摘要:

AbstractAs outcomes research gains new importance in the practice of medicine, scientists publishing the results of clinical trials inJBMRmust gain new appreciation for the elegant scientific methods and principles of analysis that make such investigations credible. Over the past year, during my tenure as Editor of theJournal, I have become progressively more interested in assuring that the clinical research reported inJBMRis of the highest quality. With this in mind, I asked John Feussner, M.D., a leading researcher in health outcomes investigations, to review recent manuscripts dealing with clinical trials that were published inJBMRand to search for areas in which we can make improvements. In the accompanying editorial, Dr. Feussner reports the result of his review. Not to my surprise, he was able to find errors of commission and omission that have affected several of the reported studies in theJournal. Although concern might be raised based upon reaching this conclusion from a review of a limited number of papers, it is more important to concentrate on the correctable factors that have been raised. Indeed, while many may consider this disquieting, I prefer to believe that the gauntlet has been thrown down and that we will respond to the challenges Dr. Feussner has provided us. In this regard, we must modify our clinical trials methodology and adhere to the principles that he has outlined in the accompanying editorial and allow that these principles guide our review of submitted manuscripts in the future. I believe that those of us in the editorial office are ready to refine the review process, paying newly directed attention to the methodological and analytical plans underlying clinical trials, and thereby move the quality of published clinical research in theJournalto even higher standards. The questions remains, however, Are you, the scientist/author and the scientist/reviewer, ready?

ISSN:0884-0431    

DOI:10.1002/jbmr.5650110702

出版商:John Wiley and Sons and The American Society for Bone and Mineral Research (ASBMR)    

年代:1996

数据来源: WILEY

摘要:

AbstractTwo variants of an mRNA sequence are identified that are expressed at high levels in rat ameloblasts during the formation of the enamel matrix. The sequences contain open reading frames for 407 and 324 amino acid residues, respectively. The encoded proteins, which we call amelins, are rich in proline, glycine, leucine, and alanine residues and contain the peptide domain DGEA, an integrin recognition sequence. The sequences coding for the C‐terminal 305 amino acid residues, the 3′ nontranslated part, and a microsatellite repeat at the nontranslated 5′ region are identical in both mRNA variants. The remaining 5′ regions contain 338 nucleotides unique to the long variant, 54 common nucleotides, and 46 nucleotides present only in the short variant. Eleven nucleotides have the potential to code for 5 amino acids of both proteins in different reading frames. The reading frame of the longer variant includes codons for a typical N‐terminal signal peptide. The amelins are likely to be constituents of the enamel matrix and the only proteins that have so far been implicated in binding interactions between the ameloblast surface and its extracellular matrix. (J Bone Miner Res 1996;1

ISSN:0884-0431    

DOI:10.1002/jbmr.5650110703

出版商:John Wiley and Sons and The American Society for Bone and Mineral Research (ASBMR)    

年代:1996

数据来源: WILEY

摘要:

AbstractSince 1974, when Slavkin and his collaborators proposed the epithelial origin of cementum, many experiments have been carried out to provide evidence for deposition of enamel‐related proteins along the root surface. However, neither amelogenin nor other proteins have fully satisfied expectations. In previous studies, we have identified a novel mRNA coding for an extracellular‐like protein which we called amelin. It was expressed at high levels in secretory and postsecretory ameloblasts in rat molars and incisors. In situ hybridization experiments described in the present study also localized the amelin message to epithelial cells adjacent to the peripheral surface of newly deposited dentin in the root end and to cells embedded in cellular cementum in molars. In incisors, the amelin RNA positive cells were detected in the area where cementum formation had been initiated. No amelogenin RNA signal was found in the cells at the root surface. We postulate that the epithelial cells of the root sheath as well as the ameloblasts are synthesizing amelin which might be one of the key proteins coupled to the process of cementogenesis. (J Bone Miner Res 1996;11:892

ISSN:0884-0431    

DOI:10.1002/jbmr.5650110704

出版商:John Wiley and Sons and The American Society for Bone and Mineral Research (ASBMR)    

年代:1996

数据来源: WILEY

ISSN:0884-0431    

DOI:10.1002/jbmr.5650110705

出版商:John Wiley and Sons and The American Society for Bone and Mineral Research (ASBMR)    

年代:1996

数据来源: WILEY

摘要:

