W.A. Grasser's research while affiliated with The University of Western Ontario and other places
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Publications (42)
Prostaglandin E(2) (PGE(2)) exerts diverse biological effects through four G-protein-coupled cell surface receptor subtypes, EP1-4. This study's objective was to characterize EP1-4 receptor mRNA expression within pregnant guinea pig myometrium during early implantation stage (gestation day [GD] 6) and late stage gestation (GD 50) and evaluate in vi...
We have recently shown that human recombinant BMP-6 (rhBMP-6), given systematically, can restore bone in animal models of osteoporosis. To further elucidate the underlying mechanisms of new bone formation following systemic application of BMPs, we conducted gene expression profiling experiments using bone samples of oophrectomised mice treated with...
Bone is accrued and maintained primarily through the coupled actions of bone-forming osteoblasts and bone-resorbing osteoclasts. Cumulative in vitro studies indicated that proline-rich tyrosine kinase 2 (PYK2) is a positive mediator of osteoclast function and activity. However, our investigation of PYK2−/− mice did not reveal evidence supporting an...
We tested the efficacy of three selective agonists of prostaglandin E(2) (PGE(2)) receptor, EP2 (CP-536,745-01), EP2/4 (CP-043,305-02), and EP4 (CP-044,519-02), in two models of acute and chronic kidney failure. In the nephrotoxic mercury chloride (HgCl(2)) rat model of acute kidney failure systemically administered EP4 agonist reduced the serum cr...
CP432 is a newly discovered, nonprostanoid EP4 receptor selective prostaglandin E2 agonist. CP432 stimulates trabecular and cortical bone formation and restores bone mass and bone strength in aged ovariectomized rats with established osteopenia.
The purpose of this study was to determine whether a newly discovered, nonprostanoid EP4 receptor select...
Heptanoic acid lactams, exemplified by 2, were identified as highly selective EP4 agonists via high throughput screening. Lead optimization led to the identification of lactams with a 30-fold increase in EP4 potency in vitro. Compounds demonstrated robust bone anabolic effects when administered in vivo in rat models of osteoporosis.
Prostaglandin E2 (PGE2) exerts its biological effects through 4 different receptor subtypes, EP-1, EP-2, EP-3, and EP-4. Recently we have demonstrated the importance of the prostaglandin E2 receptor subtype EP-2 in the healing of bone defects and fractures. This discovery led to the identification of CP-533,536, an EP-2 selective agonist, a promisi...
The skeleton has the unique ability to repair and heal itself following injury [1, 2]. This process is a cascade of synchronized events involving many systemic and local signaling molecules [3]. However, in approximately 10% of cases, fractured bones heal more slowly (malunion) or fail to heal (nonunion) requiring additional costly medical interven...
The P2X7 nucleotide receptor is an ATP-gated ion channel expressed widely in cells of hematopoietic origin. Our purpose was to explore the involvement of the P2X7 receptor in bone development and remodeling by characterizing the phenotype of mice genetically modified to disrupt the P2X7 receptor [knockout (KO)]. Femoral length did not differ betwee...
The morbidity and mortality associated with impaired/delayed fracture healing remain high. Our objective was to identify a small nonpeptidyl molecule with the ability to promote fracture healing and prevent malunions. Prostaglandin E2 (PGE2) causes significant increases in bone mass and bone strength when administered systemically or locally to the...
Myostatin is hypothesized to regulate skeletal muscle mass and to be a potential target for therapeutic intervention in sarcopenia. To clarify whether myostatin is invariably associated with sarcopenia, this study examined the levels of expression of myostatin mRNA and protein in Sprague Dawley rats during aging- and denervation-induced sarcopenia....
HMG-CoA reductase inhibitor (statin) treatment is frontline therapy for lowering plasma cholesterol levels in patients with hyperlipidemia. In a few case studies, analysis of clinical data has revealed a decreased risk of fracture in patients on statin therapy. However, this reduction in the incidence of fracture is not always observed nor is it su...
The intracellular signaling events of the bone morphogenetic proteins (BMPs) involve the R-Smad family members Smad1, Smad5, Smad8 and the Co-Smad, Smad4. Smads are currently considered to be DNA-binding transcriptional modulators and shown to recruit the master transcriptional co-activator CBP/p300 for transcriptional activation. SNIP1 is a recent...
Background The intracellular signaling events of the Bone Morphogenetic Proteins (BMPs) involve the R-Smad family members Smad1, Smad5, Smad8 and the Co-Smad, Smad4. Smads are currently considered to be DNA-binding transcriptional modulators and shown to recruit the master transcriptional co-activator CBP/p300 for transcriptional activation. SNIP1...
