Biomedical subjects

Naoyuki Takahashi

Publications and source records attributed to Naoyuki Takahashi.

At least 19 recordsLinked to original sources

PubMed2007

Osteoprotegerin reduces the serum level of receptor activator of NF-kappaB ligand derived from osteoblasts.

Osteoprotegerin (OPG) is a decoy receptor for receptor activator of NF-kappaB ligand (RANKL). We previously reported that OPG deficiency elevated the circulating level of RANKL in mice. Using OPG(-/-) mice, we investigated whether OPG is involved in the shedding of RANKL by cells expressing RANKL. Osteoblasts and activated T cells in culture released a large amount of RANKL in the absence of OPG. OPG or a soluble form of receptor activator of NF-kappaB (the receptor of RANKL) suppressed the release of RANKL from those cells. OPG- and T cell-double-deficient mice showed an elevated serum RANKL level equivalent to that of OPG(-/-) mice, indicating that circulating RANKL is mainly derived from bone. The serum level of RANKL in OPG(-/-) mice was increased by ovariectomy or administration of 1alpha,25-dihydroxyvitamin D(3). Expression of RANKL mRNA in bone, but not thymus or spleen, was increased in wild-type and OPG(-/-) mice by 1alpha,25-dihydroxyvitamin D(3). These results suggest that OPG suppresses the shedding of RANKL from osteoblasts and that the serum RANKL in OPG(-/-) mice exactly reflects the state of bone resorption.

ADAM Proteins↗

PubMed2006

New 19-nor-(20S)-1alpha,25-dihydroxyvitamin D3 analogs strongly stimulate osteoclast formation both in vivo and in vitro.

2-Methylene-19-nor-(20S)-1alpha,25-dihydroxyvitamin D3 (2MD), an analog of 1alpha,25-dihydroxyvitamin D3 [1alpha,25(OH)2D3], has been shown to strongly induce bone formation both in vitro and in vivo. We have synthesized four substituents at carbon 2 of 2MD (2MD analogs), four stereoisomers at carbon 20 of the respective 2MD analogs (2MD analog-C20 isomers) and four 2MD analogs with an oxygen atom at carbon 22 (2MD-22-oxa analogs) and examined their ability to stimulate osteoclastogenesis and induce hypercalcemia. 2MD analogs were 100 times as potent as 1alpha,25(OH)2D3 in stimulating the formation of osteoclasts in vitro and in inducing the expression of receptor activator of NF-kappaB ligand (RANKL) and 25-hydroxyvitamin D3-24 hydroxylase mRNAs in osteoblasts. The osteoclast-inducing activities of 2MD analog-C20 isomers and 2MD 22-oxa analogs were much weaker than those of 2MD analogs. In addition, the activity of a 2MD analog in inducing dentine resorption was much stronger than that of 1alpha,25(OH)2D3 in the pit formation assay. Affinities to the vitamin D receptor and transcriptional activities of these compounds did not always correlate with their osteoclastogenic activities. Osteoprotegerin-deficient (OPG-/-) mice provide a suitable model for investigating in vivo effects of 2MD analogs because they exhibit extremely high concentrations of serum RANKL. The same amounts of 2MD analogs and 1alpha,25(OH)2D3 were administered daily to OPG-/- mice for 2 days. The elevation in serum concentrations of RANKL and calcium was much greater in 2MD analog-treated OPG-/- mice than in 1alpha,25(OH)2D3-treated ones. A 2MD analog was much more potent than 1alpha,25(OH)2D3 in causing hypercalcemia and in increasing soluble RANKL with enhanced osteoclastogenesis even in wild-type mice. In contrast, the administration of the 2MD analog to c-fos-deficient mice failed to induce osteoclastogenesis and hypercalcemia. These results suggest that new substituents at carbon 2 of 2MD strongly stimulate osteoclast formation in vitro and in vivo, and that osteoclastic bone resorption is indispensable for their hypercalcemic action of 2MD analogs in vivo.

Animals↗

PubMed2006

A critical role for interleukin-6 family-mediated Stat3 activation in osteoblast differentiation and bone formation.

