The cross-talk between osteoclasts and osteoblasts in response to strontium treatment: Involvement of osteoprotegerin (original) (raw)
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Osteoporosis International, 2009
The effect of strontium ranelate (SR) on human osteoblast differentiation was tested. SR induced osteoblastic proliferation, in vitro mineralization, and increased the expression of osteocyte markers. SR also elicited an osteoprotegerin (OPG) secretory response. We conclude that SR promotes the osteoblast maturation and osteocyte differentiation while promoting an additional antiresorptive effect. Introduction SR is a new treatment for osteoporosis that reduces the risk of hip and vertebral fractures in postmenopausal women. This study sought to investigate the extent, to which SR modulates human osteoblast differentiation. Methods Adult human primary osteoblasts (NHBC) were exposed to SR under mineralizing conditions in long-term cultures. Osteoblast differentiation status was investigated by cell-surface phenotypic analysis. Expression of genes associated with osteoblast/osteocyte differentiation was examined using real-time RT-PCR. Secreted OPG was assayed by enzyme-linked immunosorbent assay.
Molecular Pharmacology, 2010
Strontium ranelate exerts both an anticatabolic and an anabolic effect on bone cells. To further investigate the mechanism by which strontium ranelate inhibits bone resorption, the effects of varying concentrations of Sr o 2ϩ on osteoclastic differentiation were studied using RAW 264.7 cells and peripheral blood monocytic cells (PBMCs). We report that increasing concentrations of Sr o 2ϩ down-regulate osteoclastic differentiation and tartrate-resistant acid phosphatase activity, leading to inhibition of bone resorption (Ϫ48% when PBMCs were cultured for 14 days in the presence of 2 mM Sr o 2ϩ ). Using a dominantnegative form of the calcium-sensing receptor (CaR) and a small interfering RNA approach, we provide evidences that the inhibition of osteoclast differentiation by Sr o 2ϩ is mediated by stimulation of the CaR. Moreover, our results suggest that the effects of Sr o 2ϩ on osteoclasts are, at least in part, mediated by inhibition of the receptor activator of nuclear factor-B ligand (RANKL)-induced nuclear translocation of nuclear factor-B and activator protein-1 in the early stages of osteoclastic differentiation. In conclusion, our data indicate that Sr 2ϩ directly inhibits the formation of mature osteoclasts through downregulation of RANKL-induced osteoclast differentiation and decreases osteoclast differentiation through the activation of the CaR.
Journal of Orthopaedic Research, 2010
In vitro studies have demonstrated that strontium (Sr) could increase osteogenic differentiation of bone marrow stromal cells (BMSCs). We investigated the in vivo effect of Sr on BMSCs. Thirty-six female rats were randomly divided into the following groups: sham operated and treated with either vehicle (Sham þ Veh) or Sr compound (Sham þ Sr) and ovariectomized and treated with either vehicle (OVX þ Veh) or Sr compound (OVX þ Sr). Vehicle and Sr were orally administrated daily starting immediately after the surgery and continuing for 12 weeks. The anabolic effect of Sr on trabecular bone was determined at the structural and tissue level by microCT and histomorphometry, respectively. Colony formation assays demonstrated that BMSCs exhibited higher osteogenic colony but lower adipogenic colony in Sr-treated versus Veh-treated OVX rats. The mRNA level of osteogenic genes was higher, while the mRNA level of adipogenic genes was lower in BMSCs from Sr-treated versus Veh-treated Sham and OVX rats. The effect of Sr on rat BMSCs was reproducible in human BMSCs. Taken together, this study suggests that the anabolic effect of Sr on normal or osteoporotic bones is associated with increased osteoblastic differentiation of BMSCs. ß
BioMed research international, 2014
Age-related bone loss and osteoporosis are associated with bone remodeling changes that are featured with decreased trabecular and periosteal bone formation relative to bone resorption. Current anticatabolic therapies focusing on the inhibition of bone resorption may not be sufficient in the prevention or reversal of age-related bone deterioration and there is a big need in promoting osteoblastogenesis and bone formation. Enhanced understanding of the network formed by key signaling pathways and molecules regulating bone forming cells in health and diseases has therefore become highly significant. The successful development of agonist/antagonist of the PTH and Wnt signaling pathways are profits of the understanding of these key pathways. As the core component of an approved antiosteoporosis agent, strontium takes its effect on osteoblasts at multilevel through multiple pathways, representing a good example in revealing and exploring anabolic mechanisms. The recognition of strontium ...
