Blockade of Wnt inhibitor Dickkopf-1 improves bone mass and microstructure of osteogensis imperfecta

2014 ◽  
Author(s):  
Feng-Sheng Wang ◽  
Wen-Hong Su ◽  
Pei-Chin Chuang ◽  
Su-Ren Kuo ◽  
Jih-Yang Ko
Keyword(s):  
Bone Mass ◽  
Wnt Inhibitor ◽  
Dickkopf 1

SAT0460 Low Bone Mass in Patients with Systemic Sclerosis: Relationships with Dickkopf-1 Levels and 25-Hydroxyvitamin D Status

2014 ◽  
Vol 73 (Suppl 2) ◽  
pp. 760.2-760
Author(s):  
B. Seriolo ◽  
R. Brizzolara ◽  
S. Soldano ◽  
A. Casabella ◽  
L. Molfetta ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Bone Mass ◽  
Low Bone Mass ◽  
Hydroxyvitamin D ◽  
25 Hydroxyvitamin D ◽  
Dickkopf 1

scholarly journals Hyperthyroidism and Hypothyroidism in Male Mice and Their Effects on Bone Mass, Bone Turnover, and the Wnt Inhibitors Sclerostin and Dickkopf-1

Endocrinology ◽  
2015 ◽  
Vol 156 (10) ◽  
pp. 3517-3527 ◽  
Author(s):  
Elena Tsourdi ◽  
Eddy Rijntjes ◽  
Josef Köhrle ◽  
Lorenz C. Hofbauer ◽  
Martina Rauner
Keyword(s):  
Thyroid Hormone ◽  
Bone Density ◽  
Bone Mass ◽  
Bone Turnover ◽  
Thyroid Hormones ◽  
Wnt Signaling ◽  
Cortical Bone ◽  
Bone Remodeling ◽  
Wnt Inhibitors ◽  
Dickkopf 1

Thyroid hormones are key regulators of bone homeostasis, and Wnt signaling has been implicated in thyroid hormone-associated bone loss. Here we tested whether hyperthyroidism and hypothyroidism interfere with dickkopf-1 (DKK1) and sclerostin, two inhibitors of Wnt signaling. Twelve-week-old male C57BL/6 mice were rendered either hyperthyroid or hypothyroid. Hyperthyroid mice displayed decreased trabecular (−54%, P < .001) and cortical bone density (−5%, P < .05) and reduced cortical thickness (−15%, P < .001), whereas hypothyroid mice showed a higher trabecular bone density (+26%, P < .001) with unchanged cortical bone parameters. Histomorphometry and biochemical markers of bone remodeling indicated high bone turnover in hyperthyroid mice and low bone turnover in hypothyroid mice. In vivo, serum DKK1 concentrations were decreased in hyperthyroid mice (−24%, P < .001) and increased in hypothyroid mice (+18%, P < .01). The increase of the number of DKK1-positive cells in hypothyroid mice was confirmed at the tissue level. Interestingly, sclerostin was increased in both disease models, although to a higher extent in hyperthyroid mice (+50%, P < .001, and +24%, P < .05). Serum sclerostin concentrations adjusted for bone mass were increased by 3.3-fold in hyperthyroid (P < .001) but not in hypothyroid mice. Consistently, sclerostin mRNA expression and the number of sclerostin-positive cells were increased in hyperthyroid but not in hypothyroid mice. Our data show that thyroid hormone-induced changes in bone remodeling are associated with a divergent regulation of DKK1 and sclerostin. Thus, the modulation of Wnt signaling by thyroid hormones may contribute to thyroid hormone-associated bone disease and altered expression of Wnt inhibitors may emerge as potential therapeutic targets.

scholarly journals p21CIP-1/WAF-1 Induction Is Required to Inhibit Prostate Cancer Growth Elicited by Deficient Expression of the Wnt Inhibitor Dickkopf-1

2010 ◽  
Vol 70 (23) ◽  
pp. 9916-9926 ◽  
Author(s):  
Christopher L. Hall ◽  
Honglai Zhang ◽  
Shobun Baile ◽  
Mats Ljungman ◽  
Stuart Kuhstoss ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Growth ◽  
Wnt Inhibitor ◽  
Dickkopf 1

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 Vías de señalización anabólicas en el hueso y su potencial aplicación en la terapéutica

2017 ◽  
Vol 1 (1) ◽  
pp. 12-19
Author(s):  
Ariana Sierra ◽  
Adriana Medina ◽  
William Rojas ◽  
Henry Tovar ◽  
Carlos Révérend ◽  
...  
Keyword(s):  
Bone Mass ◽  
Bone Architecture ◽  
Bone Morphogenetic Protein 2 ◽  
Current Management ◽  
Morphogenetic Protein ◽  
Anabolic Therapy ◽  
Local Use ◽  
Humanized Monoclonal Antibodies ◽  
Dickkopf 1 ◽  
Stimulation Of

