scholarly journals Effects of Parathyroid Hormone, Alendronate and Odanacatib on the mineralisation process in intracortical and endocortical Haversian bone of ovariectomized rabbits

2018 ◽  
Author(s):  
Christina Vrahnas ◽  
Pascal R Buenzli ◽  
Thomas A Pearson ◽  
Brenda L Pennypacker ◽  
Mark J Tobin ◽  
...  
Keyword(s):  
Parathyroid Hormone ◽  
Bone Formation ◽  
Cortical Bone ◽  
Bone Strength ◽  
Bone Matrix ◽  
Cathepsin K ◽  
Bone Composition ◽  
Carbonate Substitution ◽  
Matrix Maturation

AbstractAlthough cortical bone strength depends on optimal bone composition, the influences of standard therapeutic agents for osteoporosis on bone mineral accrual in cortical bone are not understood. This study compared effects on cortical bone composition of two current therapeutic approaches for osteoporosis: the anti-resorptive bisphosphonate alendronate (ALN), and anabolic intermittent parathyroid hormone (PTH). The experimental anti-resorptive cathepsin K inhibitor, odanacatib (ODN) which inhibits resorption without inhibiting bone formation, was also tested.To determine effects of these agents on Haversian remodeling and mineral accrual, we compared ALN (100μg/kg/2xweek), PTH(1-34) (15μg/kg, 5x/week) and ODN (7.5μM/day) administered for 10 months commencing 6 months after ovariectomy (OVX) in skeletally mature rabbits by histomorphometry. We used synchrotron-based Fourier-transform infrared microspectroscopy (sFTIRM), coupled to fluorochrome labelling, to measure maturation of the cortical matrix in situ at both endocortical and intracortical sites of bone formation.PTH and ODN, but not ALN, treatment increased bone toughness, and PTH treatment stimulated bone formation, not only on endocortical and periosteal bone, but also in intracortical pores. In Sham and OVX rabbits, normal matrix maturation was observed at both endocortical and intracortical sites including: mineral accrual (increasing mineral:matrix), carbonate substitution (carbonate:mineral) and collagen molecular compaction (amide I:II) in situ in endocortical and intracortical bone. ALN treatment reduced bone formation on these surfaces. In ALN-treated bone, while intracortical bone matured normally, endocortical bone did not show a significant increase in mineral:matrix. ODN treatment resulted in slower mineral accrual and limited carbonate substitution. While PTH-treatment did not modify matrix maturation in endocortical bone, the initial stages of mineral accrual were slower in intracortical bone.In conclusion, these three classes of therapy have differing effects on both bone formation, and the process of bone matrix maturation. ALN suppresses bone formation, and the normal process of matrix maturation in endocortical bone. ODN does not suppress bone formation, but limits mineral accrual. PTH stimulates bone formation, and the matrix formed matures normally in endocortical bone. The ability of PTH treatment to stimulate bone formation in intracortical bone may provide a novel additional mechanism by which PTH increases bone strength.

scholarly journals Porcupine inhibitors impair trabecular and cortical bone mass and strength in mice

2018 ◽  
Vol 238 (1) ◽  
pp. 13-23 ◽  
Author(s):  
Thomas Funck-Brentano ◽  
Karin H Nilsson ◽  
Robert Brommage ◽  
Petra Henning ◽  
Ulf H Lerner ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Bone Loss ◽  
Bone Formation ◽  
Bone Mass ◽  
Trabecular Bone ◽  
Cortical Bone ◽  
Bone Strength ◽  
Bending Test ◽  
Bone Homeostasis ◽  
Mineral Density

WNT signaling is involved in the tumorigenesis of various cancers and regulates bone homeostasis. Palmitoleoylation of WNTs by Porcupine is required for WNT activity. Porcupine inhibitors are under development for cancer therapy. As the possible side effects of Porcupine inhibitors on bone health are unknown, we determined their effects on bone mass and strength. Twelve-week-old C57BL/6N female mice were treated by the Porcupine inhibitors LGK974 (low dose = 3 mg/kg/day; high dose = 6 mg/kg/day) or Wnt-C59 (10 mg/kg/day) or vehicle for 3 weeks. Bone parameters were assessed by serum biomarkers, dual-energy X-ray absorptiometry, µCT and histomorphometry. Bone strength was measured by the 3-point bending test. The Porcupine inhibitors were well tolerated demonstrated by normal body weight. Both doses of LGK974 and Wnt-C59 reduced total body bone mineral density compared with vehicle treatment (P < 0.001). Cortical thickness of the femur shaft (P < 0.001) and trabecular bone volume fraction in the vertebral body (P < 0.001) were reduced by treatment with LGK974 or Wnt-C59. Porcupine inhibition reduced bone strength in the tibia (P < 0.05). The cortical bone loss was the result of impaired periosteal bone formation and increased endocortical bone resorption and the trabecular bone loss was caused by reduced trabecular bone formation and increased bone resorption. Porcupine inhibitors exert deleterious effects on bone mass and strength caused by a combination of reduced bone formation and increased bone resorption. We suggest that cancer targeted therapies using Porcupine inhibitors may increase the risk of fractures.