Signal transduction and activator of transcription (Stat) 3 is a transcription factor that is activated by a variety of cytokines and growth factors, including IL-6 family cytokines. These cytokines regulate bone homeostasis and have been reported to regulate the differentiation of osteoblasts and osteoclasts through Stat3 activation in vitro, but the in vivo physiological role of Stat3 in bone homeostasis is unknown. Here, we report that gp130 knock-in mice gp130(F759/F759), in which IL-6 family cytokine-mediated Stat3 activation is enhanced, showed an osteosclerotic phenotype. To further clarify the role of Stat3 in bone formation, we generated mice with osteoblast-specific disruption of the Stat3 gene via the Cre-LoxP recombination system using alpha1(I)-collagen promoter Cre transgenic mice. The alpha1(I)Cre;Stat3(flox/-) mice showed an osteoporotic phenotype because of a reduced bone formation rate. Thus, the Stat3 signal in osteoblasts plays a pivotal role in bone formation in vivo.

Alkaline Phosphatase↗

PubMed2006

Establishment of primary cultures for mouse ameloblasts as a model of their lifetime.

To understand how the properties of ameloblasts are spatiotemporally regulated during amelogenesis, two primary cultures of ameloblasts in different stages of differentiation were established from mouse enamel epithelium. Mouse primary ameloblasts (MPAs) prepared from immature enamel epithelium (MPA-I) could proliferate, whereas those from mature enamel epithelium (MPA-M) could not. MPA-M but not MPA-I caused apoptosis during culture. The mRNA expression of amelogenin, a marker of immature ameloblasts, was down-regulated, and that of enamel matrix serine proteiase-1, a marker of mature ameloblasts, was induced in MPA-I during culture. Using green fluorescence protein as a reporter, a visualized reporter system was established to analyze the promoter activity of the amelogenin gene. The region between -1102bp and -261bp was required for the reporter expression in MPA-I. These results suggest that MPAs are valuable in vitro models for investigation of ameloblast biology, and that the visualized system is useful for promoter analysis in MPAs.

Ameloblasts↗

PubMed2006

Osteoblasts provide a suitable microenvironment for the action of receptor activator of nuclear factor-kappaB ligand.

Deficiency of osteoprotegerin (OPG), a soluble decoy receptor for receptor activator of nuclear factor-kappaB ligand (RANKL), in mice induces osteoporosis caused by enhanced bone resorption. Serum concentrations of RANKL are extremely high in OPG-deficient (OPG(-/-)) mice, suggesting that circulating RANKL is involved in osteoclastogenesis. RANKL(-/-) mice exhibit osteopetrosis, with the absence of osteoclasts. We examined the requirements for osteoclastogenesis using OPG(-/-) mice, RANKL(-/-) mice, and a system involving bone morphogenetic protein 2 (BMP-2)-induced ectopic bone formation. When collagen disks containing BMP-2 (BMP-2-disks) or vehicle were implanted into OPG(-/-) mice, osteoclast-like cells (OCLs) and alkaline phosphatase-positive OCLs appeared in BMP-2-disks but not the control disks. F4/80-positive osteoclast precursors were similarly distributed in both BMP-2- and control disks. Cells expressing RANKL were detected in the BMP-2-disks, and the addition of OPG to the disk inhibited OCL formation. Muscle cells in culture differentiated into alkaline phosphatase-positive cells in the presence of BMP-2 and accordingly expressed RANKL mRNA in response to PTH. This suggests that RANKL expressed by osteoblasts is a requirement for osteoclastogenesis. We then examined how osteoblasts are involved in osteoclastogenesis other than RANKL expression, using RANKL(-/-) mice. BMP-2- and control disks were implanted into RANKL(-/-) mice, which were injected with RANKL for 7 d. Many OCLs were observed in the BMP-2-disks and bone tissues but not the control disks. These results suggest that osteoblasts also play important roles in osteoclastogenesis through offering the critical microenvironment for the action of RANKL.

