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Author(s): David L Waning [1]; Khalid S Mohammad [1]; Steven Reiken [2]; Wenjun Xie [2]; Daniel C Andersson [2]; Sutha John [1]; Antonella Chiechi [1]; Laura E Wright [1]; Alisa [...], Cancer-associated muscle weakness is a poorly understood phenomenon, and there is no effective treatment. Here we find that seven different mouse models of human osteolytic bone metastases--representing breast, lung and prostate cancers, as well as multiple myeloma--exhibited impaired muscle function, implicating a role for the tumor-bone microenvironment in cancer-associated muscle weakness. We found that transforming growth factor (TGF)-[beta], released from the bone surface as a result of metastasis-induced bone destruction, upregulated NADPH oxidase 4 (Nox4), resulting in elevated oxidization of skeletal muscle proteins, including the ryanodine receptor and calcium (Ca[sup.2+]) release channel (RyR1). The oxidized RyR1 channels leaked Ca[sup.2+], resulting in lower intracellular signaling, which is required for proper muscle contraction. We found that inhibiting RyR1 leakage, TGF-[beta] signaling, TGF-[beta] release from bone or Nox4 activity improved muscle function in mice with MDA-MB-231 bone metastases. Humans with breast- or lung cancer-associated bone metastases also had oxidized skeletal muscle RyR1 that is not seen in normal muscle. Similarly, skeletal muscle weakness, increased Nox4 binding to RyR1 and oxidation of RyR1 were present in a mouse model of Camurati-Engelmann disease, a nonmalignant metabolic bone disorder associated with increased TGF-[beta] activity. Thus, pathological TGF-[beta] release from bone contributes to muscle weakness by decreasing Ca[sup.2+]-induced muscle force production.

Increasing evidence shows the therapeutic superiority of herbal extracts in comparison to isolated single constituents. One of the reasons may be attributed to the synergy effect of compound combinations. Flavonoids [...]

Problem statement: The purpose of this study was to histopathology and biomechanics evaluate the effect of sodium fluoride on cancellous bone defect healing in rat model. Approach: The experiment was conducted on 40 male adult SD rats which were divided into four groups of control and experiments. After induction of general anesthesia, a hole in size of 2x3 mm in diameter and depth was made using a dental bit in the inner aspect of the between condyles of right femor. In all groups, defect was left untreated. Control group was given distilled water and the other three groups were exposed to fluoridated water at different concentrations (8, 30 and 60 mg F-/L). After 45 days all rats were sacrificed and the histopathological and biomechanical penetration tests of the distal femoral bone were performed. Results: In control group, defect seemed to be filled with adipous tissue and sparse hematogenic cells and in spite of a poor osteogenic activity and some osteoblasts could already be seen. In experiment groups, many osteoblasts groupings and young bone trabeculas increased in number and bone trabeculas more organized. Histopathologically findings show that 30 mg F-/L sodium fluoride in drinking water has been better effect than other groups. The mean load for fracturing in control group was 173.01 [+ or -] 23.05 and in experiment groups 8, 30 and 60mg were 177.31 [+ or -] 33.71, 181.90 [+ or -] 36.81 and 168.51 [+ or -] 54.35. Differences observed in biomechanically findings were significant between 30mg group and other groups (p Conclusion: The results of this study show that fluoride level at 30 mg [F.sup.-][L.sup.-1] in drinking water increases compressive strength of cancellous bone defect in healing process and could stimulate osteogenesis in femoral cancellous bone defect in rats. Key words: Sodium fluoride, cancellous bone, healing process, adult male rats, osteoblasts groupings, general anesthesia, biomechanics evaluate, osteoporotic patients, laboratory animal, INTRODUCTION Sodium fluoride in clinical use for treatment of osteoporosis and vertebral fractures (Demos et al., 2001; Apostolova and Brenne, 2010). Clinical studies have been shown that sodium fluoride is [...]

