and lipid metabolism.

Results

Circulating level of soluble RAGE correlate with osteopenia and osteoporosis level. Serum sRAGE resulted clearly associated on the one hand to bone fragility and, on the other hand, with BMI and leptin. sRAGE is particularly informative because serum sRAGE is able to provide, as a single marker, information about both the aspects of osteoporotic disease, represented by bone fragility and lipid metabolism.

Conclusions

The measure serum level of sRAGE could have a potential diagnostic role in the monitoring of osteoporosis progression, in particular in the evaluation of fracture risk, starting from the prevention and screening stage, to the osteopenic level to osteoporosis.

     

Ancient and diverged TGF-β signaling components in Nasonia vitripennis

The transforming growth factor beta (TGF)-β signaling pathway and its modulators are involved in many aspects of cellular growth and differentiation in all metazoa. Although most of the core components of the pathway are highly conserved, many lineage-specific adaptations have been observed including changes regarding paralog number, presence and absence of modulators, and functional relevance for particular processes. In the parasitic jewel wasp Nasonia vitripennis, the bone morphogenetic proteins (BMPs), one of the major subgroups of the TGF-β superfamily, play a more fundamental role in dorsoventral (DV) patterning than in all other insects studied so far. However, Nasonia lacks the BMP antagonist Short gastrulation (Sog)/chordin, which is essential for polarizing the BMP gradient along the DV axis in most bilaterian animals. Here, we present a broad survey of TGF-β signaling in Nasonia with the aim to detect other lineage-specific peculiarities and to identify potential mechanisms, which explain how BMP-dependent DV pattering occurs in the early Nasonia embryo in the absence of Sog.     

Use of fluorescence microspectral method for studying bone marrow EGFP+ cell transplantation in 5-fluorouracil-treated mice

In this paper the experimental results of bone marrow transplantation from C57BL/6-Tg(ACTB-EGFP)1Osb/J transgenic mice into C57BL/6 mice subjected to 5-fluorouracil treatment are represented. It has been shown that EGFP⁺ cell engraftment in bone marrow, spleen and thymus of host mice after 5-Fu treatment significantly increased. More long-term engraftment was recorded after transplantation between closely related donors and 5-fluorouracil treatment hosts. We have also obtained data on differences in the dynamics of EGFP⁺ cell engraftment in host investigated organs. To assess the effect of the donor’s bone marrow cells on the host immune system, functional activity of the synthetic apparatus (synthetic activity) of cells in bone marrow, spleen, thymus and blood have been investigated with fluorescence microspectral method. The results obtained allow of improving techniques for bone marrow transplantation without host irradiation in order to minimize the adverse effects.     

Biodegradable Effect of PLGA Membrane in Alveolar Bone Regeneration on Beagle Dog

Guided bone regeneration (GBR) is a principle adopted from guided tissue regeneration (GTR). Wherein, GBR is used for the healing of peri-implant bony dehiscences, for the immediate placement of implants into extraction sockets and for the augmentation of atrophic alveolar ridges. This procedure is done by the placement of a resorbable or non-resorbable membrane that will exclude undesirable types of tissue growth between the extraction socket and the soft tissue to allow only bone cells to regenerate in the surgically treated lesion. Here, we investigated the biodegradable effect of polylactic-co-glycolic acid (PLGA) membrane in the alveolar bone on Beagle dogs. Results show that both collagen and PLGA membrane had been fully resorbed, biodegraded, at four weeks post-operative reentry into the alveolar bone. Histological results under light microscopy revealed formation of new bone trabeculae in the extraction sites on both collagen and PLGA membrane. In conclusion, PLGA membrane could be a potential biomaterials for use on GBR and GTR. Nevertheless, further studies will be necessary to elucidate the efficiency and cost effectiveness of PLGA as GBR membrane in clinical.     