Animals↗

PubMed2006

Gastric inhibitory polypeptide as an endogenous factor promoting new bone formation after food ingestion.

Calcium plays a fundamental role as second messenger in intracellular signaling and bone serves as the body's calcium reserve to tightly maintain blood calcium levels. Calcium in ingested meal is the main supply and inadequate calcium intake causes osteoporosis and bone fracture. Here, we describe a novel mechanism of how ingested calcium is deposited on bone. Meal ingestion elicits secretion of the gut hormone gastric inhibitory polypeptide (GIP) from endocrine K cells in the duodenum. Bone histomorphometrical analyses revealed that bone formation parameters in the mice lacking GIP receptor (GIPR(-/-)) were significantly lower than those of wild-type (GIPR(+/+)) mice, and that the number of osteoclasts, especially multinuclear osteoclasts, was significantly increased in GIPR(-/-) mice, indicating that GIPR(-/-) mice have high-turnover osteoporosis. In vitro examination showed the percentage of osteoblastic cells undergoing apoptosis to be significantly decreased in the presence of GIP. Because GIPR(-/-) mice exhibited an increased plasma calcium concentration after meal ingestion, GIP directly links calcium contained in meal to calcium deposition on bone.

Animals↗

PubMed2006

[Bone destruction caused by osteoclasts].

Lipopolysaccharide (LPS) and muramyl dipeptide (MDP) are components of bacterial cell walls that cause innate immune responses and inflammation. Toll-like receptor 4 (TLR4) is a receptor for LPS and transduces signals through myeloid differentiation factor 88 (MyD88), which plays essential roles in the TLR/interleukin (IL)-1R signaling and activates MAP/ERK kinase (MEK)/ERK pathway to induce receptor activator of NF-kappaB ligand (RANKL) expression in osteoblasts. Osteoblasts express nucleotide oligomerization domain (NOD)2, an intracellular sensor for MDP, in response to LPS, IL-1 and TNF. NOD2 binds receptor-interacting protein (RIP2), a serine/threonine kinase which transduces NF-kappaB signaling. MDP synergistically enhances osteoclast formation induced by LPS, IL-1 and TNF through RANK ligand up-regulation in osteoblasts. TLR4 and NOD2 recognize bacterial components on cell surfaces and inside cells, respectively, and these signals up-regulate RANKL expression in osteoblasts, which results in enhancing osteoclast formation and function.

Acetylmuramyl-Alanyl-Isoglutamine↗

PubMed2006

[The pathophysiology of osteoporosis/osteopenia in gene mutant mice].

Osteoporosis is a systemic skeletal disease characterized by low bone mass and the microarchitectural deterioration of bone tissue. The pathophysiology of osteoporosis is complex, involving a broad spectrum of endogenous and environmental factors. Recently, molecular and genetic approaches are revealing that genetic backgrounds are important for the pathophysiology of osteoporosis. We discuss about recent findings of osteoporosis and osteopenia caused by monogenic mutations in humans and mice.

Animals↗

PubMed2006

[Bone and bone related biochemical examinations. Bone and collagen related metabolites. Regulatory mechanisms of osteoclast differentiation and function].

Osteoclast differentiation is tightly regulated by osteoblasts. Osteoblasts express two cytokines, macrophage colony-stimulating factor (M-CSF) and receptor activator of NF-kappaB ligand (RANKL), essential for osteoclast differentiation. Osteoclast precursors firstly differentiate into mononuclear osteoclasts in response to M-CSF and RANKL. Nuclear factor of activated T cells 1 (NFATc1) is a transcription factor, which is involved in the determination of osteoclast differentiation. The mononuclear osteoclast then fuses each other to form the multinucleated cell. Dendritic cell-specific transmembrane protein (DC-STAMP) plays an important role in the fusion of mononuclear osteoclasts. Osteoclasts recognize bone and form ruffled borders and clear zones on the bone surface (polarization). Polarizing osteoclasts construct active vascular transportation systems to resorb bone efficiently. RANK-TRAF6 (TNF receptor-associated factor 6) -mediated signals key roles in both osteoclast differentiation and function. In this article, I will review the recent findings on osteoclast differentiation and function.