Local or systemic stem cell delivery has the potential to promote repair of a variety of damaged or degenerated tissues. Although various stem cell sources have been investigated for bone repair, few comparative reports exist, and cellular distribution and viability postimplantation remain key issues. In this study, we quantified the ability of tissue-engineered constructs containing either human fetal or adult stem cells to enhance functional repair of nude rat critically sized femoral defects. After 12 weeks, defects treated with cell-seeded polymer scaffolds had significantly higher bone ingrowth and torsional strength compared to those receiving acellular scaffolds, although there were no significant differences between the cell sources. Next, stem cells were labeled with fluorescent quantum dots (QDs) in an attempt to noninvasively track their distribution after delivery on scaffolds. Clear fluorescence was observed at implantation sites throughout the study; however, beginning 7-10 days after surgery, signals were also observed at contralateral sites treated with acellular QD-free scaffolds. Although immunostaining for human nuclei revealed retention of some cells at the implantation site, no human cells were detected in the control limb defects. Additional histological analysis of implantation and control defect tissues revealed macrophages containing endocytosed QDs. Furthermore, QD-labeling appeared to diminish transplanted cell function resulting in reduced healing responses. In summary, augmentation of polymeric scaffolds with stem cells derived from fetal and adult tissues significantly enhanced healing of large segmental bone defects; however, QD labeling of stem cells eliminated the observed therapeutic effect and failed to conclusively track stem cell location long-term in vivo. bone tissue engineering | cell tracking | in vivo | quantum dots | stem cells doi/10.1073/pnas.0905444107

Tibial dyschondroplasia (TD) is a prevalent skeletal abnormality associated with rapid growth rate in many avian species. It is characterized by the presence of a nonvascularized, nonmineralized lesion that extends from the epiphyseal growth plate into the metaphysis of the proximal tibiotarsal bones. In this study, we examined the expression of 4 members of the matrix metalloproteinase (MMP) family (MMP-2, -3, -9, and -13) in thiram-induced TD lesions and in the process of recovery from TD, by in situ hybridization analysis and quantitative real-time PCR. A model for the induction and recovery of TD was established, consisting of 3 groups of broilers: (1) thiram group, chicks fed a thiram-enriched diet to induce TD; (2) recovery group, chicks fed a thiram-enriched diet during the first week of the experiment and a normal diet from the second week on; and (3) control group, chicks fed a normal diet throughout the experimental period. In agreement with our previous data, the 4 MMP were diminished in the TD lesion (P < 0.05); however, in the current study we show that the growth plate was able to repair itself and that the MMP reappeared during the process of recovery from TD. Our results strengthen the link between MMP expression and growth-plate impairment, and we suggest that gelatinase activity (MMP-2 and 9) facilitates this process. Key words: avian, growth plate, matrix metalloproteinase, tibial dyschondroplasia doi: 10.2527/jas.2009-2068

Human mesenchymal stem cells offer a potential alternative to embryonic stem cells in clinical applications. The ability of these cells to self-renew and differentiate into multiple tissues, including bone, cartilage, [...]

A protective role for vitamin K in bone health has been suggested based on its role as an enzymatic cofactor. In observational studies, vitamin K insufficiency is generally associated with lower bone mass and increased hip fracture risk. However, these findings are not supported in randomized controlled trials (RCT) of phylloquinone (vitamin [K.sub.1]) supplementation and bone loss at the hip in the elderly. This suggests that increased vegetable and legume intakes may simultaneously improve measures of vitamin K status and skeletal health, even though the mechanisms underlying these improvements may be independent of each other. Menaquinone-4 (vitamin [K.sub.2]), when given at pharmacological doses, appears to protect against fracture risk and bone loss at the spine. However, there are emerging data that suggest the efficacy of vitamin K supplementation on bone loss is inconclusive.

This paper describes a new approach for laser bone treatment according to a preoperative plan. The advantages of using laser systems are the free choice of the cutting geometry and the possibility of bone treatment without any severe thermal damage. On the other hand, the control of bone removal depth is difficult. Due to the lack of haptical feedback, it is only possible to control the bone removal visually. In addition, by selecting wrong laser parameters and incorrect handling, the tissue can sustain thermal damage. To solve this problem, an approach of navigated and model-based calculation of depth ablation has been investigated. The focus of this paper was to verify the feasibility of precise and safe laser bone removal by combining navigation information with mathematical and volumetric modeling. For the mathematical modeling, known approaches are used. On the basis of CT data, cavities in a bovine bone were planned with a navigation system. With an optical measurement system, the position of the laser handpiece was calculated relative to the bone. Using a mathematical model, the theoretical cavity depth was calculated for each laser pulse and displayed on the navigation screen. Thereby, the material removal was determined in a volume model. With this information, five cavities were created by the laser using constant energy settings. A final measurement of the cavities' depths showed an error of less than 1 mm. Index Terms--Bone treatment, medical information system, medical laser and medical navigation, medical treatment, power control.