AbstractInterleukin‐6 (IL‐6) is a multifunctional cytokine that is produced not only by a variety of normal cells but also by cancer cells. IL‐6 produced by cancer cells stimulates the proliferation of these cancer cells in an autocrine/paracrine manner and causes paraneoplastic syndromes including hypercalcemia, cachexia, and leukocytosis. We have reported previously that a human oral squamous cancer associated with hypercalcemia produces large amounts of IL‐6, that animals bearing this cancer exhibit elevated levels of plasma IL‐6, and that neutralizing antibodies to human IL‐6 reverse hypercalcemia in tumor‐bearing animals, indicating an important role of IL‐6 in the hypercalcemia in this model. Because these cancer cells overexpress epidermal growth factor receptors (EGFR) with intrinsic tyrosine kinase (TK) activity similar to many other squamous cancers, we examined the effects of herbimycin A, a tyrosine kinase inhibitor, on IL‐6 production and hypercalcemia in animals bearing this cancer to develop a new approach to treat the hypercalcemia associated with malignancy. Intraperitoneal administration (once a day for 2 days) of herbimycin A to cancer‐bearing hypercalcemic mice reduced the plasma levels of human IL‐6 and impaired the hypercalcemia. During 2‐day treatment with herbimycin A, no changes were observed in tumor size. Of interest, plasma levels of mouse, but not human, soluble IL‐6 receptors were also elevated. However, herbimycin A showed no effects on plasma levels of mouse soluble IL‐6 receptors. Herbimycin A suppressed the tyrosine autophosphorylation of EGFR and IL‐6 mRNA expression and production, all of which were stimulated by EGF. The data raise the possibility that TK inhibitors may be potential mechanism‐based therapeutic agents for the treatment of hypercalcemia associated with squamous cancers which overexpress EGFR. (J

ISSN:0884-0431    

DOI:10.1002/jbmr.5650110706

出版商:John Wiley and Sons and The American Society for Bone and Mineral Research (ASBMR)    

年代:1996

数据来源: WILEY

摘要:

AbstractThe present study was performed to examine the effect of the high concentration of extracellular calcium ([Ca2+]e) on osteoclast‐like cell formation and bone‐resorbing activity in the presence or absence of osteoblasts. High [Ca2+]e(3 and 5 mM) significantly stimulated osteoclast‐like cell formation in osteoblast‐containing mouse bone cell cultures, although high [Ca2+]edid not affect the formation of osteoclast‐like cells from hemopoietic blast cells supported by granulocyte‐macrophage colony‐stimulating factor in mouse spleen cell cultures. The osteoclast‐like cells, newly formed by high [Ca2+]ein the presence of osteoblasts, possessed the ability to form pits on the dentine slices. The conditioned medium from osteoblastic MC3T3‐E1 cells treated with high [Ca2+]e(5 mM) significantly increased the formation of osteoclast‐like cells from hemopoietic blast cells, compared with the control medium. Dantrolene, an inhibitor of calcium mobilization from the intracellular calcium pool, and indomethacin significantly blocked high [Ca2+]e‐stimulated osteoclast‐like cell formation in the presence of osteoblasts, although voltage‐dependent calcium channel blockers and anti‐insulin‐like growth factor I antibody did not affect it. High [Ca2+]e, however, significantly stimulated the bone‐resorbing activity of mature osteoclasts in osteoblast‐containing mouse bone cell cultures, although high [Ca2+]einhibited bone‐resorbing activity in isolated rabbit osteoclasts. An increase in the extracellular magnesium concentration (5 mM) affected neither osteoclast‐like cell formation nor bone‐resorbing activity. In conclusion, high [Ca2+]estimulated osteoclast‐like cell formation and bone‐resorbing activity of mature osteoclasts, presumably via ost

ISSN:0884-0431    

DOI:10.1002/jbmr.5650110707

出版商:John Wiley and Sons and The American Society for Bone and Mineral Research (ASBMR)    

年代:1996

数据来源: WILEY

摘要:

AbstractWe investigated the effects of the sex hormone progesterone (Prog) and the synthetic glucocorticoid dexamethasone (Dex) on proliferation and differentiation of progenitor cells of osteogenic, adipocytic, and hemopoietic lineages in cell populations derived from explants of adult female rat lumbar vertebrae. The cell populations were obtained by culturing bone explants in plasma clots immersed in α‐minimum essential medium plus 10% fetal calf serum (standard medium) and then subculturing the outgrowth cells in standard medium plus 50 μg/ml of ascorbic acid, 5 mM β‐glycerophosphate, and with or without Prog or Dex. On day 6 of culture, these populations were analyzed for cAMP responses to parathyroid hormone (PTH), prostaglandin E2(PGE2), and isoproterenol (IPT). Increases in intracellular cAMP were seen in response to PTH, PGE2, and IPT, and culturing in medium containing Prog increased these responses. At various time periods between days 4–27 of culture, the cultures were evaluated for the presence of bone nodules, alkaline phosphatase (AP)‐positive colonies, adipocytes, monocytes, and macrophages. Prog and Dex increased the number of bone nodules and AP‐positive colonies. The effect of Prog on bone nodule formation was smaller than that of Dex. In addition, the effect of Dex on bone nodule formation was evident after 10 days of culture, while the Prog‐induced effects became significant at days 16–20 of culture. Both hormones also increased the number of Sudan IV‐positive colonies (adipocytes), certain types of α‐naphthyl butyrate esterase (α‐NBE)‐positive colonies (monocytes, macrophages, and T‐lymphocytes), and ED2‐positive colonies (macrophages). Prog‐treated cultures contained more colonies of small spindle‐shaped α‐NBE‐positive cells and fewer colonies of small round α‐NBE‐positive cells when compared with Dex‐treated cultures. These data indicate that cell populations derived from adult rat lumbar vertebrae contain, among others, osteoprogenitors and progenitors for adipocytes and macrophages that are stimulated to proliferate and differentiate by Prog and Dex. The data also suggest that the effects of Prog and Dex differ qualitatively and qua