Targeting subchondral bone in osteoporotic osteoarthritis

The identification of well-defined phenotypes along the course of the disease may open new avenues for personalized management in osteoarthritis (OA). In vivo research carried out in various animal models as well as epidemiological and clinical data support the existence of a particular phenotype – osteoporotic OA. In fact, subchondral bone has become a potential therapeutic target in OA. Depending on the ratio between formation and resorption, subchondral bone remodeling can culminate in either a sclerotic or an osteoporotic phenotype. Patients with osteoporotic OA may thus achieve clinical and structural benefit from treatment with bone-targeted interventions.Subchondral bone has become a potential therapeutic target in osteoarthritis (OA). In a previous issue of Arthritis Research & Therapy, Wang and colleagues demonstrate that osteoporosis aggravates cartilage damage in an experimental model of knee OA in rats [1]. Interestingly, the authors also describe that extracorporeal shockwave therapy (ESWT), a mechanical therapeutic intervention probably acting at subchondral bone, may reduce OA progression [1]. The significance of these findings in experimental osteoporotic OA relates to the search for well-defined phenotypes in human OA that will lead to personalized therapy.The controversy regarding the relationship between subchondral bone quality and cartilage integrity originates from the complex biological and mechanical nature of the osteochondral junction [2]. OA progression is often accompanied by increased subchondral bone remodeling that enables mechanical forces to dynamically modify its structure. Depending on the ratio between formation and resorption, subchondral bone can exhibit either a sclerotic or an osteoporotic phenotype [3]. These phenotypes may represent up to 70% and 30% of patients in daily practice, respectively [4]. Furthermore, OA in females can display a different pathogenic profile from OA in males. In this sense, it is reasonable to underline the consequences of estrogen deficiency during menopause [5]. A low estrogen state could induce a deleterious effect on all articular tissues of the knee joint, the subchondral bone being particularly affected due to its capacity for high bone turnover. Thus, during early post menopause, estrogen deficiency may be a risk factor for the development of knee OA. Taking all these facts into consideration, the characterization of patients with either sclerotic or osteoporotic OA phenotypes may enable individualized targeted therapy [3].The effects of estrogen deficiency on the knee joint have been reported in various experimental animal models of OA. The findings obtained by Wang and colleagues on subchondral bone quality and articular cartilage damage support previous research carried out in rabbits, in which osteoporosis aggravated instability-induced OA [6]. In this combined model, the induction of systemic and subchondral osteoporosis associated with increased bone remodeling resulted in worse cartilage damage compared with control animals. Greater fragility of the subchondral bone was suggested to account for the aggravation of cartilage damage when early OA and osteoporosis coexist [7]. In a further study carried out in the same model, the intermittent administration of parathyroid hormone 1-34, a bone-forming agent, was used to increase subchondral bone density and quality [8]. As a consequence, the improvement of subchondral bone integrity was associated with reduced progression of cartilage damage in OA preceded by osteoporosis. In a similar approach, the inhibition of bone resorption by pamidronate in osteoporotic mice alleviated the instability-induced OA histological score with a reduction in the expression of aggrecanases [9]. Several experimental models therefore indicate that osteopenia/osteoporosis induces an accelerated progression of knee OA that can be reversed not only by bone-forming agents but also by antiresorptive drugs.These findings in animal models could be translated to humans, and together with epidemiological and clinical data they support the existence of a particular phenotype – osteoporotic OA [10]. Indeed, this phenotype characterized by decreased density and high remodeling at subchondral bone defines a subgroup of patients treatable with specific agents. In fact, beneficial effects of bone-acting drugs in OA are increasingly reported, but reliable conclusions regarding their efficacy are hindered by methodological drawbacks in study design [10]. Identifying patients with osteoporotic OA may improve the success of bone-directed agents.The original approach of using ESWT in OA by Wang and colleagues remains intriguing. These authors have reported previously that the application of ESWT to subchondral bone of the proximal tibia showed a chondroprotective effect in the initiation of knee OA and regression of established OA of the knee in rats. These effects were attributed to the ESWT multifunctional actions on cartilage and bone. Yet achieving such beneficial effects in this osteoporotic OA model suggests that the main mechanism of action of ESWT may be improving subchondral bone structure [1]. However, some limitations on the study design and the lack of adequate standardization of dosages and optimal frequency, as well as little information regarding the molecular mechanisms underlying the effects of ESWT, hold back the achievement of solid results. In any case, this study points out the potential benefit of nonpharmacological interventions aiming to improve mechanical properties of articular tissues in OA.In summary, the study by Wang and colleagues further supports the existence of the osteoporotic OA subtype and the potential benefit of bone-acting therapeutic interventions. Consequently, the identification of patient phenotypes along with the discovery of specific therapeutic interventions targeting relevant pathogenic mechanisms during the course of the disease could lead to a personalized approach to the management of OA.     