Osteoclastogenesis is a tightly regulated biological process, and deregulation can lead to severe bone disorders such as osteoporosis. The regulation of osteoclastic signaling is incompletely understood, but ubiquitination of TNF receptor--associated factor 6 (TRAF6) has recently been shown to be important in mediating this process. We therefore investigated the role of the recently identified deubiquitinating enzyme CYLD in osteoclastogenesis and found that mice with a genetic deficiency of CYLD had aberrant osteoclast differentiation and developed severe osteoporosis. Cultured osteoclast precursors derived from CYLD-deficient mice were hyper-responsive to RANKL-induced differentiation and produced more and larger osteoclasts than did controls upon stimulation. We assessed the expression pattern of CYLD and found that it was drastically upregulated during RANKL-induced differentiation of preosteoclasts. Furthermore, CYLD negatively regulated RANK signaling by inhibiting TRAF6 ubiquitination and activation of downstream signaling events. Interestingly, we found that CYLD interacted physically with the signaling adaptor p62 and thereby was recruited to TRAF6. These findings establish CYLD as a crucial negative regulator of osteoclastogenesis and suggest its involvement in the p62/TRAF6 signaling axis., Introduction Normal bone physiology is regulated by the harmonic actions of osteoblasts and osteoclasts (OCs), cells that mediate bone formation and bone resorption, respectively (1). OCs are multinucleated cells that [...]

The capacity to direct migration (&apos;homing&apos;) of blood-borne cells to a predetermined anatomic compartment is vital to stem cell-based tissue engineering and other adoptive cellular therapies. Although multipotent mesenchymal stromal cells (MSCs, also termed &apos;mesenchymal stem cells&apos;) hold the potential for curing generalized skeletal diseases, their clinical effectiveness is constrained by the poor osteotropism of infused MSCs (refs. 1-3). Cellular recruitment to bone occurs within specialized marrow vessels that constitutively express vascular E-selectin (4,5), a lectin that recognizes sialofucosylated determinants on its various ligands. We show here that human MSCs do not express E-selectin ligands, but express a CD44 glycoform bearing [alpha]-2,3-sialyl modifications. Using an [alpha]-1,3-fucosyltransferase preparation and enzymatic conditions specifically designed for treating live cells, we converted the native CD44 glycoform on MSCs into hematopoietic cell E-selectin/L-selectin ligand (HCELL) (6), which conferred potent E-selectin binding without effects on cell viability or multipotency. Real-time intravital microscopy in immunocompromised (NOD/SCID) mice showed that intravenously infused [HCELL.sup.+] MSCs infiltrated marrow within hours of infusion, with ensuing rare foci of endosteally localized cells and human osteoid generation. These findings establish that the HCELL glycoform of CD44 confers tropism to bone and unveil a readily translatable roadmap for programming cellular trafficking by chemical engineering of glycans on a distinct membrane glycoprotein., Generalized skeletal diseases, such as osteoporosis and osteogenesis imperfecta, are currently incurable and cause considerable morbidity and mortality. MSCs hold great promise for treating or curing congenital and acquired bone [...]

Osteoblasts are essential for maintaining bone mass, avoiding osteoporosis, and repairing injured bone. Activation of osteoblast G protein-coupled receptors (GPCRs), such as the parathyroid hormone receptor, can increase bone mass; however, the anabolic mechanisms are poorly understood. Here we use 'Rs1,' an engineered GPCR with constitutive [G.sub.s] signaling, to evaluate the temporal and skeletal effects of [G.sub.s] signaling in murine osteoblasts. In vivo, Rs1 expression induces a dramatic anabolic skeletal response, with midfemur girth increasing 1,200% and femur mass increasing 380% in 9-week-old mice. Bone volume, cellularity, areal bone mineral density, osteoblast gene markers, and serum bone turnover markers were also elevated. No such phenotype developed when Rs1 was expressed after the first 4 weeks of postnatal life, indicating an exquisite temporal sensitivity of osteoblasts to Rs1 expression. This pathway may represent an important determinant of bone mass and may open future avenues for enhancing bone repair and treating metabolic bone diseases. RASSL | constitutive [G.sub.s] activity | bone formation | cyclic AMP | McCune-Albright syndrome

Acquired osteosclerosis is a rare disorder of bone formation but an important consideration in adults with sclerotic bones or elevated bone density results. In such patients, malignancy, hepatitis C, and [...]

