Basic osteoblast growth factor II (bOGF-II)

Details Basic osteoblast growth factor II (bOGF-II) Basic osteoblast growth factor II (bOGF-II)

1996-02-26

2000-04-04

Kemmerer, Elizabeth C.

Chemistry: molecular biology and microbiology

Micro-organism, tissue cell culture or enzyme using process...

Recombinant dna technique included in method of making a...

435 691, 4352523, 435325, 530300, 530324, 530350, 530397, 530399, 536 231, 536 235, 436501, C07K 1451, C07K 14475

Patent

active

060460334

DESCRIPTION:

BRIEF SUMMARY
RELATED APPLICATION

This application is a national stage application of International (PCT) Application JP95/01270 filed Jun. 26, 1995.


FIELD OF THE INVENTION

This invention relates to a novel protein, basic osteoblast growth factor II (bOGF-II) which stimulates osteoblast growth, and methods for producing the protein.


BACKGROUND ART

Human bones are always remodelling by the repeated process of resorption and reconstitution. In the process, osteoblasts and osteoclasts are considered to be the calls mainly in charge of bone formation and bone resorption, respectively. A typical example of disease caused by abnormal bone metabolism proceeded by the bone cells is osteoporosis. The disease is known to be provoked by the condition in which bone resorption by osteoclasts exceeds bone formation by osteoblasts, but the mechanism of osteoporosis has not yet been completely elucidated. Osteoporosis causes pain in the bone and makes the bone fragile, leading to fracture. Since osteoporosis increases the number of bedridden old people, it has become a social issue with the increasing number of old people. Therefore, efficacious drugs for the treatment of the disease are expected to be developed. Bone mass reduction caused by the abnormal bone metabolism is thought to be treated by inhibiting bone resorption, improving bone formation, or improving the balanced metabolism.
Bone formation is expected to be promoted by stimulating growth, differentiation, or activation of osteoblasts. Recently, cytokines which stimulates growth or differentiation of osteoblasts have been attracted public attention and have been intensively studied. Many cytokines are reported to stimulate the growth of osteoblasts, i.e. fibroblast growth factor (FGF) (Rodan S. B. at al., Endocrinology vol.121, p1917, 1987), insulin-like growth f actor-I (IGF-I) (Hock J. M. et al., Endocrinology vol. 122, p254, 1988), insulin-like growth factor-II (IGF-II) (McCarthy T. et al., Endocrinology vol.124, p301, 1989), and bone morphogenetic protein (BMP) (Sampath T.K. etl al., J. Biol Chem. vol.267, p20532, 1992, Knutsen R. et al., Biochem. Biophys. Res. Commun. vol.194, p1352, 1993, and Akira Yamaguchi et al., Zikken Igaku vol.10, p2003, 1992). Many cytokines are also reported to stimulate the differentiation of osteoblasts, i.e. transforming growth factor-s (TGF-P) (Centrella M. et al., J. Biol. Chem. vol.262, p2869, 1987), insulin-like growth factor (IGF), and bone morphogenetic protein (Takuwa :Y. et al., Biochem. Biophys. Res. Commun. vol.174, p96, 1991, and Knutsen R. et al., Biochem. Biophys. Res. Commun. vol.194, p1352, 1993). These cytokines are expected to be efficacious drugs for improving bone mass by stimulating bone formation; some of the cytokines such as bone morphogenetic proteins are now investigated in clinical trials for their effects to cure the patients with bone diseases.
Examples of drug products now clinically utilized for the treatment of bone diseases and for shortening the treatment period are dihydroxy vitamine D.sub.3, calcitonin and its derivatives, hormones such as estradiol, lprif lavon, and calcium preparations. However, these drug products do not provide satisfactory therapeutic effects, and novel drug substances have been expected to be developed. As mentioned, bone metabolism is controlled in the balance between bone resorption and bone formation. Therefore, cytokines which stimulate osteoblast growth and osteogenesis are expected to be developed as drug for the treatment of bone diseases such as osteoporosis.
The inventors have intensively searched for osteoblast growth factors, and have found a novel osteoblast growth factor. The inventors have also established methods for accumulating the protein in a high concentration and purifying it efficiently.
A cDNA clone encoding this protein was isolated by using the partial amino-acid sequences of the native bOGF-II protein. Moreover, bOGF-II was produced by the genetic engineering techniques with this cDNA. The object of the invention is to provide a novel osteoblast grow

REFERENCES:
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Bowie et al. Science 247:1306-1310, 1990.
Lewin. Science 237:1570, 1987.
Ngo et al. The Protein Folding Problem & Tertiary Structure Prediction, Merz et al, eds, Boston, 1994.
Wood et al. Mol. Endocrinol. 2:1176-1185, 1988.
Georges et al., pp. 127-149 in Macromolecular Sequencing and Synthesis: Selected Methods and Applications, ed. D. H. Schlesinger, Alan R. Liss, Inc., NY, 1988.

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