Decreased activity of osteocyte autophagy with aging may contribute to the bone loss in senile population

Age-related bone loss is a major cause of osteoporosis and osteoporotic fractures in the elderly. However, the underlying molecular mechanism of age-related bone loss is still poorly understood. The aim of this study was to clarify whether autophagy in osteocytes was involved in age-related bone loss. Male Sprague–Dawley (SD) rats in 3, 9, and 24 month old were used to mimic the age-related bone loss in men. Micro-CT evaluation, histomorphometric analysis, and measurement of bone turnover rate verified age-related bone loss in the male SD rats. Immunofluorescent histochemistry, RT-PCR, and Western blot assessment demonstrated that the expression of LC3-II, LC3-II/I, Beclin-1, and Ulk-1 in the osteocytes decreased with age, while SQSTM1/p62 and apoptosis in the osteocytes increased. A significant correlation between the markers of osteocyte autophagy and bone mineral density in the proximal tibia was revealed. However, osteocyte autophagy was not correlated with osteocyte apoptosis in the process of aging. These results suggested that osteocyte autophagy was possibly involved in the age-related bone loss. Decreased activity of osteocyte autophagy independent of apoptosis might contribute to the age-related bone loss in senile osteoporosis.     

Mass-spectrometric analysis of proteasome subunits exhibiting endoribonuclease activity

Proteasomes function as the main nonlysosomal machinery of intracellular proteolysis and are involved in the regulation of the majority of important cellular processes. Despite the considerable progress that has been made in understanding the functioning of proteasomes, some issues (in particular, the RNase activity of these ribonucleoprotein complexes and its regulation) remain poorly investigated. In this study, we found to several proteins with electrophoretic mobility that corresponds to that of 20S subunits of the core proteasome complex exhibit endoribonuclease activity with respect to the sense and antisense sequences of the c-myc mRNA 3′-UTR. Mass-spectrometric analysis of tryptic hydrolysates of these proteins showed that the samples contained 20S proteasome subunits—α1 (PSMA6), α5 (PSMA5), α6 (PSMA1), and α7 (PSMA3). A number of new phosphorylation sites of α1 (PSMA6) and α7 (PSMA3) subunits were found, and a form of α5 (PSMA5) subunit with a deletion of 20 N-terminal amino-acid residues was identified. The observed differences in the manifestation of endonuclease activity by individual subunits are apparently due to posttranslational modifications of these proteins (in particular, phosphorylation). It was shown that the specificity of RNase activity changes upon proteasome dephosphorylation and under the influence of Ca²⁺ and Mg²⁺ cations. It is concluded that posttranslational modifications of proteasome subunits affect the specificity of their RNase activity.     

Remodelling of collagen fibre transition stretch and angular distribution in soft biological tissues and cell-seeded hydrogels

The extracellular matrix in many biological tissues is adapted to its mechanical environment. In this study, a phenomenological model for collagen remodelling is introduced that incorporates angular remodelling (fibre reorientation) and the adaptation of the so-called transition stretch. This is achieved by introducing a local stress-free configuration for the collagen network by a multiplicative decomposition of the deformation gradient and the appropriate definition of the anisotropic free Helmholtz energy potentials and structure tensors. The collagen network is either treated using discrete fibre directions or a continuous angular distribution. The first part of the study illustrates the influence of force- and displacement-controlled loading on either stress- or deformation-driven remodelling processes in tissues with various degrees of fibre reinforcement. The model is then applied to recent experimental studies of collagen remodelling, specifically periosteum adaptation (Foolen et?al. in J Biomech 43(16):3168–3176, 2010), collagen gel (Thomopoulos et?al. in J Biomech Eng 127(5):742–750, 2005) and fibrin cruciform (Sander et?al. in Ann Biomed Eng 1–16, 2010) compaction. The model is able to capture the basic effects of an adapting transition stretch over time in the periosteal simulations, as well as the compaction and the development of structural anisotropy in the collagen and fibrin gels. The model can potentially be applied to elucidate structure–function relationships, better interpret in vitro experiments involving collagen remodelling, and help investigate aspects of certain pathologies, such as connective tissue contracture.     

