scholarly journals Sclerostin and Dickkopf-1 as Therapeutic Targets in Bone Diseases

2012 ◽  
Vol 33 (5) ◽  
pp. 747-783 ◽  
Author(s):  
Hua Zhu Ke ◽  
William G. Richards ◽  
Xiaodong Li ◽  
Michael S. Ominsky
Keyword(s):  
Monoclonal Antibody ◽  
Bone Formation ◽  
Bone Mass ◽  
Bone Repair ◽  
Wnt Pathway ◽  
Bone Growth ◽  
Biomechanical Properties ◽  
Bone Diseases ◽  
Metabolic Bone Diseases ◽  
Dickkopf 1

The processes of bone growth, modeling, and remodeling determine the structure, mass, and biomechanical properties of the skeleton. Dysregulated bone resorption or bone formation may lead to metabolic bone diseases. The Wnt pathway plays an important role in bone formation and regeneration, and expression of two Wnt pathway inhibitors, sclerostin and Dickkopf-1 (DKK1), appears to be associated with changes in bone mass. Inactivation of sclerostin leads to substantially increased bone mass in humans and in genetically manipulated animals. Studies in various animal models of bone disease have shown that inhibition of sclerostin using a monoclonal antibody (Scl-Ab) increases bone formation, density, and strength. Additional studies show that Scl-Ab improves bone healing in models of bone repair. Inhibition of DKK1 by monoclonal antibody (DKK1-Ab) stimulates bone formation in younger animals and to a lesser extent in adult animals and enhances fracture healing. Thus, sclerostin and DKK1 are emerging as the leading new targets for anabolic therapies to treat bone diseases such as osteoporosis and for bone repair. Clinical trials are ongoing to evaluate the effects of Scl-Ab and DKK1-Ab in humans for the treatment of bone loss and for bone repair.

Metabolic Bone Diseases in the Pediatric Population

2021 ◽  
Vol 25 (01) ◽  
pp. 094-104
Author(s):  
Valentina Testini ◽  
Laura Eusebi ◽  
Umberto Tupputi ◽  
Francesca Anna Carpagnano ◽  
Francesco Bartelli ◽  
...  
Keyword(s):  
Bone Mass ◽  
Bone Turnover ◽  
Bone Growth ◽  
Pediatric Population ◽  
Bone Diseases ◽  
Metabolic Bone Diseases ◽  
Mineral Balance ◽  
Metabolic Bone ◽  
Mineral Structure ◽  
Made In

AbstractBone plays an important role in regulating mineral balance in response to physiologic needs. In addition, bone is subject to a continuous remodeling process to maintain healthy bone mass and growth. Metabolic bone diseases are a heterogeneous group of diseases caused by abnormalities of bone mass, mineral structure homeostasis, bone turnover, or bone growth. In pediatrics, several significant advances have been made in recent years in the diagnosis of metabolic bone diseases (e.g., osteogenesis imperfecta, hyperparathyroidism, rickets, renal osteodystrophy, pediatric osteoporosis, and osteopetrosis). Imaging is fundamental in the diagnosis of these pathologies.

scholarly journals Gut microbiota induce IGF-1 and promote bone formation and growth

2016 ◽  
Vol 113 (47) ◽  
pp. E7554-E7563 ◽  
Author(s):  
Jing Yan ◽  
Jeremy W. Herzog ◽  
Kelly Tsang ◽  
Caitlin A. Brennan ◽  
Maureen A. Bower ◽  
...  
Keyword(s):  
Bone Formation ◽  
Gut Microbiota ◽  
Bone Mass ◽  
Bone Growth ◽  
Serum Levels ◽  
Short Chain Fatty Acids ◽  
Skeletal Growth ◽  
Microbial Colonization ◽  
Adult Mice ◽  
Specific Pathogen

