scholarly journals Sclerostin Is an Osteocyte-expressed Negative Regulator of Bone Formation, But Not a Classical BMP Antagonist

2004 ◽  
Vol 199 (6) ◽  
pp. 805-814 ◽  
Author(s):  
Rutger L. van Bezooijen ◽  
Bernard A.J. Roelen ◽  
Annemieke Visser ◽  
Lianne van der Wee-Pals ◽  
Edwin de Wilt ◽  
...  
Keyword(s):  
Bone Formation ◽  
Transcriptional Activation ◽  
Negative Regulator ◽  
C2c12 Cells ◽  
High Bone Mass ◽  
Alp Activity ◽  
Osteoblast Activity ◽  
Sost Gene ◽  
High Bone ◽  
Bmp Antagonist

Sclerosteosis, a skeletal disorder characterized by high bone mass due to increased osteoblast activity, is caused by loss of the SOST gene product, sclerostin. The localization in bone and the mechanism of action of sclerostin are not yet known, but it has been hypothesized that it may act as a bone morphogenetic protein (BMP) antagonist. We show here that SOST/sclerostin is expressed exclusively by osteocytes in mouse and human bone and inhibits the differentiation and mineralization of murine preosteoblastic cells (KS483). Although sclerostin shares some of the actions of the BMP antagonist noggin, we show here that it also has actions distinctly different from it. In contrast to noggin, sclerostin did not inhibit basal alkaline phosphatase (ALP) activity in KS483 cells, nor did it antagonize BMP-stimulated ALP activity in mouse C2C12 cells. In addition, sclerostin had no effect on BMP-stimulated Smad phosphorylation and direct transcriptional activation of MSX-2 and BMP response element reporter constructs in KS483 cells. Its unique localization and action on osteoblasts suggest that sclerostin may be the previously proposed osteocyte-derived factor that is transported to osteoblasts at the bone surface and inhibits bone formation.

High bone mass gained by exercise in growing male mice is increased by subsequent reduced exercise

2004 ◽  
Vol 97 (3) ◽  
pp. 806-810 ◽  
Author(s):  
Jian Wu ◽  
Xin Xiang Wang ◽  
Mitsuru Higuchi ◽  
Kazuhiko Yamada ◽  
Yoshiko Ishimi
Keyword(s):  
Bone Mineral Density ◽  
Bone Formation ◽  
Bone Mass ◽  
Exercise Group ◽  
Mineral Apposition Rate ◽  
Male Mice ◽  
Sedentary Control ◽  
Mineral Density ◽  
High Bone Mass ◽  
High Bone

Exercise-induced bone gains are lost if exercise ceases. Therefore, continued exercise at a reduced frequency or intensity may be required to maintain these benefits. In this study, we evaluated whether 4 wk of reduced exercise after 4 wk of running exercise in growing male mice results in the maintenance of high bone mass. Five-week-old mice were divided into the following groups: 1) baseline control; 2) 4-wk control; 3) 4-wk exercise; 4) 8-wk control; 5) 4-wk exercise followed by 4-wk cessation of training; and 6) 4-wk exercise followed by reduced exercise at half the frequency. The regimen consisted of exercise 6 days/wk, and the reduced exercise regimen consisted of running 3 days/wk on a treadmill for 30 min/day, at 12 m/min on a 10° uphill slope. Running exercise significantly increased bone mineral density of the femur, periosteal mineral apposition rate, bone formation rate, percent labeled perimeter at the midfemur, and osteogenic activity of bone marrow cells. However, these parameters declined to the age-matched sedentary control after cessation of training. In contrast, the reduced exercise group had significantly higher mineral apposition rate compared with those of the sedentary control and cessation of training groups. Furthermore, bone mineral density for the reduced exercise group was significantly higher than those for the other groups. These results suggest that the high bone formation gained through exercise can be maintained, and bone mass was further increased by subsequent exercise even if the exercise frequency is reduced.