Conserved and divergent processing of neuroligin and neurexin genes: from the nematode C. elegans to human

Neuroligins are cell-adhesion proteins that interact with neurexins at the synapse. This interaction may contribute to differentiation, plasticity and specificity of synapses. In humans, single mutations in neuroligin-encoding genes are implicated in autism spectrum disorder and/or mental retardation. Moreover, some copy number variations and point mutations in neurexin-encoding genes have been linked to neurodevelopmental disorders including autism. Neurexins are subject to extensive alternative splicing, highly regulated in mammals, with a great physiological importance. In addition, neuroligins and neurexins are subjected to proteolytic processes that regulate synaptic transmission modifying pre- and postsynaptic activities and may also regulate the remodelling of spines at specific synapses. Four neuroligin genes exist in mice and five in human, whilst in the nematode Caenorhabditis elegans, there is only one orthologous gene. In a similar manner, in mammals, there are three neurexin genes, each of them encoding two major isoforms named α and β, respectively. In contrast, there is one neurexin gene in C. elegans that also generates two isoforms like mammals. The complexity of the genetic organization of neurexins is due to extensive processing resulting in hundreds of isoforms. In this review, a wide comparison is made between the genes in the nematode and human with a view to better understanding the conservation of processing in these synaptic proteins in C. elegans, which may serve as a genetic model to decipher the synaptopathies underpinning neurodevelopmental disorders such as autism.     

Plants and environment: Two decades of research at the Canberra phytotron

The research carried out at the Canberra phytotron, CERES, during the first twenty years of its operation is reviewed as a case study of the opportunities, problems and value of phytotron research. The climatic responses of a large number of species, both wild and domesticated, are examined as well as those of fungal and viral pathogens and rhizobial symbionts. Some aspects of the design of CERES are briefly considered, and a few aspects of the variation between plants in climatic response, with the C₄ photosynthetic syndrome taken as a case history of the linkages between biochemistry, anatomy and response to climate. Research in ecology, forestry, horticulture, plant pathology, rhizobial microbiology, anatomy and ultrastructure—and specific aspects of biochemistry, plant nutrition and genetics—are reviewed to indicate the range of botanical disciplines which can profit from access to a phytotron. The ecological research at CERES, much of it with trees and perennial grasses, particularly highlights the value of combining field and phytotron studies. Work on seed proteins, hybrid vigor and plant growth regulators is also reviewed. The next part of the paper considers the effects of the major environmental factors, temperature, daylength, irradiance, atmospheric CO₂ level and water stress, together with their interactions and the problems of correlating phytotron and field responses. The effect of these factors on the various processes of growth and development are considered, and the stages of development most sensitive to them. An evolutionary perspective on yield potential is then discussed, leading to a consideration of photosynthesis, translocation, partitioning and storage organ growth as yield-determining processes. The final part considers the uses of phytotrons in agricultural, horticultural and forestry research, in terms of examples from work at CERES on the manipulation of breeding systems, the clarification of plant breeding objectives, the use of phytotron conditions for selection, the prediction of adaptation and spread, and models for yield prediction and pest management. Several areas requiring more attention are identified, and some conclusions are drawn on the value of access to a phytotron such as CERES for botanical research of many kinds.     

Comparative Effects of Hispidulin,Genistein, and Icariin with Estrogen on Bone Tissue in Ovariectomized Rats

Icariin, Genistein, and Hispidulin have been proven to have estrogen-like and antiosteoporotic activity and can be potentially used for the treatment of osteoporosis. The present study found that Icariin, Genistein, and Hispidulin treatments, emulating estrogen, significantly contributed to bone density. Comparative effects of Icariin, Genistein, and Hispidulin with estrogen on in ovariectomized rats were investigated. Our results showed that genistein was found to have superior bone protective effects against osteoporosis among genistein, Icariin, and Hispidulin.     

Pacemakers in aggregation fields of Dictyostelium discoideum: does a single cell suffice?

In this paper we address the following question: can a single cell of the cellular slime mold Dictyostelium discoideum serve as a pacemaker for the aggregation phase? Whether or not this is possible is determined by the relative importance of cyclic AMP production due to self-stimulation as compared to diffusion of cyclic AMP away from the cell and extracellular degradation. We determine the conditions under which a single cell on an infinite place can emit periodic signals of cyclic AMP using a model developed previously for signal relay and adaptation in Dictyostelium. Elsewhere it has been shown that this model provides an accurate representation of the stimulus-response behavior of Dictyostelium for a variety of experimental conditions.     

The Potential Role of Rho GTPases in Alzheimer's Disease Pathogenesis

Alzheimer's disease (AD) is characterized by a wide loss of synapses and dendritic spines. Despite extensive efforts, the molecular mechanisms driving this detrimental alteration have not yet been determined. Among the factors potentially mediating this loss of neuronal connectivity, the contribution of Rho GTPases is of particular interest. This family of proteins is classically considered a key regulator of actin cytoskeleton remodeling and dendritic spine maintenance, but new insights into the complex dynamics of its regulation have recently determined how its signaling cascade is still largely unknown, both in physiological and pathological conditions. Here, we review the growing evidence supporting the potential involvement of Rho GTPases in spine loss, which is a unanimously recognized hallmark of early AD pathogenesis. We also discuss some new insights into Rho GTPase signaling framework that might explain several controversial results that have been published. The study of the connection between AD and Rho GTPases represents a quite unchartered avenue that holds therapeutic potential.     