Para el manejo actual de la osteoporosis contamos con la terapia antirresortiva, que estabiliza la arquitectura ósea sin lograr su restauración y la anabólica (teriparatida: único aprobado por la FDA) que restaura y aumenta la masa ósea. La identificación de reguladores moleculares con efecto anabólico sobre el hueso ha permitido el desarrollo de nuevas terapias para el manejo de esta patología cada vez más prevalente.La vía de señalización Wnt/?-catenina aumenta la masa ósea a través de la diferenciación de células mesenquimales hacia osteoblastos y mediante el estímulo de la replicación de preosteoblastos e inhibición de la apoptosis de osteoblastos y osteocitos, siendo las proteínas esclerostina y DKK1 (Dickko- pf 1) sus principales antagonistas. Se encuentran actualmente en desarrollo anticuerpos monoclonales humanizados contra estas proteínas (Ac anti esclerostina y anti DDK1) que tienen a un efecto formador de hueso.Otra alternativa de uso local es la Proteína Morfogénica de Hueso 2, recombinante humana (rhBMP-2), con capacidad osteogénica, que ha demostrado aumentar la resistencia ósea en zonas de fracturas, acelerando la consolidación de las mismas.Estos nuevos reguladores del remodelado óseo representan una alternativa terapéutica de la osteoporosis y otros trastornos asociados al desequilibrio entre la resorción y la formación ósea.Summary The current management of osteoporosis includes antiresorptive therapy, which stabilizes bone architecture without achieving its restoration, and anabolic therapy (Teriparatide: the only agent approved thus far by the FDA), which restores and increases bone mass. The identification of molecular regulators with anabolic effect on bone has allowed for developing new therapies for the management of this increasingly prevalent condition. The Wnt/?-catenin signaling pathway increases bone mass via differentiation of mesenchymal cells into osteoblasts, stimulation of pre-osteoblasts replication and inhibition of the apoptosis of osteoblasts and osteocytes, with the proteins Sclerostin and DKK1 (Dickkopf 1) being its main antagonists. Humanized monoclonal antibodies against these proteins (anti-sclerostin and anti-DDK1 Ab), which have bone forming effects, are currently being developed. Another alternative is the local use of human recombinant bone morphogenetic protein 2, (rhBMP-2), a protein with osteogenic capacity, which has been shown to increase bone strength at fracture areas, accelerating their consolidation. These new bone remodeling regulators represent a therapeutic alternative for osteoporosis and other disorders associated with an imbalance between bone resorption and formation.

Microvascular regression is induced by wnt inhibitor dickkopf‐1 (DKK‐1) in a rat mesentery model

2008 ◽  
Vol 22 (S2) ◽  
pp. 70-70
Author(s):  
Jason T Glaw ◽  
Thomas C Skalak
Keyword(s):  
Rat Mesentery ◽  
Wnt Inhibitor ◽  
Dickkopf 1

Wnt Inhibitor Dickkopf-1 as a Target for Passive Cancer Immunotherapy

2010 ◽  
Vol 70 (13) ◽  
pp. 5326-5336 ◽  
Author(s):  
Nagato Sato ◽  
Takumi Yamabuki ◽  
Atsushi Takano ◽  
Junkichi Koinuma ◽  
Masato Aragaki ◽  
...  
Keyword(s):  
Cancer Immunotherapy ◽  
Wnt Inhibitor ◽  
Dickkopf 1

scholarly journals Serum levels of sclerostin, Dickkopf-1, and secreted frizzled-related protein-4 are not changed in individuals with high bone mass causing mutations in LRP5

2014 ◽  
Vol 25 (10) ◽  
pp. 2383-2388 ◽  
Author(s):  
C. A. Simpson ◽  
D. Foer ◽  
G. S. Lee ◽  
J. Bihuniak ◽  
B. Sun ◽  
...  
Keyword(s):  
Bone Mass ◽  
Serum Levels ◽  
Related Protein ◽  
High Bone Mass ◽  
High Bone ◽  
Dickkopf 1

scholarly journals Thiazolidinediones increase the wingless-type MMTV integration site family (WNT) inhibitor Dickkopf-1 in adipocytes: a link with osteogenesis

Diabetologia ◽  
2009 ◽  
Vol 53 (3) ◽  
pp. 536-540 ◽  
Author(s):  
B. Gustafson ◽  
B. Eliasson ◽  
U. Smith
Keyword(s):  
Integration Site ◽  
Wnt Inhibitor ◽  
Dickkopf 1
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