High bone mass in the STR/ort mouse results from increased bone formation and impaired bone resorption and is associated with extramedullary hematopoiesis

2012 ◽  
Vol 31 (1) ◽  
pp. 71-81 ◽  
Author(s):  
Juliane Pasold ◽  
Robby Engelmann ◽  
Johannes Keller ◽  
Sarah Joost ◽  
Robert P. Marshall ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Bone Formation ◽  
Bone Mass ◽  
Extramedullary Hematopoiesis ◽  
High Bone Mass ◽  
High Bone

Myeloma Cells Induce Osteoblast Suppression through Sclerostin Secretion

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2961-2961 ◽  
Author(s):  
Silvia Colucci ◽  
Giacomina Brunetti ◽  
Angela Oranger ◽  
Giorgio Mori ◽  
Francesca Sardone ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Formation ◽  
Bone Disease ◽  
Culture System ◽  
Conflicts Of Interest ◽  
Negative Regulator ◽  
Type I ◽  
Myeloma Cells ◽  
Myeloma Bone Disease ◽  
Osteoblast Activity

Abstract Abstract 2961 Reduced osteoblast activity contributes to the development of multiple myeloma-bone disease. Wingless-type (Wnt) signalling pathway is critical in osteoblastogenesis, and it is negatively regulated by molecules such as frizzled-related proteins (sFRPs), Dickkopf proteins (DKKs) and sclerostin. Myeloma cells are known to induce inhibition of osteoblastogenesis through Wnt antagonists such as DKK-1 and sFRP-2 and -3 whereas the role of sclerostin, an osteocyte-expressed negative regulator of bone formation, has not been yet investigated. We provide novel evidence showing sclerostin expression by myeloma cells from patients with multiple myeloma-bone disease and human myeloma cell lines (HMCLs). By means of a co-culture system of bone marrow stromal cells (BMSCs) and HMCLs, we demonstrated that sclerostin expression by myeloma cells and HMCLs is responsible for reduced expression of major osteoblastic specific proteins namely bone-specific alkaline phosphatase, collagen-type I, bone sialoprotein II and osteocalcin as well as decreased mineralized nodule formation and attenuated expression of member of the AP-1 transcription factor family (i.e. Fra-1, Fra-2 and Jun-D). The addition of a neutralizing anti-sclerostin antibody to our co-culture system can restore the above parameters, through the intranuclear accumulation of β-catenin in BMSCs. On the other hand, we demonstrated that sclerostin is also involved in inducing increased receptor activator of nuclear factor-k B ligand (RANKL) and decreased osteoprotegerin (OPG) expression in osteoblasts, contributing to the enhanced osteoclast activity occurring in patients with multiple myeloma-bone disease. Our data suggest that myeloma cells contribute to the suppression of bone formation through sclerostin secretion. Disclosures: No relevant conflicts of interest to declare.

Homozygous Dkk1 Knockout Mice Exhibit High Bone Mass Phenotype Due to Increased Bone Formation

2017 ◽  
Vol 102 (1) ◽  
pp. 105-116 ◽  
Author(s):  
Michelle M. McDonald ◽  
Alyson Morse ◽  
Aaron Schindeler ◽  
Kathy Mikulec ◽  
Lauren Peacock ◽  
...  
Keyword(s):  
Bone Formation ◽  
Bone Mass ◽  
Knockout Mice ◽  
High Bone Mass ◽  
High Bone ◽  
High Bone Mass Phenotype

scholarly journals Functions of vasopressin and oxytocin in bone mass regulation

2015 ◽  
Vol 113 (1) ◽  
pp. 164-169 ◽  
Author(s):  
Li Sun ◽  
Roberto Tamma ◽  
Tony Yuen ◽  
Graziana Colaianni ◽  
Yaoting Ji ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bone Formation ◽  
Bone Mass ◽  
High Bone Mass ◽  
Nuclear Extracts ◽  
High Bone ◽  
High Bone Mass Phenotype ◽  
Opposing Effects ◽  
G Protein Coupled

Prior studies show that oxytocin (Oxt) and vasopressin (Avp) have opposing actions on the skeleton exerted through high-affinity G protein-coupled receptors. We explored whether Avp and Oxtr can share their receptors in the regulation of bone formation by osteoblasts. We show that the Avp receptor 1α (Avpr1α) and the Oxt receptor (Oxtr) have opposing effects on bone mass: Oxtr−/− mice have osteopenia, and Avpr1α−/− mice display a high bone mass phenotype. More notably, this high bone mass phenotype is reversed by the deletion of Oxtr in Oxtr−/−:Avpr1α−/− double-mutant mice. However, although Oxtr is not indispensable for Avp action in inhibiting osteoblastogenesis and gene expression, Avp-stimulated gene expression is inhibited when the Oxtr is deleted in Avpr1α−/− cells. In contrast, Oxt does not interact with Avprs in vivo in a model of lactation-induced bone loss in which Oxt levels are high. Immunofluorescence microscopy of isolated nucleoplasts and Western blotting and MALDI-TOF of nuclear extracts show that Avp triggers Avpr1α localization to the nucleus. Finally, a specific Avpr2 inhibitor, tolvaptan, does not affect bone formation or bone mass, suggesting that Avpr2, which primarily functions in the kidney, does not have a significant role in bone remodeling.