scholarly journals Thrombospondins 1 and 2 affect lysyl oxidase protein and collagen matrix maturation in cortical bone of growing male and female mice via non-redundant pathways

2018 ◽  
Author(s):  
Dylan Shearer ◽  
Madison O Mervis ◽  
Eugene Manley ◽  
Anita B Reddy ◽  
Andrea I Alford
Keyword(s):  
Cortical Bone ◽  
Lysyl Oxidase ◽  
Bone Matrix ◽  
Collagen Matrix ◽  
Serum Starvation ◽  
Hydroxyproline Content ◽  
Male And Female ◽  
Total Signal ◽  
Female Mice ◽  
Matrix Maturation

AbstractThrombospondin-2-deficiency is associated with impaired matrix maturation in osteoblasts and cortical bone of growing mice. Here we addressed the possibility that lysyl oxidase (LOX) contributes to this phenotype. After overnight serum starvation, pro-LOX levels were elevated compared to wild-type in marrow-derived osteoblasts from male and female TSP2−/− mice. The liberated LOX pro-peptide (LOPP) was faintly visible in serum-starved cultures. When serum was maintained, pro-LOX content was not affected by TSP2 status, but relative LOPP levels were elevated in cultures from female TSP2−/− mice. Two isoforms of pro-LOX at 75 kDa and 50 kDa were detected in detergent soluble protein extracts of diaphyseal tissue from growing mice. In female mice, TSP2 status did not affect detergent soluble pro-LOX content or the relative contribution of each band to the total signal. Instead, levels of the 50 kDa band were reduced in female TSP1−/− samples. In male diaphyseal tissue, total pro-LOX content and the contribution each isoform made to the total signal was not affected by TSP1 or TSP2 status. We did not detect 32 kDa mature LOX in detergent soluble preparations of cells or whole bone tissue. Detergent insoluble hydroxyproline content was reduced in diaphyseal tissue obtained from female TSP1−/− and TSP2−/− mice. In male diaphyseal cortical samples, TSP2 but not TSP1 deficiency was associated with reduced insoluble hydroxyproline content. Our data suggest that the trimeric thrombospondins contribute to bone matrix quality via non-redundant mechanisms that are dependent on the unique tissue milieu of the male and female skeleton.

An In Silico Model for the Prediction of Changes in Mineral Density in Cortical Bone Remodeling

2019 ◽  
Vol 142 (1) ◽  
Author(s):  
Rafael R. Mattazio ◽  
Pedro Y. Noritomi ◽  
Zilda C. Silveira
Keyword(s):  
Parathyroid Hormone ◽  
Cortical Bone ◽  
Bone Remodeling ◽  
In Silico ◽  
Vigorous Physical Activity ◽  
Bone Matrix ◽  
Numerical Error ◽  
Mineral Density ◽  
In Silico Model ◽  
Proposed Model

Abstract An in silico model for the estimation of volumetric bone mineral density (vBMD) changes at a cortical bone site subjected to mechanobiological bone remodeling is proposed in this manuscript. Mechanisms of cell differentiation, receptor–ligand binding, mechanical signaling, and resorption or deposition of bone matrix were considered, therefore providing a comprehensive description of mechanobiological bone remodeling in the bone microenvironment and enabling the analysis of temporal evolution of disease or therapy scenarios. The proposed model is composed by five modules, namely, bone cells populations, mechanobiology, volume fractions and porosity, mineral density, and structural stiffness. The model is an extension of other models found in the literature because equations for the obtaining of cortical vBMD and the binding of parathyroid hormone (PTH) to parathyroid hormone 1 receptor are included. The proposed model showed a satisfactory agreement with the solutions of other in silico models found in the literature. Simulations of walking and running exercise routines were performed for the evaluation of model capability regarding the control of the numerical error and prediction of vBMD. The computational method used to solve the case study controlled the relative numerical error by less than 1 × 10−7 for approximately 1.7 × 106 time steps. The predicted values correlate with the concept of increasing BMD by vigorous physical activity; however, they contrast with the specific effect of physical activities on cortical vBMD.

