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Michela Rossi, Giulia Battafarano, Viviana De Martino, Alfredo Scillitani, Salvatore Minisola, and Andrea Del Fattore

investigation. The bone-specificity, that let sclerostin be a good target for bone diseases without side-effects, is not the main property of TGFβ that, beyond the important role in all phases of chondrogenesis, mesenchymal condensation, matrix deposition and

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Norihiko Kato, Keiichiro Kitahara, Susan R Rittling, Kazuhisa Nakashima, David T Denhardt, Hisashi Kurosawa, Yoichi Ezura, and Masaki Noda

TJ 2000 Therapeutic approaches to bone diseases. Science 289 1508 –1514. Rosen CJ & Bilezikian JP 2001 Clinical review 123: hot topic. Anabolic therapy for osteoporosis. Journal of Clinical Endocrinology and

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G. H. BELL and D. P. CUTHBERTSON

Clinicians have long been familiar with diseases of the endocrine system in which alterations of bone shape occur, and chemical investigations have now shed some light on these conditions. Of all hormones the growth-promoting factor of the anterior pituitary gland is undoubtedly the most potent in inducing skeletal change. The pituitary may exert a direct control over bone growth and the effects of other hormones—e.g. those of the thyroid and parathyroid glands and the gonads—may have to be explained on the basis of their effects on the production of this growth-promoting factor. On the other hand, the converse may hold, viz. the action of the pituitary may be indirect.

While there is considerable quantitative information about the gross metabolic changes in bone disease, there is little or no information about the nature of the physicochemical alterations, if any, produced [Logan, 1940]. It is well known that there is an increase

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H. M. Docherty and D. A. Heath

Over the past years the explanation of the hypercalcaemia associated with malignancy has changed repeatedly. Theories have come and gone and, in some cases, come again. The search for new hypercalcaemic factors is gaining momentum and major new breakthroughs seem imminent.

The original explanation of the hypercalcaemia of malignancy was that it was due to bone metastases physically causing the release of calcium from bone. This simple theory, though widely believed, was not supported by any evidence. Many patients with extensive bone disease had normal serum calcium values, many were hypercalcaemic in the absence of bone metastases, and certain malignancies had high or low incidences of hypercalcaemia despite similar rates of bone metastases, c.f. squamous cell and small cell carcinoma of the lung. That certain malignancies might produce a humoral factor was suggested by the work of Gordan, Cantino, Erhardt et al. (1966) who claimed to have isolated vitamin D-like

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T Yamashita, A Nifuji, K Furuya, Y Nabeshima, and M Noda

Bone diseases such as osteoporosis and osteoarthritis are regarded as age-associated diseases, and occur in a significantly increasing number of patients, but the underlying mechanisms of these age-associated bone diseases are not yet clear. We have established a transgenic mouse line by an insertion mutation. These mice exhibit many features related to precocious aging. Homozygote mutant mice, which lack expression of the newly identified targeted gene,klotho (kl), exhibit atherosclerosis, emphysema, hypogonadism and calcification of soft tissues, and die within 3-4 months. We describe here the radiological and histological characteristics of the skeletal abnormalities in the bones of the mice with a mutation in the kl gene locus. In heterozygous mice (+/kl), the skeletal patterns and structures remain normal and most features are similar to those in the wild-type, whereas histological examinations of homozygous mice (kl/kl) show abnormal elongation of the trabecular bone(s) in the epiphyses of long bones. As with their long bones, on radiographic examination the mid parts of the vertebral bones of these mice show less radiopacity compared with the wild-type, again resembling human vertebrae of osteoporotic patients. The elongation of the trabecular bones results in high radiopacity on both ends of each of the vertebrae, and in the epiphyses of the long bones. Cancellous bone volume in the epiphyses of the homozygote mice is three times that of the wild-type mice. The kl/kl mice are smaller than the wild-type litter mates and hence the size of their long bones is less than that of the wild-type litter mates. These observations, and the osteopenia in the vertebrae and long bones in these mice, suggest the presence of abnormality in bone metabolism, the elongation of the trabecular bone apparently resulting from the relatively low levels of bone resorption. Therefore, thekl/kl mutant mice could serve as an interesting tool to study the effects of the lack of the product of the new gene,klotho, on bone metabolism.

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T Kukita, A Kukita, T Watanabe, and T Iijima

Although calcitonin has been clinically utilized as a primary treatment for several metabolic bone diseases, its inhibitory effects against osteoclastic function diminish after several days owing to the calcitonin 'escape phenomenon'. We have previously found a unique cell-surface antigen (Kat1-antigen) expressed on rat osteoclasts. Here we show evidence that, in the presence of calcitonin, the Kat1-antigen is involved in osteoclastogenesis. Treatment of bone marrow cultures for forming osteoclast-like cells with anti-Kat1-antigen monoclonal antibody (mAb Kat1) provoked a marked stimulation of osteoclast-like cell formation only in the presence of calcitonin but not in its absence. Osteoclastogenesis stimulated by the receptor activator of nuclear factor kappa B (NF-kappaB) ligand/osteoclast differentiation factor was further augmented by mAb Kat1 in the presence of calcitonin. Furthermore, even in the presence of the osteoprotegerin/osteoclast inhibitory factor, mAb Kat1 induced osteoclast-like cell formation. Our current data suggest that the Kat1-antigen is a molecule that is distinct from receptor activator of NF-kappaB. The presence of the unique Kat1-antigen on cells in the osteoclast lineage appears to contribute to the fine regulation of osteoclastogenesis in vivo. Expression of this cell-surface molecule in cells in the osteoclast lineage may partly explain the mechanism responsible for the escape phenomenon.