Bone morphogenetic proteins (BMPs) are members of the transforming growth factor-beta (TGF-beta) gene superfamily of growth and differentiation factors. Members of the BMP family were originally cloned and characterized by their ability to induce ectopic bone formation. Of the various BMPs cloned, the bone inductive ability of BMP-7 (OP-1) and BMP-...
The transforming growth factor-β (TGF-β) superfamily is a large group of structurally related proteins that play various important roles during embryonic development, as well as in adult life. This superfamily in addition to TGF-βs also contains the inhibins, activins, Mullerian inhibiting substance, and bone morphogenetic proteins (BMPs), as well...
Members of the transforming growth factor-beta (TGF-beta) superfamily of growth and differentiation factors have been identified in a wide variety of organisms, ranging from invertebrates to mammals. Bone morphogenetic proteins (BMPs) constitute a subgroup of proteins belonging to the TGF-beta superfamily. BMPs were initially identified by their ab...
We have discovered a new, nonsteroidal, potent estrogen agonist/antagonist, CP-336,156. CP-336,156 binds selectively and with high affinity to the human estrogen receptor-alpha with a half-inhibition concentration of 1.5 nM, which is similar to that seen with estradiol (4.8 nM). When given orally to immature (3-week-old) female Sprague-Dawley rats...
The incidence of postmenopausal osteoporosis is increasing as the population ages. Even though estrogen replacement therapy has proven beneficial in reducing the number of skeletal fractures, the known risks and associated side-effects of estrogen replacement therapy make compliance poor. Recent research has focused on the development of tissue spe...
Osteocalcin (Oc), an abundant gamma-carboxylated protein (mol wt, 5800) of bone matrix, is used as a serum marker of bone turnover because it is considered to be uniquely synthesized by the osteoblast. Our finding of Oc messenger RNA (mRNA) in rat tibial diaphyseal marrow led us to investigate the cellular origins of Oc mRNA in peripheral blood and...
Osteocalcin (Oc), an abundant γ-carboxylated protein (mol wt, 5800) of bone matrix, is used as a serum marker of bone turnover because it is considered to be uniquely synthesized by the osteoblast. Our finding of Oc messenger RNA (mRNA) in rat tibial diaphyseal marrow led us to investigate the cellular origins of Oc mRNA in peripheral blood and bon...
Parathyroid hormone-related protein (PTHrP) is produced by various normal and neoplastic tissues. Even if the physiological function(s) of PTHrP is unclear, evidence suggests that the protein may participate in the local regulation of smooth muscle contractility. We show here that PTHrP is produced in endothelial cells cultured from human umbilical...
Matrix protein effects on the differentiated activity of osteoclasts were examined in order to understand the functional significance of bone protein interactions with osteoclasts. Bone acidic glycoprotein 75 (BAG 75) from rat calvariae inhibited the resorption of bone by isolated rat osteoclasts with IC50 = 1 nM compared to IC50 = 10 nM for chicke...
Parathyroid hormone-related protein (PTHrP) gene expression in the pregnant rat uterus has been shown to be dependent on occupancy of the uterus by the fetus. To further test the hypothesis that the synthesis of PTHrP in smooth muscle tissue is regulated by mechanical stretch, we conducted experiments using the rat urinary bladder as a model of an...
Studies of the mode of action of the bisphosphonate alendronate showed that 1 d after the injection of 0.4 mg/kg [3H]alendronate to newborn rats, 72% of the osteoclastic surface, 2% of the bone forming, and 13% of all other surfaces were densely labeled. Silver grains were seen above the osteoclasts and no other cells. 6 d later the label was 600-1...
The phylogenetic conservation of the primary structure of PTH-related protein (PTHrP) supports an important, yet undetermined, role(s) for this molecule in the biology of birds and mammals. As an initial step toward understanding the function of PTHrP in birds, we investigated the expression of PTHrP mRNA in tissues of the egg-laying hen. This anal...
The venom protein, s-echistatin, originally derived from the saw-scaled viper Echis carinatus, was found to be a potent inhibitor of bone resorption by isolated osteoclasts. This Arg24-Gly25-Asp26-(RGD)-containing protein inhibited the excavation of bone slices by rat osteoclasts (IC50 = 0.1 nM). It also inhibited the release of [3H]proline from la...
We present microinjection data in support of an indirect approach by which cytoplasmic protein interactions important in the processes of bone resorption can be elucidated. Three polyclonal antibodies (M1, M3, M5) raised against myosin II from perfused rat liver differently affected the actin-activated Mg ATPase of myosin II. These antibodies micro...