Appreciation of the role of the gut microbiome in regulating vertebrate metabolism has exploded recently. However, the effects of gut microbiota on skeletal growth and homeostasis have only recently begun to be explored. Here, we report that colonization of sexually mature germ-free (GF) mice with conventional specific pathogen-free (SPF) gut microbiota increases both bone formation and resorption, with the net effect of colonization varying with the duration of colonization. Although colonization of adult mice acutely reduces bone mass, in long-term colonized mice, an increase in bone formation and growth plate activity predominates, resulting in equalization of bone mass and increased longitudinal and radial bone growth. Serum levels of insulin-like growth factor 1 (IGF-1), a hormone with known actions on skeletal growth, are substantially increased in response to microbial colonization, with significant increases in liver and adipose tissue IGF-1 production. Antibiotic treatment of conventional mice, in contrast, decreases serum IGF-1 and inhibits bone formation. Supplementation of antibiotic-treated mice with short-chain fatty acids (SCFAs), products of microbial metabolism, restores IGF-1 and bone mass to levels seen in nonantibiotic-treated mice. Thus, SCFA production may be one mechanism by which microbiota increase serum IGF-1. Our study demonstrates that gut microbiota provide a net anabolic stimulus to the skeleton, which is likely mediated by IGF-1. Manipulation of the microbiome or its metabolites may afford opportunities to optimize bone health and growth.

scholarly journals Mesenchymal Stem Cells for Bone Repair and Metabolic Bone Diseases

2009 ◽  
Vol 84 (10) ◽  
pp. 893-902 ◽  
Author(s):  
Anita H. Undale ◽  
Jennifer J. Westendorf ◽  
Michael J. Yaszemski ◽  
Sundeep Khosla
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Bone Repair ◽  
Bone Diseases ◽  
Metabolic Bone Diseases ◽  
Metabolic Bone

scholarly journals Insights into Material and Structural Basis of Bone Fragility from Diseases Associated with Fractures: How Determinants of the Biomechanical Properties of Bone Are Compromised by Disease

2006 ◽  
Vol 28 (2) ◽  
pp. 151-164 ◽  
Author(s):  
P. Chavassieux ◽  
E. Seeman ◽  
P. D. Delmas
Keyword(s):  
Mineral Content ◽  
Biomechanical Properties ◽  
Bone Fragility ◽  
Bone Diseases ◽  
Material Composition ◽  
Structural Basis ◽  
Metabolic Bone Diseases ◽  
Metabolic Bone ◽  
Composition And Structure ◽  
Minimal Trauma

Minimal trauma fractures in bone diseases are the result of bone fragility. Rather than considering bone fragility as being the result of a reduced amount of bone, we recognize that bone fragility is the result of changes in the material and structural properties of bone. A better understanding of the contribution of each component of the material composition and structure and how these interact to maintain whole bone strength is obtained by the study of metabolic bone diseases. Disorders of collagen (osteogenesis imperfecta and Paget’s disease of bone), mineral content, composition and distribution (fluorosis and osteomalacia); diseases of high remodeling (postmenopausal osteoporosis, hyperparathyroidism, and hyperthyroidism) and low remodeling (osteopetrosis, pycnodysostosis); and other diseases (idiopathic male osteoporosis, corticosteroid-induced osteoporosis) produce abnormalities in the material composition and structure that lead to bone fragility. Observations in patients and in animal models provide insights on the biomechanical consequences of these illnesses and the nature of the qualities of bone that determine its strength.

scholarly journals Modulation of Dickkopf-1 Attenuates Glucocorticoid Induction of Osteoblast Apoptosis, Adipocytic Differentiation, and Bone Mass Loss

Endocrinology ◽  
2008 ◽  
Vol 149 (4) ◽  
pp. 1793-1801 ◽  
Author(s):  
Feng-Sheng Wang ◽  
Jih-Yang Ko ◽  
Da-Wei Yeh ◽  
Huei-Ching Ke ◽  
Hsing-Long Wu
Keyword(s):  
Bone Formation ◽  
Bone Mass ◽  
Bone Tissue ◽  
Bone Mass Loss ◽  
Osteogenic Cells ◽  
Dkk1 Expression ◽  
Adipocytic Differentiation ◽  
Glucocorticoid Induction ◽  
Dickkopf 1 ◽  
Dexamethasone Suppression

