LRP receptor family member associated bone disease

Abstract

A dozen years ago the identification of causal mutations in the low-density lipoprotein receptor-related protein 5 (LRP5) gene involved in two rare bone disorders propelled research in the bone field in totally new directions. Since then, there have been an explosion in the number of reports that highlight the role of the Wnt/β-catenin pathway in the regulation of bone homeostasis. In this review we discuss some of the most recent reports (in the past 2 years) highlighting the involvement of the members of the LRP family (LRP5, LRP6, LRP4, and more recently LRP8) in the maintenance of bone and their implications in bone diseases. These reports include records of new single nucleotides polymorphisms (SNPs) and haplotypes that suggest variants in these genes can contribute to subtle variation in bone traits to mutations that give rise to extreme bone phenotypes. All of these serve to further support and reinforce the importance of this tightly regulated pathway in bone. Furthermore, we discuss provocative reports suggesting novel approaches through inhibitors of this pathway to treat rarer diseases such as Osteoporosis-Pseudoglioma Syndrome (OPPG), Osteogenesis Imperfecta (OI), and Sclerosteosis/Van Buchem disease. It is hoped that by understanding the role of each component of the pathway and their involvement in bone diseases that this knowledge will allow us to develop new, more effective therapeutic approaches for more common diseases such as post-menopausal osteoporosis, osteoarthritis, and rheumatoid arthritis as well as these rarer bone diseases.

Multifarious effects of 17-β-estradiol on apolipoprotein E receptors gene expression during osteoblast differentiation <i>in vitro </i>

“…A number of reports were exploded to highlight the role of the Wnt/β-catenin pathway in the regulation of bone homeostasis (57)(58)(59). Recently, the most highlighted members of the LDLR family involved in the maintenance of bone metabolism were LRP5, LRP6, LRP4, and Apoer2 (26,60). Interestingly, results in the current study showed that all of these four members were induced during osteoblast differentiation (Figure 1).…”

Osteogenesis imperfecta

“…4b). Homozygous or biallelic LRP5 loss of function mutations cause osteoporosis pseudoglioma syndrome [103][104][105] , whereas heterozygous gain of function mutations cause van Buchem disease type 2 (or endosteal hyperostosis) 106 . Wnt1 −/− mice are embryonically lethal and have severe brain abnormalities but no reported skeletal phenotype, whereas the Swaying mouse (which is homozygous for a single nucleotide deletion in Wnt1 in exon 3) survives post natally, has severe osteopenia and a cerebellar defect, similar to some human WNT1 mutations 99,107 .…”

Genetics of pediatric bone strength

“…48 Similarly, loss of function mutations in LRP5, which encodes a transmembrane WNT co-receptor that synergistically binds WNT along with the frizzled receptor, disrupt normal signaling and lead to low-bone mass (osteoporosis-pseudoglioma syndrome), whereas gain of function mutations result in high bone mass. In addition, other members of the LRP family are involved in the maintenance of bone, 49 and a variant B84 kb upstream of LRP3 has been associated with pediatric bone mass during the mid-to-late stages of puberty. 41 RANK, a member of the tumor necrosis factor receptor subfamily, is found on the surface of osteoclasts and together with its ligand RANKL regulates the formation, activation and survival of osteoclasts during normal bone modeling and remodeling.…”