epidermal-growth-factor and Osteoporosis

LRP5, along with LRP6 and their Drosophila homolog, Arrow, constitute a novel subclass of the LDL receptor superfamily. The arrangement of structural motifs in these receptors is different from the other members of the superfamily, and only recently have we begun to understand the functional importance of human LRP5 (and LRP6). Whole genome positional cloning studies have identified a number of mutations in LRP5 that underlie inherited human diseases/phenotypes, particularly those involving the skeleton and the eye. A number of studies have illustrated the importance of Lrp5/6/Arrow as a co-receptor with Frizzled for the Wnt proteins and their critical role in the regulation of the Wnt/beta-catenin signaling pathway. The cataloging of these human mutations, in combination with engineered mutations in mice and other studies involving gene/protein modifications, has led to a better understanding of the function of the various domains in LRP5/6. In this review, we discuss a number of studies that have revealed a wide variety of protein-protein interactions that occur with the various structural motifs in the Lrp5 protein. Ultimately, these interactions regulate the activity of the Wnt/beta-catenin signaling pathway and the role it plays in processes such as bone mass accrual and vision.

Topics: Amino Acid Sequence; Animals; Bone Density; Drosophila Proteins; Epidermal Growth Factor; Humans; LDL-Receptor Related Proteins; Low Density Lipoprotein Receptor-Related Protein-5; Low Density Lipoprotein Receptor-Related Protein-6; Mice; Mutation; Osteoporosis; Protein Sorting Signals; Protein Structure, Tertiary; Receptors, Cell Surface; Receptors, LDL; Repetitive Sequences, Amino Acid

Topics: Animals; Arthritis, Rheumatoid; Bone Development; Bone Resorption; Epidermal Growth Factor; Hormones; Humans; Interleukin-1; Lymphotoxin-alpha; Osteoblasts; Osteoclasts; Osteoporosis; Peptides; Periodontal Diseases; Transforming Growth Factors; Tumor Necrosis Factor-alpha

We have recently shown that human recombinant BMP-6 (rhBMP-6), given systematically, can restore bone in animal models of osteoporosis. To further elucidate the underlying mechanisms of new bone formation following systemic application of BMPs, we conducted gene expression profiling experiments using bone samples of oophrectomised mice treated with BMP-6. Gene set enrichment analysis revealed enrichment of insulin-like growth factor-I and epidermal growth factor related pathways in animals treated with BMP-6. Significant upregulation of IGF-I and EGF expression in bones of BMP-6 treated mice was confirmed by quantitative PCR. To develop an in vitro model for evaluation of the effects of BMP-6 on cells of human origin, we cultured primary human osteoblasts. Treatment with rhBMP-6 accelerated cell differentiation as indicated by the formation of mineralised nodules by day 18 of culture versus 28-30 days in vehicle treated cultures. In addition, alkaline phosphatase gene expression and activity were dramatically increased upon BMP-6 treatment. Expression of IGF-I and EGF was upregulated in human osteoblast cells treated with BMP-6. These results collectively indicate that BMP-6 exerts its osteoinductive effect, at least in part, through IGF-I and EGF pathways, which can be observed both in a murine model of osteopenia and in human osteoblasts.

Topics: Alkaline Phosphatase; Animals; Bone Morphogenetic Protein 6; Bone Morphogenetic Proteins; Cell Differentiation; Cells, Cultured; Disease Models, Animal; Epidermal Growth Factor; Female; Humans; Insulin-Like Growth Factor I; Mice; Mice, Inbred Strains; Osteoblasts; Osteogenesis; Osteoporosis; Ovariectomy; Signal Transduction

Osteoporosis pseudoglioma syndrome (OPPG) is an autosomal recessive disorder due to mutations in the low-density lipoprotein receptor-related protein 5 (LRP5) gene. Here, we report two novel missense mutations found in a southern Chinese family of a non-consanguineous marriage. Three out of four children had blindness, low bone mineral density (BMD) and multiple fractures in their childhood. Genotyping by DNA sequencing demonstrated 2 new mutations in exon 7 of the LRP5 gene. Tryptophans at amino acid residue positions 478 and 504 were replaced by arginine (W478R) and cysteine (W504C), respectively. While the parents that possessed either heterozygous W478R or W504C were apparently normal, all affected subjects were compound heterozygotes for the W478R and W504C mutations in the LRP5 gene. W478R is located immediately C-terminal to the third YWTD repeat of the second YWTD/EGF domain in LRP5, while W504C is located between the third and the fourth YWTD repeats of the second YWTD/EGF domain in LRP5. Using LRP5-related proteins, such as the low-density lipoprotein receptor (LDLR) and nidogen as reference models, a homology model of LRP5 suggested that the observed mutations may affect the molecular interactions of LRP5 and so lead to the observed OPPG phenotypes.

Topics: Adolescent; Base Sequence; Child; Epidermal Growth Factor; Exons; Female; Glioma; Heterozygote; Humans; Introns; LDL-Receptor Related Proteins; Low Density Lipoprotein Receptor-Related Protein-5; Male; Middle Aged; Models, Molecular; Mutation; Osteoporosis; Pedigree; Polymorphism, Genetic; Protein Structure, Quaternary; Syndrome