Biomedical subjects

Sadaaki Takeyama

Publications and source records attributed to Sadaaki Takeyama.

7 recordsLinked to original sources

PubMed2006

Current topics in pharmacological research on bone metabolism: inhibitory effects of bisphosphonates on the differentiation and activity of osteoclasts.

Despite the extensive use of bisphosphonates (BPs) in the treatment of metabolic bone diseases associated with increased osteoclastic bone resorption, the precise mechanism of their action on bone metabolism is still unclear. To clarify at which stages of osteoclast differentiation and activation that BPs influence, we examined the osteoclasts generated from mononuclear precursors and osteoclasts in the calvaria by laser scanning confocal microscopy. The studies showed that BPs inhibit lipopolysaccharide- or parathyroid hormone-induced osteoclast differentiation, fusion, attachment, actin ring formation, and activation and that both beta3 integrin and osteopontin have an important role in cytoskeletal rearrangements associated with cell attachment and resorption in osteoclasts.

Actins↗

PubMed2006

[Application of bisphosphonates for periodontitis].

Bisphosphonates are known as highly effective inhibitors of osteoclastic bone resorption that selectively affect osteoclasts. They are world-wildly used for the treatment of metabolic bone diseases with excessive bone resorption such as osteoporosis and Paget's disease. Alveolar bone loss in periodontitis results from local inflammatory reactions by periodontopathic bacteria. It has been reported that bisphosphonates efficiently prevent experimentally induced alveolar bone resorption in animals with periodontitis, and that bisphosphonate therapy improves the outcome of periodontal treatment in human being. Administration of bisphosphonates may be an appropriate adjunctive treatment to preserve periodontal bone mass. Further studies are needed regarding topical drug delivery system, effective dose and frequency of administration, possible side effects, and which bisphosphonate is suitable for periodontitis.

Animals↗

PubMed2005

Osteoclast responses to lipopolysaccharide, parathyroid hormone and bisphosphonates in neonatal murine calvaria analyzed by laser scanning confocal microscopy.

Because the development and activity of osteoclasts in bone remodeling is critically dependent on cell-cell and cell-matrix interactions, we used laser confocal microscopy to study the response of osteoclasts to lipopolysaccharide (LPS; 10 microg/ml), parathyroid hormone (PTH; 10(-8) M), and bisphosphonates (BPs; 1-25 microM clodronate or 0.1-2.5 microM risedronate) in cultured neonatal calvaria. Following treatment with LPS or PTH (<48 hr), osteopontin (OPN) and the alphavbeta3 integrin were found colocalized with the actin ring in the sealing zone of actively resorbing osteoclasts. In contrast, non-resorbing osteoclasts in BP-treated cultures showed morphological abnormalities, including retraction of pseudopods and vacuolization of cytoplasm. In the combined presence of LPS and BP, bone-resorbing osteoclasts were smaller and the sealing zone diffuse, reflecting reduced actin, OPN, and beta3 integrin staining. Depth analyses of calvaria showed that the area of resorbed bone was filled with proliferating osteoblastic cells that stained for alkaline phosphatase, collagen type I, and bone sialoprotein, regardless of the presence of BPs. These studies show that confocal microscopy of neonatal calvaria in culture can be used to assess the cytological relationships between osteoclasts and osteoblastic cells in response to agents that regulate bone remodeling in situ, avoiding systemic effects that can compromise in vivo studies and artifacts associated with studies of isolated osteoclasts.

Acid Phosphatase↗

PubMed2003

[Pharmacological actions and pharmacokinetics of bisphosphonates].

Bisphosphonates are potent inhibitors of osteoclastic bone resorption and have been used for the treatment of various metabolic bone diseases such as osteoporosis and hypercalcemia of malignancy. However, the pharmacological action, the mechanism of action, and even side effects vary depending on the chemical structure of the side chain attached to the carbon atom of P-C-P bond. This review discussed about the pharmacological characteristics and possible application of different classes of bisphosphonates with different side chains.

English Abstract↗

PubMed2002

Histamine stimulates production of osteoclast differentiation factor/receptor activator of nuclear factor-kappaB ligand by osteoblasts.

Histamine H(1),H(2), and H(3) receptors are expressed by osteoblastic MC3T3-E1 (E1) cells derived from mouse calvaria. Expression of the osteoclast differentiation factor (ODF)/receptor activator of nuclear factor-kappaB ligand (RANKL) transcript was induced in E1 cells and bone marrow stromal cells (ST2). Histamine markedly increased the steady-state level of ODF/RANKL mRNA in a dose-dependent manner. The effect of histamine on expression of ODF/RANKL mRNA by E1 cells was transient, with a peak at 6h. Western blot analysis revealed that histamine increased production of ODF/RANKL protein by E1 cells at 12h. In cocultures of E1 cells and mouse bone marrow cells, histamine stimulated osteoclastogenesis in the presence of 1,25-dihydroxyvitamin D(3) and this effect was blocked by preincubation with neutralizing antibody against ODF/RANKL. These results suggest that histamine regulates osteoclastogenesis, at least in part, through induction of ODF/RANKL expression by osteoblasts and bone marrow stromal cells.

Animals↗

PubMed2002

Expression of receptor activator of NF-kappa B ligand and osteoprotegerin in culture of human periodontal ligament cells.

The receptor activator of NF-kappa B ligand (RANKL) and its decoy receptor, osteoprotegerin (OPG), are the important proteins implicated in osteoclastogenesis. In this study, we investigated the expressions of RANKL and OPG in cultured human periodontal ligament (PDL) cells and their roles in osteoclastogenesis. Northern blotting revealed that the OPG mRNA was down-regulated remarkably by application of 10-8 m one-alpha, 25-dihydroxyvitamin D3[1,25-(OH)2D3] and 10-7 m dexamethasone (Dex). In contrast, RANKL mRNA was up-regulated by the same treatment. Western blotting demonstrated decrease of OPG by the application of 1,25-(OH)2D3 and Dex. Tartrate-resistant acid phosphatase-positive multinuclear cells were markedly induced when the PDL cells were cocultured with mouse bone marrow cells in the presence of an anti-OPG antibody together with 1,25-(OH)2D3 and Dex. These results indicate that PDL cells synthesize both RANKL and OPG and that inactivation of OPG may play a key role in the differentiation of osteoclasts.

Acid Phosphatase↗

PubMed2002

[Bisphosphonates and adhesion molecules].

Bisphosphonates are highly effective inhibitors of osteoclastic bone resorption. They can be divided into two groups with distinct mechanisms of action. The nitrogen-containing bisphosphonates (pamidronate, alendronate, risedronate, incadronate etc) can inhibit the mevalonate pathway in osteoclasts and inhibit protein prenylation of small G proteins including Rho, which might lead to alter cytoskeletal organization and cell motility. Others, like etidronate and clodronate, do not inhibit protein prenylation and can be incorporated into ATP-containing compounds that may be cytotoxic to osteoclasts. Further studies would be required to elucidate the molecular mechanism of bisphosphonate actions.

English Abstract↗