Long-term glucocorticoid treatment impairs the survival and bone formation of osteogenic cells, leading to bone mass loss. The Wnt inhibitor Dickkopf-1 (DKK1) acts as a potent bone-remodeling factor that mediates several types of skeletal disorders. Whereas excess glucocorticoid is known to disturb Wnt signaling in osteogenic cells, modulation of the skeletally deleterious effects of DKK1 to alleviate glucocorticoid induction of bone loss has not been tested. In this study, knockdown of DKK1 expression by end-capped phosphorothioate DKK1 antisense oligonucleotide (DKK1-AS) abrogated dexamethasone suppression of alkaline phosphatase activity and osteocalcin expression in MC3T3-E1 preosteoblasts. Exogenous DKK1-AS treatment alleviated dexamethasone suppression of mineral density, trabecular bone volume, osteoblast surface, and bone formation rate in bone tissue and ex vivo osteogenesis of primary bone-marrow mesenchymal cells. The DKK1-AS inhibited adipocyte volume in the marrow cavity of steroid-treated bone tissue. Immunohistochemical observation revealed that DKK1-AS abrogated dexamethasone-induced DKK1 expression and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end-labeling of osteoblasts adjacent to trabecular bone. Knocking down DKK1 abrogated dexamethasone-modulated expression of nuclear β-catenin and phosphorylated Ser473-Akt and survival of osteoblasts and adipocytic differentiation of mesenchymal progenitor cell cultures. Taken together, knocking down DKK1 alleviated the deleterious effect of glucocorticoid on bone microstructure. The DKK1-AS treatment appeared to protect bone tissue by modulating β-catenin and Akt-mediated survival as well as the osteogenic and adipogenic activities of glucocorticoid-stressed osteoprogenitor cells. Interference with the osteogenesis-inhibitory action of DKK1 has therapeutic potential for preventing glucocorticoid induction of osteopenia.

scholarly journals Conducting PEEK Nanocomposites with Electrophoretically Deposited Bioactive Coating for Bone Tissue Regeneration and Multi-Modal Therapeutic Applications

2020 ◽  
Author(s):  
Miaomiao He ◽  
Ce zhu ◽  
Huan Xu ◽  
dan Sun ◽  
Chen Chen ◽  
...  
Keyword(s):  
Bone Tissue ◽  
Tissue Regeneration ◽  
Bone Repair ◽  
Graphene Nanosheets ◽  
Biomechanical Properties ◽  
Bone Diseases ◽  
Bone Tissue Regeneration ◽  
Order Of Magnitude

The use of polyetheretherketone (PEEK) has grown exponentially in the biomedical field in recent decades due to its outstanding biomechanical properties. However, its lack of bioactivity/osteointegration remains an unresolved issue towards its wide use in orthopedic applications. In this work, graphene nanosheets have been incorporated into PEEK to obtain multifunctional nanocomposites. Due to the formation of electrical percolation network and the π-π* conjugation between graphene and PEEK, the resulting composites have achieved twelve order of magnitude enhancement in its electrical conductivity, and have enabled electrophoretic deposition of bioactive/anti-bacterial coating consisting of stearyltrimethylammonium chloride (STAC) modified hydroxyapatite (HA). The coated composite implant showed significant boosting of BMSC cell proliferation in vitro. In addition, the strong photothermal conversion effect of the graphene nanofillers have enabled laser induced heating of our nanocomposite implants, where the temperature of the implant can reach 45 oC in 150 s. The unique multi-functionality of our composite implant has also been demonstrated for photothermal applications such as enhancing bacterial (E. coli and S. aureus) eradication and tumor cell (MG63) inhibition, as well as bone tissue regeneration in vivo. The results suggest the strong potential of our multi-functional implant in bone repair applications as well as multi-modal therapy of challenging bone diseases such as osteosarcoma and osteomyelitis