Animals↗

PubMed2005

Prostaglandin E2 strongly inhibits human osteoclast formation.

Prostaglandin E(2) (PGE(2)) enhances osteoclast formation in mouse macrophage cultures treated with receptor activator of nuclear factor-kappaB ligand (RANKL). The effects of PGE(2) on human osteoclast formation were examined in cultures of CD14(+) cells prepared from human peripheral blood mononuclear cells. CD14(+) cells differentiated into osteoclasts in the presence of RANKL and macrophage colony-stimulating factor. CD14(+) cells expressed EP2 and EP4, but not EP1 or EP3, whereas CD14(+) cell-derived osteoclasts expressed none of the PGE(2) receptors. PGE(2) and PGE(1) alcohol (an EP2/4 agonist) stimulated cAMP production in CD14(+) cells. In contrast to mouse macrophage cultures, PGE(2) and PGE(1) alcohol inhibited RANKL-induced human osteoclast formation in CD14(+) cell cultures. H-89 blocked the inhibitory effect of PGE(2) on human osteoclast formation. These results suggest that the inhibitory effect of PGE(2) on human osteoclast formation is mediated by EP2/EP4 signals. SaOS4/3 cells have been shown to support human osteoclast formation in cocultures with human peripheral blood mononuclear cells in response to PTH. PGE(2) inhibited PTH-induced osteoclast formation in cocultures of SaOS4/3 cells and CD14(+) cells. Conversely, NS398 (a cyclooxygenase 2 inhibitor) enhanced osteoclast formation induced by PTH in the cocultures. The conditioned medium of CD14(+) cells pretreated with PGE(2) inhibited RANKL-induced osteoclast formation not only in human CD14(+) cell cultures, but also in mouse macrophage cultures. These results suggest that PGE(2) inhibits human osteoclast formation through the production of an inhibitory factor(s) for osteoclastogenesis of osteoclast precursors.

Adult↗

PubMed2005

Transcytosis of calcium from bone by osteoclast-like cells evidenced by direct visualization of calcium in cells.

'Transcytosis' of calcium (Ca) from bone by osteoclasts was identified by using a newly developed method that uses fixed or living osteoclast-like cells previously differentiated in vitro, a Ca-specific cell-membrane-impermeable fluorescent dye, and confocal laser scanning microscopy. This method, called the cell-membrane-impermeable dye method, revealed that in fixed osteoclast-like cells, a large quantity of Ca was confined within vacuoles and transported toward the apical cell membrane in the cells. These Ca-confined vacuoles were co-localized with marker proteins of both ruffled border and lysosome. The vacuoles were disrupted when treated with an inhibitor of ruffled border ATPase. In living osteoclast-like cells, Ca-confined vacuoles were again preferentially located at the central region and near the apical cell membrane. These results suggest actual transcytosis of Ca from bone by osteoclasts, and are the first direct evidence of the significant role of osteoclasts in the entire process of Ca metabolism in bone.

Adenosine Triphosphatases↗

PubMed2005

Experimental spinal fusion with recombinant human bone morphogenetic protein-2 delivered by a synthetic polymer and beta-tricalcium phosphate in a rabbit model.