Molecular Medicine Reports, 2012
The aim of the present study was to compare the osteoclast-inhibiting ability of recombinant osteoprotegerin (OPG) protein (rhOPG-Fc) and recombinant receptor activator of nuclear factor κB (rhRANK) in vitro and in vivo. Osteoclasts were cultured with either rhOPG-Fc or rhRANK for 9 days. The number of tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells and resorption pits in bone slices were then counted. In the in vivo investigation, female mice were bilaterally ovariectomized (OVX) and intraperitoneally injected with 3 mg/kg rhOPG-Fc or rhRANK for 12 weeks, respectively. Bone metabolism, bone mineral density and microstructure changes were then evaluated. The number of TRAP-positive cells and bone resorption pits decreased significantly following culture with either rhOPG-Fc or rhRANK, and this was more marked following culture with rhRANK compared with rhOPG-Fc. The levels of calcium and alkaline phosphatase in the serum were similar pre-OVX and after 12 weeks of treatment, while the levels of phosphorus in the serum were higher following treatment with rhRANK compared with rhOPG. The bone mineral density (BMD) of the whole body, femoral neck and L4 lumbar vertebral body in the mice treated with either rhOPG-Fc or rhRANK increased markedly. In addition, the mice treated with rhRANK exhibited significantly higher BMD in the femoral neck and lumbar vertebral body compared with those treated with rhOPG-Fc. Microcomputed tomography analysis demonstrated that the mice treated with rhRANK exhibited an increased bone volume and structure model index, and decreased trabecular spacing compared with those treated with rhOPG-Fc. rhRANK increased the inhibition of osteoclast differentiation and bone resorption, and rescued OVX-induced osteoporosis more effectively compared with rhOPG-Fc.
Strontium can increase some osteoblasts without increasing hematopoietic stem cells
Blood, 2007
hematopoietic stem cells Strontium can increase some osteoblasts without increasing http://bloodjournal.hematologylibrary.org/content/111/3/1173.full.html Updated information and services can be found at: (3131 articles) Hematopoiesis and Stem Cells Articles on similar topics can be found in the following Blood collections http://bloodjournal.hematologylibrary.org/site/misc/rights.xhtml#repub\_requests
Endocrinology, 2011
Clinical studies have revealed a blunting of the bone anabolic effects of parathyroid hormone treatment in osteoporotic patients in the setting of pre-or cotreatment with the antiresorptive agent alendronate (ALN). Sclerostin monoclonal antibody (Scl-Ab) is currently under clinical investigation as a new potential anabolic therapy for postmenopausal osteoporosis. The purpose of these experiments was to examine the influence of pretreatment or cotreatment with ALN on the bone anabolic actions of Scl-Ab in ovariectomized (OVX) rats. Ten-month-old osteopenic OVX rats were treated with ALN or vehicle for 6 wk, before the start of Scl-Ab treatment. ALN-pretreated OVX rats were switched to Scl-Ab alone or to a combination of ALN and Scl-Ab for another 6 wk. Vehicle-pretreated OVX rats were switched to Scl-Ab or continued on vehicle to serve as controls. Scl-Ab treatment increased areal bone mineral density, volumetric bone mineral density, trabecular and cortical bone mass, and bone strength similarly in OVX rats pretreated with ALN or vehicle. Serum osteocalcin and bone formation rate on trabecular, endocortical, and periosteal surfaces responded similarly to Scl-Ab in ALN or vehicle-pretreated OVX rats. Furthermore, cotreatment with ALN did not have significant effects on the increased bone formation, bone mass, and bone strength induced by Scl-Ab in the OVX rats that were pretreated with ALN. These results indicate that the increases in bone formation, bone mass, and bone strength with Scl-Ab treatment were not affected by pre-or cotreatment with ALN in OVX rats with established osteopenia.