Metabolic Syndrome

2014 ◽  
pp. 527-531
Author(s):  
Rajesh K. Garg
Keyword(s):  
Metabolic Syndrome ◽  
Bone Mass ◽  
Organic Matrix ◽  
Bone Diseases ◽  
Tight Coupling ◽  
Noncollagenous Proteins ◽  
Metabolic Bone Diseases ◽  
Skeletal Fragility ◽  
Metabolic Bone ◽  
The Matrix

Bone is a dynamic and complex organ that undergoes constant remodeling. It consists of an organic matrix (collagen and some noncollagenous proteins), minerals (calcium and phosphate in hydroxyapatite crystals), and water. Normally bone mass is maintained by a tight coupling of bone breakdown by osteoclasts followed by bone formation by osteoblasts. This chapter summarizes three metabolic bone diseases. Osteoporosis is characterized by a decreased bone mass with a normal mineral-to-matrix ratio and superimposed skeletal fragility and fractures; osteomalacia occurs when there is a reduced mineralization of the matrix; and Paget's disease is a disorder in which there is excessive, disorganized bone resorption and formation.

scholarly journals A novel RGB-trichrome staining method for routine histological analysis of musculoskeletal tissues

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Francisco Gaytan ◽  
Concepción Morales ◽  
Carlos Reymundo ◽  
Manuel Tena-Sempere
Keyword(s):  
Musculoskeletal System ◽  
Bone Repair ◽  
Staining Method ◽  
Three Dimensional ◽  
Bone Diseases ◽  
Metabolic Bone Diseases ◽  
Skeletal Tissue ◽  
Musculoskeletal Tissues ◽  
Clear Identification ◽  
Staining Methods

Abstract Morphometry and histology are essential approaches for investigation and diagnosis of musculo-skeletal disorders. Despite the advent of revolutionary methods of image analysis and high resolution three-dimensional imaging technology, basic conventional light microscopy still provides an incisive overview of the structure and tissue dynamics of the musculoskeletal system. This is crucial to both preclinical and clinical research, since several clinically relevant processes, such as bone repair, osteoarthritis, and metabolic bone diseases, display distinct, if not pathognomonic, histological features. Due to the particular characteristics of the skeletal tissues (i.e., the existence of mineralized extracellular matrices), a large number of staining methods applicable to either decalcified or undecalcified tissues are available. However, it is usually the case that several staining methods need to be sequentially applied in order to achieve the different endpoints required to fully assess skeletal tissue structure and dynamics, and to allow morphometric quantification. We describe herein a novel staining method, the RGB trichrome, amenable for application to decalcified, paraffin embedded human musculoskeletal tissues. The acronym RGB corresponds to the three primary dyes used: picrosirius Red, fast Green, and alcian Blue. Although these individual pigments are commonly used either isolated, in binary combinations, or as part of more complex polychrome staining methods, when merged in the RGB trichrome staining produce high-quality/high-contrast images, permitting not only clear identification of different tissues (i.e., the different types of cartilage, bone and fibrous connective tissue), but also discrimination between calcified and uncalcified bone and cartilage, as well as an unexpected diversity of shades of color, while displaying singular properties among polychrome staining methods, such as the unveiling of the bone osteocyte dendritic/canalicular network. Hence, we propose the RGB trichrome as simple but highly-reliable tool for the preclinical and clinical study of the musculoskeletal system.