STUDY DESIGN: An experimental animal study to achieve posterolateral intertransverse process spine fusion with recombinant bone morphogenetic protein in combination with a new delivery system. OBJECTIVE: To evaluate the efficacy of a new synthetic biodegradable bone-inducing material containing recombinant human bone morphogenetic protein-2 (rhBMP-2) as a bone-graft substitute for posterolateral intertransverse process fusion in a rabbit model. SUMMARY OF BACKGROUND DATA: rhBMP-2, a powerful bone-inducing cytokine, has been used as a bone graft substitute in combination with animal-derived collagen to achieve spinal fusion in animal models. However, the minimum dose of rhBMP-2 required to obtain solid posterolateral intertransverse process fusion was high on the basis of previous reports (>100 microg in rabbit models). To improve the efficacy, performance of rhBMP-2, and the safety of the delivery system for this protein, a more sophisticated system is required. METHODS: To fabricate one implant for one-side L4-L5 intertransverse process fusion, beta-tricalcium phosphate (beta-TCP) powder (300 microg), a polymer gel (PLA-DX-PEG block copolymer; 300 microg) and rhBMP-2 (7.5, 15, or 30 microg) were mixed and manually shaped to resemble a rod. Through a posterolateral approach, two implants were placed on both sides (1 per side) by surgery so as to bridge the transverse processes of adult New Zealand white rabbits (n = 27). In control animals, implants without rhBMP or autogenous cortico-cancellous bone chips from the iliaccrest were placed in a similar location. The lumbar vertebrae were recovered 6 weeks after surgery. The posterolateral fusion was examined by manual palpation, radiography, biomechanical testing, and histology. RESULTS: Rabbits that received 15 or 30 microg of rhBMP-2 showed consistent fusion. However, solid fusion was seen in 2 of 5 rabbits with autografting and rabbits that received 7.5 microg of rhBMP-2. Fusion was not observed in the rabbits that did not receive rhBMP-2. CONCLUSIONS: Consistent spinal fusion was obtained by implanting a biodegradable bone-inducing implant composed of beta-TCP, PLA-DX-PEG, and rhBMP-2 within a period of 6 weeks. The rhBMP-2 doses required for the spinal fusion were significantly lower than those reported previously.

Animals↗

PubMed2005

Muramyl dipeptide enhances osteoclast formation induced by lipopolysaccharide, IL-1 alpha, and TNF-alpha through nucleotide-binding oligomerization domain 2-mediated signaling in osteoblasts.

Muramyl dipeptide (MDP) is the minimal essential structural unit responsible for the immunoadjuvant activity of peptidoglycan. As well as bone-resorbing factors such as 1alpha,25-dihydroxyvitamin D3 (1alpha,25(OH)2D3) and PGE2, LPS and IL-1alpha stimulate osteoclast formation in mouse cocultures of primary osteoblasts and hemopoietic cells. MDP alone could not induce osteoclast formation in the coculture, but enhanced osteoclast formation induced by LPS, IL-1alpha, or TNF-alpha but not 1alpha,25(OH)2D3 or PGE2. MDP failed to enhance osteoclast formation from osteoclast progenitors induced by receptor activator of NF-kappaB ligand (RANKL) or TNF-alpha. MDP up-regulated RANKL expression in osteoblasts treated with LPS or TNF-alpha but not 1alpha,25(OH)2D3. Osteoblasts expressed mRNA of nucleotide-binding oligomerization domain 2 (Nod2), an intracellular sensor of MDP, in response to LPS, IL-1alpha, or TNF-alpha but not 1alpha,25(OH)2D3. Induction of Nod2 mRNA expression by LPS but not by TNF-alpha in osteoblasts was dependent on TLR4 and MyD88. MDP also enhanced TNF-alpha-induced osteoclast formation in cocultures prepared from Toll/IL-1R domain-containing adapter protein (TIRAP)-deficient mice through the up-regulation of RANKL mRNA expression in osteoblasts, suggesting that TLR2 is not involved in the MDP-induced osteoclast formation. The depletion of intracellular Nod2 by small interfering RNA blocked MDP-induced up-regulation of RANKL mRNA in osteoblasts. LPS and RANKL stimulated the survival of osteoclasts, and this effect was not enhanced by MDP. These results suggest that MDP synergistically enhances osteoclast formation induced by LPS, IL-1alpha, and TNF-alpha through RANKL expression in osteoblasts, and that Nod2-mediated signals are involved in the MDP-induced RANKL expression in osteoblasts.

Acetylmuramyl-Alanyl-Isoglutamine↗

PubMed2005

Prostaglandin E2 receptors EP2 and EP4 are down-regulated during differentiation of mouse osteoclasts from their precursors.