ISSN:0884-0431    

DOI:10.1002/jbmr.5650110708

出版商:John Wiley and Sons and The American Society for Bone and Mineral Research (ASBMR)    

年代:1996

数据来源: WILEY

摘要:

AbstractFormation of advanced glycation end products (AGEs) in extracellular matrix (ECM) is implicated in the development of chronic diabetic complications. However, the involvement of AGEs in diabetic bone disease has not been well established. We have examined whether AGEs are increased in the bone collagen of streptozotocin‐induced diabetic rats in vivo and whether glycation of type I collagen affects the functions of osteoblastic cells in vitro. During 12 weeks of observation, AGEs in collagen extracted from the tibiae of diabetic rats increased in a time‐dependent manner and were significantly higher than controls at every time point. In vitro, the incubation of collagen with glucose‐6‐phosphate resulted in a time‐dependent increase of AGEs. When osteoblastic cells isolated from fetal rat calvaria were cultured on AGE‐modified type I collagen, it dose‐dependently inhibited phenotypic expressions of osteoblasts. Among osteoblastic parameters, nodule formation was the most sensitive, being inhibited by ∼70% by the glycation of collagen for only 1 week. Alkaline phosphatase activity and osteocalcin secretion were inhibited by 20–30% and 15–70%, respectively, by the glycation of collagen for 1–5 weeks. These results indicate that AGE‐modified collagen affects osteoblastic cell differentiation and function in vitro and suggest that similar changes occurring in vivo may contribute to diabetic osteopenia. (J Bone Min

ISSN:0884-0431    

DOI:10.1002/jbmr.5650110709

出版商:John Wiley and Sons and The American Society for Bone and Mineral Research (ASBMR)    

年代:1996

数据来源: WILEY

摘要:

AbstractThe therapeutic utility of a single application of recombinant human transforming growth factor‐β (hTGF‐β) has not been previously tested in large osseous wounds in primates. Sixteen calvarial defects, 25 mm in diameter, were prepared in four adult male baboons (Papio ursinus). In each animal, three defects were treated with increasing doses of hTGF‐β1in conjunction with baboon insoluble collagenous bone matrix as carrier (5, 30, and 100 μg of hTGF‐β1/g of matrix). The fourth defect was implanted with collagenous matrix without hTGF‐β1as control. Serial undecalcified sections were prepared from the specimens harvested on day 30. Islands of cartilage and endochondral osteogenesis were found in hTGF‐β1‐treated defects, irrespective of the doses used. Histomorphometry of the defect site showed no significant differences between control and hTGF‐β1‐treated specimens with regard to bone and osteoid volumes. However, analysis of the regenerated tissue in proximity to the defect margins only showed that, on average, greater amounts of bone formed in specimens that were treated with 5 and 30 μg of hTGF‐β1when compared with controls. This suggests a possible effect on osteoblastic cells originating from the periosteal and endosteal spaces of the severed calvaria. Overall, however, this difference has no therapeutic implications for the healing of large cranial wounds in primates. The present findings indicate that a single application of hTGF‐β1, in conjunction with collagenous matrix, results in limited chondro‐osteogenesis in defects of membranous bone of adult baboons.

ISSN:0884-0431    

DOI:10.1002/jbmr.5650110710

出版商:John Wiley and Sons and The American Society for Bone and Mineral Research (ASBMR)    

年代:1996

数据来源: WILEY

摘要:

AbstractCytosolic Ca2+oscillations are known to occur in many cell types stimulated with agonists linked to the phosphoinositide signaling pathway. Trains of repetitive short‐lasting Ca2+spikes could be induced in articular chondrocytes by extracellular ATP, an agonist potently effective in stimulating cartilage resorption. The mechanism of these Ca2+oscillations was studied by computerized video imaging on primary cultures of articular chondrocytes. Few cycles of oscillatory activity could be evoked in the absence of extracellular Ca2+, while, for oscillations to be sustained, Ca2+influx was required. Thapsigargin irreversibly blocked Ca2+oscillations, thus demonstrating the crucial involvement of intracellular stores in triggering the rhythmic activity. Apart from activating intracellular Ca2+release, extracellular ATP also induced a noncapacitive Ca2+influx in these cells. This ATP‐mediated influx modulates both the oscillation frequency and intracellular stores refilling. In monolayers of confluent cells, Ca2+oscillations spread from cell to cell in the form of intercellular waves. Propagating waves could also be observed in the absence of extracellular Ca2+, demonstrating that Ca2+itself is not required for signal coordination. These results demonstrate that complex spatiotemporal pathways of Ca2+oscillations and intercellular Ca2+waves could be activated in articular chondrocytes during degenerative diseases. (J Bone Miner Res 1996;11:946

ISSN:0884-0431    

DOI:10.1002/jbmr.5650110711

出版商:John Wiley and Sons and The American Society for Bone and Mineral Research (ASBMR)    

年代:1996

数据来源: WILEY