Transgenic animal model of bone mass modulation

a bone mass and transgenic technology, applied in the field of gene expression, genomics and molecular biology, can solve the problems of increasing bone resorption and formation, increasing the risk of aging, and net loss of bone mass, and achieve the effect of accelerating the sequencing of the autosomal dominant gen

Inactive Publication Date: 2009-01-22
WYETH LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0019]The present invention describes the identification of the LRP5 gene and the HBM allele of the LRP5 gene on chromosome 11q13.3 by genetic linkage and mutation analysis. The LRP5 gene and the LRP5 protein which it encodes have previously been referred to as Zmax1 and Zmax1 (also Zmax) by the inventors and coworkers. The gene and its product have also been referred to by others using the designation LR3. It is understood that Zmax, Zmax1, LRP5, and LR3 are synonymous terms. The use of genetic markers linked to the genes...

Problems solved by technology

Osteoporosis affects men as well as women, and, taken with other abnormalities of bone, presents an ever-increasing health risk for an aging population.
This rapid loss is generally associated with an increase of bone resorption and formation.
However, the resorptive cycle is more dominant and the result is a net loss of bone mass.
The results of osteoporosis are both personally harmful, and also account for a large economic loss due to its chronicity and the need for extensive and long-term support hospitalization and nursing home care) from the disease sequelae.
Although this therapy frequently is successful, patient compliance is low, primarily due to the undesirable side-effects of chronic estrogen treatment.
This protocol is similar to that which is used in birth control regimens, and often is not tolerated by women because of the side-effects characteristic of progestin.
The use of calcitonin has been somewhat limited, however.
Its effects are very modest in increasing bone mineral density and the treatment is very expensive.
Senile osteoporosis is similar to postmenopausal osteoporosis in that it is marked by the loss of bone mineral density and resulting increase in fracture rate, morbidity, and associated mortality.
Treatment of this disease has not been very satisfactory.
These studies are difficult because bone mass (the phenotype) is a continuous, quantitative, polygenic trait...

Method used

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  • Transgenic animal model of bone mass modulation
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  • Transgenic animal model of bone mass modulation

Examples

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example 1

[0596]The propositus was referred by her physicians to the Creighton Osteoporosis Center for evaluation of what appeared to be unusually dense bones. She was 18 years old and came to medical attention two years previous because of back pain, which was precipitated by an auto accident in which the car in which she was riding as a passenger was struck from behind. Her only injury was soft tissue injury to her lower back that was manifested by pain and muscle tenderness. There was no evidence of fracture or subluxation on radiographs. The pain lasted for two years, although she was able to attend school full time. By the time she was seen in the Center, the pain was nearly resolved and she was back to her usual activities as a high school student. Physical exam revealed a normal healthy young woman standing 66 inches and weighing 128 pounds. Radiographs of the entire skeleton revealed dense looking bones with thick cortices. All bones of the skeleton were involved. Most importantly, th...

example 2

[0598]The present invention describes DNA sequences derived from two BAC clones from the HBM gene region, as evident in Table 8 below, which is an assembly of these clones. Clone b200e21-h (ATCC No. 98628; SEQ ID NOS: 10-11) was deposited at the American Type Culture Collection (ATCC), 10801 University Blvd., Manassas, Va. 20110-2209 U.S.A., on Dec. 30, 1997. Clone b527d12-h (ATCC No. 98907; SEQ ID NOS: 5-9) was deposited at the American Type Culture Collection (ATCC), 10801 University Blvd., Manassas, Va. 20110-2209 U.S.A., on Oct. 2, 1998. These sequences are unique reagents that can be used by one skilled in the art to identify DNA probes for the LRP5 gene, PCR primers to amplify the gene, nucleotide polymorphisms in the LRP5 gene, or regulatory elements of the LRP5 gene.

TABLE 8SEQ IDLengthContigATCC No.NO.(base pairs)b527d12-h_contig302G98072053096b527d12-h_contig306G980720626928b527d12-h_contig307G980720729430b527d12-h_contig308G980720833769b527d12-h_contig309G980720972049b200e...

example 3

Methods of Using Explant Cultures from HBM Overexpressing Transgenic and Non-Transgenic Mice

[0599]The use of transgenic animals of the invention for the identification of surrogate markers for the HBM phenotype and putative targets for bone mass modulation therapies and drugs by the methods of the invention and the identification and characterization of genes related to HBM through transcriptional profiling is demonstrated, for example, in calvaria and tibia explant cultures.

[0600]Calvaria and tibia were obtained from neonatal (12-day-old) mice, including transgenic mice expressing HBM under the bone specific type I collagen promoter (Line 19). Calvaria were pooled from 4 transgenic and 4 non-transgenic mice and digested with collegenase. The digests were plated in culture. Calvaria cultures were maintained with or without ascorbic acid and beta glycerol phosphate for 19 days. RNA was isolated at day 19.

[0601]Bone marrow stromal cells were flushed out of tibia and the tibias from in...

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Abstract

The present invention relates to methods and materials used to express the HBM protein in animal cells and transgenic animals. The present invention also relates to transgenic animals expressing the high bone mass gene, the corresponding wild-type gene, and mutants thereof. The invention provides nucleic acids, including coding sequences, oligonucleotide primers and probes, proteins, cloning vectors, expression vectors, transformed hosts, methods of developing pharmaceutical compositions, methods of identifying molecules involved in bone development, and methods of diagnosing and treating diseases involved in bone development. In preferred embodiments, the present invention is directed to methods for treating, diagnosing and preventing osteoporosis.

Description

[0001]This application claims priority to International Application No. PCT / US02 / 14876, filed May 13, 2002, and the benefit of Provisional Application Nos. 60 / 290,071 filed May 11, 2001; 60 / 291,311 filed May 17, 2001; 60 / 353,058 filed Feb. 1, 2002, and 60 / 361,293 filed Mar. 4, 2002, the disclosures of each are herein incorporated by reference in their entirety for all purposes.FIELD OF THE INVENTION[0002]The present invention relates generally to the field of genetics, genomics and molecular biology. The invention relates to methods and materials used to isolate, detect and sequence a high bone mass gene and corresponding wild-type gene, and mutants thereof. The present invention also relates to the high bone mass (HBM) gene, the corresponding wild-type gene, and mutants thereof. The genes identified in the present invention are implicated in the ontology and physiology of bone development. The invention also provides nucleic acids, proteins, cloning vectors, expression vectors, tra...

Claims

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Application Information

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IPC IPC(8): C07H21/04C07K14/51C12N15/85
CPCA01K67/0278A01K2207/15A01K2217/00A01K2217/075A01K2227/105C07K2317/34C07K14/51C07K16/2863C12N15/8509C12N2800/30A01K2267/03
Inventor ASKEW, G. ROGERBABIJ, PHILIPBEX, III, FREDERICK JAMESBODINE, PETER VAN NEST
Owner WYETH LLC
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