The bisphosphonates 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid (ABP), 3-amino-1,1-hydroxypropane-1,1-diphosphonic acid (APD), and 1-hydroxyethane-1,1-diphosphonic acid (EHDP) were compared for their ability to inhibit the osteoclastic resorption of bone in culture. This was achieved by measuring the effect of bisphosphonate concentration on...
Citations
... RANKL produced by pDC can directly affect MDSCs by inducing their differentiation into osteoclasts, which promotes bone destruction and growth of breast cancer cells (138) (Figure 1). Furthermore, infiltration of pDC in cancer is associated with elevated levels of chemokines and cytokines that are directly or indirectly related to immunosuppression and osteoclastogenesis (138). These soluble factors also induce RANKL expression, which further stimulates osteoclastogenesis. ...
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... To ensure the neoformation of tissues and organs and the cells in a scaffold, the surface must be compatible anatomically, physiologically, and histologically. New bone formation can be reinforced by using bioactive signals such as genes, tethered agents, soluble factors, total growth factor (TGF-β), and its subgroups such as bone morphogenetic protein (BMP) [8,9]. Protein adhesion initiates the initial phases of corrosion in human implants. ...
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... This process showed the importance of proteasome-mediated β-catenin degradation in osteoblast and osteoclast development. Moreover, there is evidence that proteasome may be an effective molecule to involving in Notch signaling 65 , TGF-beta and BMP signaling 66 . While Mass spectrometry technique and database is still going on to develop the efficient method to get the global protein analysis for animal, the detection of other component proteins such as proteasome could use to predict the relevant signaling. ...
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... A variety of other agents including prostaglandin E 1 and F 2␣ , and (24)(25) vitamin D3 had no effect on either cell line. Upregulation of BMP-7 by prostaglan- din E 2 in cortical and cancellous bone (40) and by retinoic acid (39) has been reported. BMP-7, which has been suggested to have an autoregulatory activity in the embryonic nephrogenic mesenchyme (33), did not significantly induce luciferase expression from p3.3. ...
... which are also present in platelets (Everts et al., 2006 andNikolidakis et al., 2006). The platelets act as an exogenous agent to provide growth factors stimulating the activity of the osteoblasts (Thiede et al., 1993). ...
... As discussed in Chapter 26, PTHrP has been shown to modulate smooth muscle cell tone in a variety of organs, including the vascular tree, where it acts as a vasodilator. Consistent with these effects, two studies have shown that PTHrP increases mammary blood flow during lactation (Davicco et al., 1993;Thiede et al., 1992). The injection of amino-terminal fragments of PTHrP into the mammary artery of dried (nonlactating) ewes was shown to increase mammary blood flow and override the vasoconstrictive effects of endothelin (Davicco et al., 1993). ...
... The above experiments have thus established the vital role of PTHrP in regulating bone calcium turnover through modulating bone metabolism during lactation. Moreover, apart from its effects on bone calcium studies in the early nineties have also acknowledged that PTHrP increases mammary blood flow during lactation (Davicco et al., 1993;Thiede et al., 1992) [81,82] . As reported by Davicco et al.(1993) [81] , an IV injection of amino-terminal fragments of PTHrP into the mammary artery of non-lactating ewes led to enhancement in arterial circulation to mammary glands and overrides the vasoconstrictive effects of vascular endothelin. ...
... Nowadays, various methods are used to protect bone health, including drugs, surgeries, and physical therapies [9]. Bisphosphonates [10], Denosumab, Calcitonin [11], and Estrogen antagonists [12] are some of the most common medications used to prevent bone loss. Nutrient factors like vitamin D, vitamin K, and calcium [13], whether obtained through diet or supplements, can also be useful for bone amplification. ...
... Thus, treatment effects of the SERM Las on thymus is dependent on functional mERα signaling. E2 treatment suppresses fat development and results in decreased fat content in both humans and rodent models (Gambacciani et al. 1997, Cooke & Naaz 2004, Stubbins et al. 2012, and the SERMs Las and Bza have been shown to have estrogen agonistic effects on adipose tissue leading to a decrease in body fat (Ke et al. 1998. However, in this study, we only saw a significant reduction in total body fat percentage in control mice after E2 treatment. ...
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... Parathyroid hormone-related protein (PTHrP) is an endogenous DSM relaxant that is released from DSM cells themselves upon bladder distension [18,30]. Since PTHrP receptors are predominantly expressed in DSM [18,26], PTHrP would act in an autocrine or paracrine fashion to cause DSM relaxation. ...
