Chemistry: molecular biology and microbiology – Apparatus – Including measuring or testing
Patent
1995-07-12
1998-12-15
Beisner, William H.
Chemistry: molecular biology and microbiology
Apparatus
Including measuring or testing
4352884, 4353051, 4353052, 4353054, 427 211, 427 227, 359396, 359398, C12M 304
Patent
active
058495690
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
This invention relates to the assessment of bone cell activity, such as osteoclast activity, which is useful in the analysis of normal bone cell processes, the determination of various metabolic bone diseases, such as osteoporosis in humans, and the evaluation of potential drug treatments to influence bone cell activity.
BACKGROUND OF THE INVENTION
There are two types of bone cells, those which make bone, osteoblasts, and those which resorb bone, osteoclasts. These cells have very precise functions and the balance between their activities is critical to the maintenance of the skeletal system. For example, in human adults, between 10 to 15% of trabecular bone surfaces are covered with osteoid (new unmineralized bone made by osteoblasts) while about 4% have active resorptive surfaces. The dynamic nature of the continuing flux of bone cell activity is illustrated by the calculation that approximately 18% of total skeletal calcium may normally be removed and deposited over a period of one year.
Osteoclasts, which resorb bone are not only of central importance in modelling abnormalities such as osteoporosis which is characterized by hypofunction, and Paget's disease where increased bone resorptive activity is seen, but also in some of the major so called metabolic bone diseases. The term metabolic bone disease refers to skeletal disorders which are generalized throughout the skeleton and thus there are no normal areas of bone in the skeleton. In these disease processes, the normal function of bone cells is modified. To assess the degree of perturbation of cell behaviour and how this may be further modified by the action of pharmaceutical agents is of central importance to both an understanding of the disease processes and the functions of the cells themselves.
The activity of osteoclasts in vivo can only be measured with animal models, where the sequelae of the activities of these cells are assessed by histological means or biochemical measurements e.g. of serum calcium levels. Several research groups have developed methods to directly observe the activity of isolated osteoclasts in vitro. Considerable success has been achieved when osteoclasts, isolated from bone marrow cell populations have been cultured on thin slices of either sperm whale dentine (Boyde et al Brit. Dent. J. 156, 216, 1984) or bone (Chambers et al J. Cell Sci. 66, 383, 1984). The latter group have been able to show that this resorptive activity is not possessed by other cells of the mononuclear phagocyte series (Chambers & Horton, Calcif Tissue Int. 36, 556, 1984). More recently, attempts to use other cell culture techniques, to study osteoclast lineage have still had to rely on the use of cortical bone slices (Amano et al. and Kerby et al J. Bone & Min. Res. 7(3), pp. 321-328 and 353-362, respectively) and it is increasingly obvious that quantitation of the resorption activity relies upon either two dimensional analysis of resorption pits of variable depth or stereo mapping of the resorption volume. Such techniques can usually provide an accuracy in result of about 40 to 60%. The latter provides far greater accuracy perhaps up to 70%, when assessing resorption of relatively thick substrata but is very time consuming and requires highly specialized equipment and training, and thus does not provide a potentially easy approach to this problem.
Furthermore, the preparation and subsequent examination of bone or dentine slices is neither an easy nor practical solution for the assessment of osteoclast activity. Specifically, these substrata cannot be proposed for routine use outside the highly specialized research laboratory environment. However, the use of artificial calcium phosphate preparations as substrata for osteoclast culture, has met with little success. Jones et al (Anat. Embryol 170, 247, 1984) reported that osteoclasts will resorb synthetic apatites in vitro but failed to provide experimental evidence and more recently Shimizu et al (Bone and Mineral 6, 261, 1989) have reported that isolated osteoclasts will
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Beisner William H.
Millenium Biologix Inc.
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