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EA Smith, EP Frankenburg, SA Goldstein, K Koshizuka, E Elstner, J Said, T Kubota, M Uskokovic, and HP Koeffler

This study explores the effects of chronic administration of vitamin D(3) compounds on several biological functions in mice. Knowledge of long-term tolerability of vitamin D(3) analogs may be of interest in view of their potential clinical utility in the management of various pathologies such as malignancies, immunological disorders and bone diseases. Four unique vitamin D(3) analogs (code names, compounds V, EO, LH and LA) and 1,25-dihydroxyvitamin D(3) (1, 25(OH)(2)D(3)) were administered i.p. for 55 weeks to Balb/c mice. Each analog had previously been shown to have potent in vitro activities. After 55 weeks of administration, the mice had a profound decrease in their serum levels of interleukin-2 (IL-2). Likewise, several analogs depressed serum immunoglobulin G concentrations (compounds LH and LA), but levels of blood lymphocytes and splenic lymphocyte subsets (CD4, CD8 and CD19) were not remarkably depressed. The percent of committed myeloid hematopoietic stem cells was 4- to 5-fold elevated in the bone marrow of the mice that received analogs LH and V; nevertheless, their peripheral blood white and red cell counts and platelets were not significantly different in any of the groups. The mice that received 1,25(OH)(2)D(3) had a decrease in bone quantity and quality with a decrease in cross-sectional area and cortical thickness, and a 50% reduction in both stiffness and failure load compared with the control group. In contrast, the cohort that received a fluorinated analog (compound EO) developed bones with significantly larger cross-sectional area and cortical thickness as well as stronger mechanical properties compared with the control group. At the conclusion of the study, body weights were significantly decreased in all experimental mice. Their blood chemistries were normal. Extensive gross and microscopic autopsy analyses of the mice at the conclusion of the study were normal, including those of their kidneys. In conclusion, the vitamin D(3) analogs were fairly well tolerated. They did suppress immunity as measured by serum IL-2 and may provide a means to depress the immune response after organ transplantation and for autoimmune diseases. Use of these analogs prevented the detrimental effects of vitamin D(3) administration on mechanical and geometric properties of bone, while one analog (compound EO) actually enhanced bone properties. These results suggest that long-term clinical trials with the analogs are feasible.

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M Jevon, A Sabokbar, Y Fujikawa, T Hirayama, SD Neale, J Wass, and NA Athanasou

A number of bone diseases characterised by excessive osteolysis (e.g. osteoporosis and Paget's disease) exhibit a marked gender difference in prevalence and are more common in the elderly population. Bone resorption is carried out by osteoclasts, which are formed by fusion of circulating mononuclear precursor cells of haematopoietic origin. In this study, we have determined whether there are gender- and age-related differences in osteoclast formation from circulating precursors. Peripheral blood mononuclear cells (PBMCs) were co-cultured with UMR106 osteoblast-like cells in the presence of macrophage-colony stimulating factor (M-CSF) and 1,25 dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) or cultured alone in the presence of sRANKL (soluble receptor activator of nuclear factor kappa B ligand) and M-CSF. As assessed by the formation of tartrate resistant acid phosphatase (TRAP)-positive (TRAP(+)) and vitronectin receptor-positive (VNR(+)) multinucleated cells (MNCs), there was no difference in the number of circulating osteoclast precursors in males and females. Lacunar resorption carried out by osteoclasts formed from these precursors was generally increased in males compared with females (P=0.03). An increase in the number of TRAP(+) and VNR(+) MNCs formed from male PBMCs was noted in response to 1,25(OH)(2)D(3) (P<0.005). An increase in lacunar resorption in cultures of PBMCs (10(5) per well) from males was also noted in response to 10(-9) M 1,25(OH)(2)D(3) (P<0.05) and sRANKL (P=0.05), but not M-CSF. The addition of dexamethasone resulted in a marked increase in osteoclast formation and lacunar resorption in both males and females. Post-menopausal females and males of comparable age showed similar levels of osteoclastogenesis. Pre-menopausal women showed similar levels of osteoclastogenesis but less resorption (P=0.01) compared with males of comparable age. These results show that there are specific gender/age-related differences in osteoclast formation and bone resorption and have implications for evaluating osteoclastogenesis in skeletal diseases such as primary osteoporosis and Paget's disease.

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Karla J Suchacki, Fiona Roberts, Andrea Lovdel, Colin Farquharson, Nik M Morton, Vicky E MacRae, and William P Cawthorn

adipose tissue. It is interesting to highlight that both calorie restriction and glucocorticoids result in the loss of adipose tissue, muscle and bone (discussed further in the text). Multiple myeloma and myeloma bone disease In the instance

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R Hardy and M S Cooper

how these are, and might be, manipulated as therapies for inflammation related bone loss. Relationship between inflammation and bone disease A relationship between inflammation and bone disease has been established in a variety of clinical settings and