Influence of osteoprotegerin (OPG) on experimentally induced ectopic bone
Folia Biologica-krakow, 2004
In this paper the effect of osteoprotegerin (OPG) on slowing down the resorption process of heterotopically induced bone tissue is described. The induced ossicle is resorbed ex inactivitate. This system is analogous to osteoporosis in immobilised skeletal bones. Bone induction was achieved in BALB/c mice after injection of a suspension of 3x10 6 HeLa cells into thigh muscle of animals immuno-suppressed by a single dose of hydrocortisone. To slow down the process of induced bone resorption, OPG was administered and the effect was measured quantitatively by weighing the mass of the induced ossicle after hydrolysis of soft tissues surrounding the induced ossicles. As an effect of the application of OPG, dry bone mass of the induced ossicles exceeded 340-540% of the values of the control specimens following 9 applications of 0.05 mg OPG per mouse every second day or 14 doses every day.
Journal of Bone and Mineral Research, 2003
Osteoprotegerin (OPG) is a naturally occurring negative regulator of osteoclast differentiation, activation, and survival. We created a recombinant form of human OPG (rhOPG), with a sustained serum half-life, to achieve prolonged antiresorptive activity. This study describes the rapid and sustained antiresorptive effects that are achieved with a single treatment with rhOPG. Male Sprague-Dawley rats (10 weeks old) were given a single bolus intravenous injection of vehicle (PBS) or rhOPG (5 mg/kg). PBS-and rhOPG-treated rats (n ؍ 6/group) were killed at 0, 0.5, 1, 2, 5, 10, 20, and 30 days post-treatment. rhOPG-treated rats were compared with their age-matched controls. The main pharmacologic effect of rhOPG was a rapid (24 h) reduction in osteoclast surface in the tibia, which reached a nadir on days 5 and 10 (95% reduction vs. vehicle controls). Osteoclast surface remained significantly reduced 30 days after the single treatment with rhOPG. Tibial cancellous bone volume was significantly increased within 5 days of rhOPG treatment (23%) and reached a peak increase of 58% on day 30. Femoral bone mineral density was significantly increased in rhOPG-treated rats on days 10 and 20. Pharmacokinetic analysis revealed that serum concentrations of rhOPG remained at measurable levels throughout the 30-day study. These data show that a single intravenous injection of rhOPG in young growing rats causes significant gains in bone volume and density, which are associated with rapid and sustained suppression of osteoclastic bone resorption. (J Bone Miner Res 2003;18:852-858)
RANKL/OPG; Critical role in bone physiology
Reviews in Endocrine and Metabolic Disorders, 2015
After it was proposed that the osteoblast lineage controlled the formation of osteoclasts, cell culture methods were developed that established this to be the case. Evidence was obtained that cytokines and hormones that promote osteoclast formation act first on osteoblast lineage cells to promote the production of a membrane-bound regulator of osteoclastogenesis. This proved to be receptor activator of NF-kB ligand (RANKL) a member of the tumor necrosis factor ligand family that acts upon its receptor RANK in the hematopoietic lineage, with interaction restricted by a decoy soluble receptor osteoprotegerin (OPG), also a product of the osteoblast lineage. The physiological roles of these factors were established through genetic and pharmacological studies, have led to a new physiology of bone, with complete revision of older ideas over the last 15 years, ultimately leading to the development of new pharmaceutical agents for bone disease.