Craniosynostosis, the fusion of one or more of the sutures of the skull vault before the brain completes its growth, is a common (1 in 2,500 births) craniofacial abnormality, [approximately equal to] 20% of which occurrences are caused by gain-of-function mutations in FGF receptors (FGFRs). We describe a genetic and pharmacological approach for the treatment of a murine model system of Crouzon-like craniosynostosis induced by a dominant mutation in Fgfr2c. Using genetically modified mice, we demonstrate that premature fusion of sutures mediated by Crouzon-like activated Fgfr2c mutant is prevented by attenuation of signaling pathways by selective uncoupling between the docking protein Frs2[alpha] and activated Fgfr2c, resulting in normal skull development. We also demonstrate that attenuation of Fgfr signaling in a calvaria organ culture with an Fgfr inhibitor prevents premature fusion of sutures without adversely affecting calvaria development. These experiments show that attenuation of FGFR signaling by pharmacological intervention could be applied for the treatment of craniosynostosis or other severe bone disorders caused by mutations in FGFRs that currently have no treatment. bone disorders | cell signaling | cell surface receptors | protein kinases | skull development

Byline: Frank Rauch (1) Keywords: Bone histomorphometry; Children; Modeling; Remodeling; Renal bone disease Abstract: Histomorphometric analysis of iliac bone samples is a key tool for studying bone metabolism and, to a lesser extent, bone mass and structure. Two types of bone metabolic activity can be distinguished: modeling and remodeling. Both processes are performed by the same effector cells, osteoblasts and osteoclasts, but differ in the way these cells are arranged. The main effect of remodeling is to renew bone, whereas modeling can lead to rapid changes in bone shape, size and mass. Standard histomorphometric analysis focuses on trabecular bone and therefore mainly provides information on remodeling. Remodeling activity changes markedly with age during development. This must be taken into account when histomorphometry is used in the pediatric setting. Remodeling disorders encountered in the context of pediatric renal bone disease include mineralization defects, as well as abnormally high remodeling activity due to secondary hyperparathyroidism or suppressed remodeling activity as a consequence of over-treatment. Children and adolescents with severe bone fragility should have a bone biopsy unless the diagnosis is obvious from noninvasive examinations. Histomorphometric analysis of transiliac bone biopsy samples is especially valuable in clinical studies, as this method provides safety and efficacy data that cannot be obtained in any other way. Author Affiliation: (1) Genetics Unit, Shriners Hospital for Children, 1529 Cedar Avenue, Montreal, Quebec, H3G 1A6, Canada Article History: Registration Date: 10/01/2006 Received Date: 23/10/2005 Accepted Date: 09/12/2005 Online Date: 07/03/2006

Evidence of the effect of purified soy isoflavones and soy protein isolates containing isoflavones on bone health in rats and in humans is inconsistent. Differences may be because of synergies or antagonisms among the isoflavones, threshold or biphasic dose effects, life stage of animals or human subjects, estrogen status, and environment-genetic interactions, including the ability to produce metabolites upon ingestion of isoflavones. At this time, the benefits of soy protein and isoflavones on bone health are inconclusive. This overview will summarize these discrepancies and will suggest future studies to clarify the conditions under which these dietary substances can be helpful for bones. KEY WORDS: * soy isoflavones * bone * estrogen status * equol

Byline: M. Zivicnjak (1), D. Franke (1), J. H. H. Ehrich (1), G. Filler (1) Keywords: Key wordsaGrowth hormone; Chronic renal failure; Morphological disproportion; Harmonization; Anthrometry; Body shape Abstract: Recombinant human growth hormone (rhGH) therapy of growth retardation in chronic renal failure (CRF) has become well established. While there are ample data about its effectiveness in restoring longitudinal growth delay, data on complex anthropometry are scarce. Twenty-three children with CRF (6 after renal transplantation) were investigated using 24 different parameters. The analysis revealed disproportionate growth in CRF. While parameters of the trunk and transverse dimension of the head were preserved, the extremities were affected more severely. Bone dimensions of the legs and arms as well as muscle mass were affected the most. RhGH therapy was effective in restoring impaired longitudinal dimensions of the body in CRF. The restoration of growth retardation occurred predominantly in the extremities. This was accompanied by an increase in transversal dimensions, circumferences and soft tissue of the extremities, as well as an increase in bone and muscle volume, indicating harmonization of the total body shape. The dimensions of trunk, forehead diameter and morphological face height remained within the normal range. There was no evidence of acromegaly in children with CRF and rhGH therapy. We conclude that rhGH therapy at a dose of 28 iU/m.sup.2/week is effective in restoring previously disproportional body structure and shape in children with CRF. Author Affiliation: (1) Department of Pediatric Nephrology, Charite, Humboldt University at Berlin, Berlin, Germany, DE (2) Division of Nephrology, Children"s Hospital of Eastern Ontario, 401 Smyth Road, Ottawa, Ontario, Canada K1H 8L1 e-mail: filler@cheo.on.ca Tel.: +1-613-7372441, Fax: +1-613-7384864, CA Article note: Received: 3 December 1999 / Revised: 27 July 2000 / Accepted: 1 August 2000