BMPs as Adsorptive Proteins for Ceramic Scaffolds

2011 ◽  
Vol 493-494 ◽  
pp. 808-812
Author(s):  
K. Ito ◽  
Masaru Murata ◽  
J. Hino ◽  
Junichi Tazaki ◽  
T. Akazawa ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Bone Morphogenetic Proteins ◽  
Bone Repair ◽  
Bone Growth ◽  
Blood Compatibility ◽  
Sodium Dodecyl ◽  
Major Band ◽  
Fluid Permeability ◽  
Inducing Factors

Body fluid permeability and blood compatibility of biomaterials are especially critical properties for regenerative bone therapy [1, 2]. To have a role in bone repair, biomaterials must have the adsorptive performance of various bone growth factors. The bone-inductive property of rabbit dentin was discovered in 1967 [3]. In our previous study, we have been researching the autograft of human demineralized dentin matrices (DDM) as a clinical study [4]. DDM is an acid-insoluble collagenous material. On the other hand, hydroxyapatite (HAp) is a mineralized material. Commercially available HAp block (APACERAM-AX®,85%-porosity with micropore) has been used as the artificial biomaterial in bone therapy [5]. Bone morphogenetic proteins (BMPs) are the strong hard tissue-inducing factors [6]. In this study, we investigated the existence of BMP-2 and -7, among proteins adsorbed to DDM and HAp, using immunoblottong analyses. The DDM granules and HAp blocks (64mm3) were implanted subcutaneously in 8-week-old Wistar rats, and sacrificed at 2 days after the implantation. Explanted DDM and HAp were homogenized by the ultrasonic procedure in phosphate-buffered saline (PBS) and the adsorbed proteins were separated on a 5-20% sodium dodecyl sulphate (SDS) polyacrylamide gradient gel by electrophoresis. For Western blotting, proteins in the gel were transferred to a polyvinylidene difluoride membrane and detected by anti-BMP-2 monoclonal antibody and anti-BMP-7 monoclonal antibody. BMP-2 and BMP-7 were detected as a major band at 50 kDa among proteins collected from the in vivo implanted DDM and HAp. BMP-2 was detected the second major band at 125 kDa in HAp and both BMP-2 and BMP-7 were detected the some minor bands in DDM and HAp. The bands of BMP-2 were stronger than those of BMP-7 in all. The DDM and HAp adsorbed BMP-2 and BMP-7. These results indicate that DDM is a useful bone substitute as much as HAp, adsorbed to the bone-inducing factors, in the bone engineering field.

Osteogenic Activity of Yellow Flag Iris (Iris pseudacorus) Extract Modulating Differentiation of Osteoblasts and Osteoclasts

2012 ◽  
Vol 40 (06) ◽  
pp. 1289-1305 ◽  
Author(s):  
Jung-Lye Kim ◽  
Hong Mei Li ◽  
Yun-Ho Kim ◽  
Yong-Jin Lee ◽  
Jae-Hoo Shim ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Bone Formation ◽  
Phosphatase Activity ◽  
Bone Diseases ◽  
Nodule Formation ◽  
Tartrate Resistant Acid Phosphatase ◽  
Raw 264.7 ◽  
Type I ◽  
Metabolic Bone Diseases ◽  
Yellow Flag

Bone integrity is maintained through a balance between bone formation by osteoblasts and bone resorption by osteoclasts. Imbalance of the process results in metabolic bone diseases such as osteoporosis. This study investigated the yellow flag iris extract (YFIE) and revealed its anti-osteoporotic effects in osteoblastic MC3T3-E1 mouse cells and RAW 264.7 murine macrophages. When osteoblasts were treated with 1–20 μg/ml YFIE in an osteogenic medium, the bone nodule formation by calcium deposits was markedly enhanced during differentiation. Consistently, YFIE stimulated alkaline phosphatase activity and collagen type I secretion with a substantial effect on osteoblast proliferation. On the other hand, RAW 264.7 macrophages were pre-incubated with 1–20 μg/ml YFIE for 5 days in the presence of receptor activator of nuclear factor-κB ligand (RANKL). Non-toxic YFIE markedly attenuated the differentiation of macrophages to multi-nucleated osteoclasts. YFIE diminished RANKL-elevated tartrate-resistant acid phosphatase activity and bone resorption. In addition, the YFIE treatment retarded RANKL-induced cathepsin K production and carbonic anhydrase II expression, both of which are involved in bone resorption. Therefore, YFIE potentially posesses therapeutic agents that may prevent osteoporosis through promoting bone formation and reducing bone resorption.

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