scholarly journals Identification of Sclerostin as a Putative New Myokine Involved in the Muscle-to-Bone Crosstalk

Biomedicines ◽  
2021 ◽  
Vol 9 (1) ◽  
pp. 71
Author(s):  
Maria Sara Magarò ◽  
Jessika Bertacchini ◽  
Francesca Florio ◽  
Manuela Zavatti ◽  
Francesco Potì ◽  
...  
Keyword(s):  
Bone Growth ◽  
Muscle Cells ◽  
Negative Regulator ◽  
C2c12 Cells ◽  
Inhibitory Role ◽  
Sost Gene ◽  
Endocrine Organs ◽  
Bone Cell Differentiation

Bone and muscle have been recognized as endocrine organs since they produce and secrete “hormone-like factors” that can mutually influence each other and other tissues, giving rise to a “bone–muscle crosstalk”. In our study, we made use of myogenic (C2C12 cells) and osteogenic (2T3 cells) cell lines to investigate the effects of muscle cell-produced factors on the maturation process of osteoblasts. We found that the myogenic medium has inhibitory effects on bone cell differentiation and we identified sclerostin as one of the myokines produced by muscle cells. Sclerostin is a secreted glycoprotein reportedly expressed by bone/cartilage cells and is considered a negative regulator of bone growth due to its role as an antagonist of the Wnt/β-catenin pathway. Given the inhibitory role of sclerostin in bone, we analyzed its expression by muscle cells and how it affects bone formation and homeostasis. Firstly, we characterized and quantified sclerostin synthesis by a myoblast cell line (C2C12) and by murine primary muscle cells by Western blotting, real-time PCR, immunofluorescence, and ELISA assay. Next, we investigated in vivo production of sclerostin in distinct muscle groups with different metabolic and mechanical loading characteristics. This analysis was done in mice of different ages (6 weeks, 5 and 18 months after birth) and revealed that sclerostin expression is dynamically modulated in a muscle-specific way during the lifespan. Finally, we transiently expressed sclerostin in the hind limb muscles of young mice (2 weeks of age) via in vivo electro-transfer of a plasmid containing the SOST gene in order to investigate the effects of muscle-specific overproduction of the protein. Our data disclosed an inhibitory role of the muscular sclerostin on the bones adjacent to the electroporated muscles. This observation suggests that sclerostin released by skeletal muscle might synergistically interact with osseous sclerostin and potentiate negative regulation of osteogenesis possibly by acting in a paracrine/local fashion. Our data point out a role for muscle as a new source of sclerostin.

scholarly journals Loss of BMPR2 leads to high bone mass due to increased osteoblast activity

2015 ◽  
Vol 128 (7) ◽  
pp. 1308-1315 ◽  
Author(s):  
J. W. Lowery ◽  
G. Intini ◽  
L. Gamer ◽  
S. Lotinun ◽  
V. S. Salazar ◽  
...  
Keyword(s):  
Bone Mass ◽  
High Bone Mass ◽  
Osteoblast Activity ◽  
High Bone

scholarly journals Amylin inhibits bone resorption while the calcitonin receptor controls bone formation in vivo

2004 ◽  
Vol 164 (4) ◽  
pp. 509-514 ◽  
Author(s):  
Romain Dacquin ◽  
Rachel A. Davey ◽  
Catherine Laplace ◽  
Régis Levasseur ◽  
Howard A. Morris ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Bone Formation ◽  
Bone Mass ◽  
Dependent Manner ◽  
Calcitonin Receptor ◽  
Low Bone Mass ◽  
High Bone Mass ◽  
High Bone

Amylin is a member of the calcitonin family of hormones cosecreted with insulin by pancreatic β cells. Cell culture assays suggest that amylin could affect bone formation and bone resorption, this latter function after its binding to the calcitonin receptor (CALCR). Here we show that Amylin inactivation leads to a low bone mass due to an increase in bone resorption, whereas bone formation is unaffected. In vitro, amylin inhibits fusion of mononucleated osteoclast precursors into multinucleated osteoclasts in an ERK1/2-dependent manner. Although Amylin +/− mice like Amylin-deficient mice display a low bone mass phenotype and increased bone resorption, Calcr +/− mice display a high bone mass due to an increase in bone formation. Moreover, compound heterozygote mice for Calcr and Amylin inactivation displayed bone abnormalities observed in both Calcr +/− and Amylin +/− mice, thereby ruling out that amylin uses CALCR to inhibit osteoclastogenesis in vivo. Thus, amylin is a physiological regulator of bone resorption that acts through an unidentified receptor.

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