Ectopic Osteoinduction by Variously Demineralized Allogenic Cortical Bone Matrix

2007 ◽  
Vol 342-343 ◽  
pp. 105-108
Author(s):  
J.T. Kim ◽  
H.J. Kang ◽  
H.N. Kim ◽  
J.Y. Choi ◽  
J.M. Lee ◽  
...  
Keyword(s):  
Bone Formation ◽  
Cortical Bone ◽  
Cellular Proliferation ◽  
Demineralized Bone Matrix ◽  
Bone Matrix ◽  
Ectopic Bone Formation ◽  
Bioactive Molecules ◽  
Muscular Tissue ◽  
Ectopic Bone ◽  
Demineralized Bone

To improve ostegenic healing efficiency by demineralized bone matrix, we evaluated the ectopic bone formation induced by variously demineralized allogenic cortical bone matrices at subcutaneous and muscular sites in rats. The rat tubular cortical bone matrices were demineralized in heated 0.6N HCl at 60 °C for 5 and 20 mins, respectively, using a controlledheat ultrasonic cleaner and implanted in rat dorsal subcutaneous pouches and thigh muscles for 1-3 weeks. The influence of the demineralized condition of bone matrix on cellular proliferation and osteogenic differentiation was also evaluated in vitro by MTT assay and ALP staining. The cortical matrices were completely demineralized within 20 mins by sonication and heating of diluted 0.6 N HCl. The sonicated bone matrices in heated acidic solution at 60 °C revealed no adverse immunogenic and inflammatory response in vivo regardless of demineralized condition. Cellular proliferation and osteoblastic differentiation was facilitated by more fully demineralized. Ectopic bone formation was induced only by demineralized bone matrices and were more favorable in fully demineralized matrices. The ectopic bone induction was more favorably in subcutaneous pouches than in muscular tissue. These findings suggest that a fully demineralized cortical bone matrix maximizes osteogenic repair by exposing more bioactive molecules which in turn induce chondro- and osteognic differentiation of mesenchymal cells around the implanted matrices, and that the sonication of diluted 0.6 N HCl heated at 60 ° C is a rapid and effective method for sterile demineralized graft preparation.

scholarly journals Efficacy of targeting bone-specific GIP receptor in ovariectomy-induced bone loss

2018 ◽  
Vol 239 (2) ◽  
pp. 215-227 ◽  
Author(s):  
Guillaume Mabilleau ◽  
Benoit Gobron ◽  
Aleksandra Mieczkowska ◽  
Rodolphe Perrot ◽  
Daniel Chappard
Keyword(s):  
Bone Loss ◽  
Bone Strength ◽  
Bone Remodelling ◽  
Bone Matrix ◽  
The Body ◽  
Whole Body ◽  
Matrix Composition ◽  
Carbonate Substitution ◽  
Alendronate Treatment ◽  
Gip Receptor

Glucose-dependent insulinotropic polypeptide (GIP) has been recognized in the last decade as an important contributor of bone remodelling and is necessary for optimal bone quality. However, GIP receptors are expressed in several tissues in the body and little is known about the direct vs indirect effects of GIP on bone remodelling and quality. The aims of the present study were to validate two new GIP analogues, called [d-Ala2]-GIP-Tag and [d-Ala2]-GIP1–30, which specifically target either bone or whole-body GIP receptors, respectively; and to ascertain the beneficial effects of GIP therapy on bone in a mouse model of ovariectomy-induced bone loss. Both GIP analogues exhibited similar binding capacities at the GIP receptor and intracellular responses as full-length GIP1–42. Furthermore, only [d-Ala2]-GIP-Tag, but not [d-Ala2]-GIP1–30, was undoubtedly found exclusively in the bone matrix and released at acidic pH. In ovariectomized animals, [d-Ala2]-GIP1–30 but not [d-Ala2]-GIP-Tag ameliorated bone stiffness at the same magnitude than alendronate treatment. Only [d-Ala2]-GIP1–30 treatment led to significant ameliorations in cortical microarchitecture. Although alendronate treatment increased the hardness of the bone matrix and the type B carbonate substitution in the hydroxyapatite crystals, none of the GIP analogues modified bone matrix composition. Interestingly, in ovariectomy-induced bone loss, [d-Ala2]-GIP-Tag failed to alter bone strength, microarchitecture and bone matrix composition. Overall, this study shows that the use of a GIP analogue that target whole-body GIP receptors might be useful to improve bone strength in ovariectomized animals.

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