Repair of Ear Cartilage Defects with Allogenic Bone Marrow Mesenchymal Stem Cells in Rabbits

The study aims to investigate the feasibility of repairing cartilaginous defects with chondrocytes induced from allogenic bone marrow mesenchymal stem cells (BMMSC) in rabbits’ ear. BMMSCs were isolated and purified from New Zealand rabbits, in vitro amplified, and cultured in chondrocyte induction medium in order to acquire chondrocytes. After 3 weeks of induction, their phenotypes were confirmed as chondrocytes, then they were implanted onto novel polymeric scaffolds made from Poly (dl-lactide-co-glycolide) (PLGA) embedded with chitosan nonwoven cloth. The experimental group was transplanted with tissue engineering cartilaginous grafts composed of chondrogenetic BMMSC/scaffolds; the scaffold group was treated with scaffolds without cells, while in the control group, nothing was implanted. Specimens were taken at 6, 12, and 18 weeks after implantation, and the healing condition was observed by hematoxylin-eosin staining and toluidine blue staining. The right and left ears with cartilage defects of eighteen rabbits were randomly divided into three groups. In the experimental group, after 18 weeks of transplantation, the gross observation indicated that the cartilaginous defects were completely repaired by chondrocytes with smooth surface and similar color with the surrounding tissue. Hematoxylin-eosin staining and toluidine blue staining suggested that the defective area was filled with mature cartilage cells with obvious lacunae but without obvious boundaries with the normal cartilage tissue, and that the new cartilage cells were evenly distributed with homogeneously dyed cytoplasm and smaller in size. The chondrocyte induced from allogenic BMMSC can be used to repair cartilage defects in rabbit’s ear.     

Role of PARP2 in DNA repair

The genome stability of higher eukaryotes depends largely on the functioning of the DNA repair systems. In turn, the precise regulation of each step of repair processes is necessary for the efficient DNA repair. Although most pathways of DNA repair have already been established, their regulation mechanisms require further investigation. Poly(ADP-ribose) polymerases (PARPs) are widely considered to be potential regulators of DNA repair. The role of the most prominent member of this protein family, i.e., PARP1, in DNA repair has been being intensively studied, while the literature data on participation in the repair processes of PARP2, the closest PARP1 homolog, are poorly summarized, although a great body of information concerning its participation in DNA repair has been accumulated. Using the PARP2-deficient model organisms and cell lines, their increased sensitivity to several DNA damaging agents was elucidated. The accumulation of PARP2 at the DNA damage sites in cells was shown. There are data that demonstrate the proteinprotein interaction of PARP2 with several proteins of the base excision repair/single-strand break repair and nonhomologous end joining. Most of the data on the PARP2 role were obtained in experiments with model organisms and cell lines; thus, it is difficult to elucidate the influence of PARP2 on specific processes in vivo. In this review, we tried to summarize data on the participation of PARP2 in the DNA repair processes, including our recent results.     

Tumor-Suppressing Effects of miR-429 on Human Osteosarcoma

Osteosarcoma is the most common primary bone tumor. Recent data indicated miRNAs may be involved in the pathogenesis of osteosarcoma, suggesting some novel targets for therapy. It is known that miR-429 is down-regulated and functions as a tumor suppressor by targeting c-myc and PLGG1 in gastric and breast cancer. However, the exact role of miR-429 in osteosarcoma remained unknown. In our study, we found MiR-429 was down-regulated in primary osteosarcoma lesion and osteosarcoma cell lines. Moreover, MiR-429 can inhibit the proliferation of osteosarcoma cell lines and induce more cell apoptosis. Also, we discovered MiR-429 plays a role in osteosarcoma by binding the 3′UTR of zinc finger E-box-binding homeobox 1 (ZEB1) mRNA, and that overexpression of ZEB1 could reverse the proliferation, subsequently blocking effect of miR-429. In conclusion, miR-429 serves as a tumor suppressor via interaction with ZEB1. Our finding may provide a new target for osteosarcoma therapy.