Prostaglandin E2 (PGE2) has been proposed to be a potent stimulator of bone resorption. However, PGE2 itself has been shown to directly inhibit bone-resorbing activity of osteoclasts. We examined the role of PGE2 in the function of mouse osteoclasts formed in vitro. Bone marrow macrophage osteoclast precursors expressed PGE2 receptors EP1, EP2, EP3beta, and EP4, and the expression of EP2 and EP4 was down-regulated during osteoclastic differentiation induced by receptor activator of NF-kappaB ligand and macrophage colony-stimulating factor. In contrast, functional EP1 was continuously expressed in mature osteoclasts. PGE2 as well as calcitonin caused intracellular Ca2+ influx in osteoclasts. However, PGE2 and 17-phenyltrinol-PGE2 (an EP1 agonist) failed to inhibit actin-ring formation and pit formation by osteoclasts cultured on dentine slices. When EP4 was expressed in osteoclasts using an adenovirus carrying EP4 cDNA, both actin-ring and pit-forming activities of osteoclasts were inhibited in an infectious unit-dependent manner. Treatment of EP4-expressing osteoclasts with PGE2 further inhibited their actin-ring and pit-forming activities. Such inhibitory effects of EP4-mediated signals on osteoclast function are similar to those that are calcitonin receptor-mediated. Thus, osteoclast precursors down-regulate their own EP2 and EP4 levels during their differentiation into osteoclasts to escape inhibitory effects of PGE2 on bone resorption.

Animals↗

PubMed2005

Prostaglandin E2 enhances osteoclastic differentiation of precursor cells through protein kinase A-dependent phosphorylation of TAK1.

Prostaglandin E2 (PGE2) synergistically enhances the receptor activator for NF-kappa B ligand (RANKL)-induced osteoclastic differentiation of the precursor cells. Here we investigated the mechanisms of the stimulatory effect of PGE2 on osteoclast differentiation. PGE2 enhanced osteoclastic differentiation of RAW264.7 cells in the presence of RANKL through EP2 and EP4 prostanoid receptors. RANKL-induced degradation of I kappa B alpha and phosphorylation of p38 MAPK and c-Jun N-terminal kinase in RAW264.7 cells were up-regulated by PGE2 in a cAMP-dependent protein kinase A (PKA)-dependent manner, suggesting that EP2 and EP4 signals cross-talk with RANK signals. Transforming growth factor beta-activated kinase 1 (TAK1), an important MAPK kinase kinase in several cytokine signals, possesses a PKA recognition site at amino acids 409-412. PKA directly phosphorylated TAK1 in RAW264.7 cells transfected with wild-type TAK1 but not with the Ser412 --> Ala mutant TAK1. Ser412 --> Ala TAK1 served as a dominant-negative mutant in PKA-enhanced degradation of I kappa B alpha, phosphorylation of p38 MAPK, and PGE2-enhanced osteoclastic differentiation in RAW264.7 cells. Furthermore, forskolin enhanced tumor necrosis factor alpha-induced I kappa B alpha degradation, p38 MAPK phosphorylation, and osteoclastic differentiation in RAW264.7 cells. Ser412 --> Ala TAK1 abolished the stimulatory effects of forskolin on those cellular events induced by tumor necrosis factor alpha. Ser412 --> Ala TAK1 also inhibited the forskolin-induced up-regulation of interleukin 6 production in RAW264.7 cells treated with lipopolysaccharide. These results suggest that the phosphorylation of the Ser412 residue in TAK1 by PKA is essential for cAMP/PKA-induced up-regulation of osteoclastic differentiation and cytokine production in the precursor cells.

Animals↗

PubMed2005

Nurse-like cells from patients with rheumatoid arthritis support the survival of osteoclast precursors via macrophage colony-stimulating factor production.