Byline: Inge M. van der Sluis (1), Annemieke M. Boot (1), Jeroen Nauta (1), Wim C. J. Hop (3), Maria C. J. W. de Jong (4), Marc R. Lilien (5), Jaap W. Groothoff (6), Ans E. van Wijk (7), Huibert A. P. Pols (8), Anita C. S. Hokken-Koelega (1), Sabine M. P. F. de Muinck Keizer-Schrama (1) Keywords: Key wordsaChronic renal failure; Growth hormone treatment; Bone mineral density; Biochemical parameters of bone turnover; Growth; Body composition Abstract: Metabolic bone disease and growth retardation are common complications of chronic renal failure (CRF). We evaluated bone mineral density (BMD), bone metabolism, body composition and growth in children with CRF, and the effect of growth hormone treatment (GHRx) on these variables. Thirty-three prepubertal patients with CRF were enrolled including 18 children with growth retardation, who were treated with growth hormone for 2 years. Every 6 months, BMD of lumbar spine and total body, and body composition were measured by dual-energy X-ray absorptiometry. Biochemical parameters of bone turnover were assessed. Mean BMD of children with CRF did not differ from normal. During GHRx, BMD and bone mineral apparent density of lumbar spine and height SDS increased, whereas BMD of total body did not change. Lean body mass increased in the GH group. Alkaline phosphatase increased significantly in the GH group only. The other biochemical parameters of bone turnover increased in both groups, none of them correlated with the changes in BMD. No serious adverse effects of GHRx were reported. In conclusion, BMD of children with CRF did not differ from healthy children. Adequate treatment with [alpha]-calcidiol or the short duration of renal failure may have attributed to the absence of osteopenia in our patients. BMD of the axial skeleton and growth improved with GHRx. Author Affiliation: (1) Department of Pediatrics, Division of Endocrinology and Nephrology, Sophia Children&apos;s Hospital Rotterdam, Rotterdam, The Netherlands, NL (2) Department of Experimental Radiology, Erasmus University Rotterdam, Rotterdam, The Netherlands, NL (3) Department of Epidemiology and Biostatistics, Erasmus University Rotterdam, Rotterdam, The Netherlands, NL (4) Department of Pediatrics, Division of Nephrology, Academic Hospital Nijmegen, Nijmegen, The Netherlands, NL (5) Department of Pediatrics, Division of Nephrology, Wilhemina Children&apos;s Hospital Utrecht, Utrecht, The Netherlands, NL (6) Department of Pediatrics, Division of Nephrology, Academic Medical Centre Amsterdam, Amsterdam, The Netherlands, NL (7) Department of Pediatrics, Division of Nephrology, Free University Hospital Amsterdam, Amsterdam, The Netherlands, NL (8) Department of Internal Medicine, Academic Hospital Rotterdam, Rotterdam, The Netherlands, NL (9) Sophia Children&apos;s Hospital, Subdivision of Endocrinology, PO Box 2060, 3000 CB Rotterdam, The Netherlands e-mail: vandesluis@alkg.azr.nl Tel.: +31-10-4636111, Fax: +31-10-4636811, NL Article note: Received: 18 April 2000 / Revised: 26 June 2000 / Accepted: 29 June 2000

A painful increase in bulk of the long bones combined with very high blood phosphate levels may run in families and be an extension of a related disease process. Two sisters and an unrelated girl, all Saudi Arabian, experienced right leg and foot pain. They were diagnosed as having increased bulk of the long bones and very high blood phosphate levels. One of the sisters also experienced calcification of collagen in the large joints, which may have been an extension of the bone and phosphate level disease process. Nonsurgical treatment with pain relievers was provided., Hyperostosis with hyperphosphatemia was first described in 1970[1] and subsequently in eight additional patients.[2-5] It presents as recurrent painful swelling of the long bones associated with hyperphosphatemia, normal renal function [...]

Research is ongoing into several promising treatments for osteogenesis imperfecta (OI). OI is a genetic disorder caused by a mutation in type I collagen, which is the primary structural protein in bones and tendons. Children with OI have delayed growth, delayed motor skills and frequent bone fractures. Braces, surgery and physical therapy are used to strengthen muscles. Growth hormone may also be useful in promoting growth. Cell replacement therapy involves replacing defective collagen cells using a bone marrow transplant. Antisense RNA can also block the production of defective collagen.