OBJECTIVE: To elucidate the role of nurse-like cells (NLCs) obtained from rheumatoid arthritis (RA) patients in bone loss during progressive synovial expansion. METHODS: CD14+ monocytes were cocultured with NLCs for 4 weeks and collected as NLC-supported CD14+ (NCD14+) monocytes. To determine their ability to differentiate into osteoclasts, NCD14+ monocytes were further cultured with macrophage colony-stimulating factor (M-CSF) together with RANKL or tumor necrosis factor alpha (TNFalpha). NCD14+ monocytes were also cocultured with SaOS-4/3 cells, which were shown to support osteoclastogenesis in response to parathyroid hormone (PTH). CD14+ monocytes were cocultured with SaOS-4/3 cells to elucidate how SaOS-4/3 cells and NLCs supported CD14+ monocytes for a long period. Synovial expansion adjacent to bone in RA patients was examined immunohistochemically to detect osteoclast precursors such as NCD14+ monocytes. RESULTS: NLCs supported the survival of CD14+ monocytes for 4 weeks. NCD14+ as well as CD14+ monocytes differentiated into osteoclasts in the presence of M-CSF together with RANKL or TNFalpha. NCD14+ monocytes also differentiated into osteoclasts in PTH-treated cocultures with SaOS-4/3 cells. SaOS-4/3 cells supported the survival of CD14+ monocytes for 4 weeks in the presence, but not absence, of PTH. Treatment of SaOS-4/3 cells with PTH up-regulated the expression of M-CSF messenger RNA. Neutralizing antibodies against M-CSF inhibited the NLC-supported survival of CD14+ monocytes. CD68+ monocytes and M-CSF+ fibroblast-like synoviocytes were colocalized in regions adjacent to the destroyed bone of RA patients. CONCLUSION: Our findings suggest that NLCs are involved in RA-induced bone destruction by maintaining osteoclast precursors via production of M-CSF.

Aged↗

PubMed2005

Dolomite supplementation improves bone metabolism through modulation of calcium-regulating hormone secretion in ovariectomized rats.

Dolomite, a mineral composed of calcium magnesium carbonate (CaMg (CO3)2), is used as a food supplement that supplies calcium and magnesium. However, the effect of magnesium supplementation on bone metabolism in patients with osteoporosis is a matter of controversy. We examined the effects of daily supplementation with dolomite on calcium metabolism in ovariectomized (OVX) rats. Dolomite was administered daily to OVX rats for 9 weeks. The same amount of magnesium chloride as that supplied by the dolomite was given to OVX rats as a positive control. Histological examination revealed that ovariectomy decreased trabecular bone and increased adipose tissues in the femoral metaphysis. Dolomite or magnesium supplementation failed to improve these bone histological features. Calcium content in the femora was decreased in OVX rats. Neither calcium nor magnesium content in the femora in OVX rats was significantly increased by dolomite or magnesium administration. Urinary deoxypyridinoline excretion was significantly increased in OVX rats, and was not affected by the magnesium supplementation. Serum concentrations of magnesium were increased, and those of calcium were decreased, in OVX rats supplemented with dolomite or magnesium. However, there was a tendency toward decreased parathyroid hormone secretion and increased calcitonin secretion in OVX rats supplemented with dolomite or magnesium. Serum 1,25-dihydroxyvitamin D(3) and osteocalcin levels were significantly increased in the supplemented OVX rats. These results suggest that increased magnesium intake improves calcium metabolism in favor of increasing bone formation, through the modulation of calcium-regulating hormone secretion.

Amino Acids↗

PubMed2005

[A new treatment for osteoporosis using fully human monoclonal antibody to RANKL, AMG 162].

RANKL is an essential factor for osteoclastogenesis. Amgen research group has developed AMG 162, a fully human monoclonal antibody to RANKL. The bone antiresorptive activity and safety of AMG 162 were evaluated in 49 healthy postmenopausal women (Phase I study). The effect of increasing amounts of AMG 162 on bone mineral density (BMD) was studied in 411 postmenopausal women with low BMD (Phase II study). A single subcutaneous dose of AMG 162 (1 mg/kg or 60 mg) suppressed bone resorption for more than 6 month without critical side effects (Phase I study), and increased BMD within 1 month in postmenopausal women (Phase II study).

Antibodies, Monoclonal↗