The low-density-lipoprotein receptor-related protein 5 (LRP5), a coreceptor in the canonical
May 10, 2019
The low-density-lipoprotein receptor-related protein 5 (LRP5), a coreceptor in the canonical Wnt signaling pathway, has been implicated in human disorders of low and high bone mass. Low-density-lipoprotein receptor-related protein 5 (LRP5) is usually a single-pass transmembrane protein that belongs to the low-density-lipoprotein receptor superfamily. One function of LRP5 is usually to serve as a coreceptor in the canonical Wnt signaling cascade (8). Several in vitro observations support this function. For example, LRP5 transduced Wnt transmission in cultured cells, and decoy forms of LRP5 could interfere with Wnt signaling (7). Additionally, yeast KRN 633 distributor two-hybrid experiments recognized Axin, a cytoplasmic component of the canonical signaling cascade, as being an LRP5-interacting partner (24). In vivo support for a role in Wnt signaling comes from studies of in which LRP5 was shown to synergize with Wnt to induce secondary axis formation (29). Furthermore, two closely related homologs of LRP5, arrow in and LRP6 in vertebrates, have also been shown to transduce Wnt transmission (29, 33), and genetic conversation between LRP5 and LRP6, with respect to limb patterning, in mice has been observed (9, 18). For humans, two disorders affecting bone mass have already been connected with mutations in LRP5. Loss-of-function mutations trigger the autosomal recessive osteoporosis-pseudoglioma symptoms (OPPG) (7). People with this disease possess skeletal fragility, because of low bone tissue mass, and blindness, because of impaired bloodstream vessel regression. The next skeletal phenotype connected with LRP5 mutation is certainly autosomal prominent high bone tissue mass (HBM), which is certainly due to heterozygous missense mutations (Fig. ?(Fig.1)1) KRN 633 distributor (4, 21, 32). Individuals in households segregating HBM can form complications connected with extreme bone formation, such as for example cranial nerve compression and serious headache (34); nevertheless, they possess reduced dangers of skeletal fracture markedly. OPPG and HBM phenotypes have already been suggested to derive from changed Wnt signaling (16). Skeletal KRN 633 distributor phenotypes have already been noted when various other Wnt signaling elements have already been altered KRN 633 distributor also. Disruption of secreted Frizzled-related proteins 1, a secreted Wnt antagonist, causes high bone tissue mass in mice (3). Elevated creation of DKK1, a canonical Wnt signaling inhibitor, by myeloma cells provides been proven to correlate with bone lesions in patients with multiple myeloma (30). Tissue-specific deletion of -catenin in skeletal precursor cells in developing mice prospects to complete failure of osteoblast differentiation (12). Transgenic mice that overexpress Wnt10b in bone marrow mesenchymal progenitor cells have significantly increased bone KRN 633 distributor mass, while Wnt10b null mice exhibit decreased bone mass (2). Alterations in bone TSPAN14 mass have also been observed in mice with osteoblast-specific deletions of -catenin or Apc, with the former having low bone mass and the latter increased bone mass (10a). Additionally, reduced bone mass in mice having osteoblast-specific overexpression of Dkk-1 has been reported in abstract form (20a). Finally, introduction of a single Lrp6 null allele onto a Lrp5 knockout background further reduced bone mineral density in mice (9), suggesting that Lrp5 and Lrp6 have partially overlapping functions in determining bone mass. Open in a separate windows FIG. 1. Schematic of LRP5 expression constructs and sites of HBM-associated missense mutations. (A) WT and high bone mass-associated mutant LRP5 protein expression constructs. Each construct contained either a WT sequence or a single HBM-associated mutation. Specific amino acid mutations (in single-letter code) and their relative locations within the first EGF-like domain name of LRP5 are noted. Constructs were full-length, untagged LRP5, full-length LRP5 that was tagged at the carboxy terminus with a myc-epitope (LRP5-myc), truncated LRP5 protein lacking the transmembrane and cytoplasmic domains but tagged at the carboxy terminus with a myc-epitope (LRP5N-myc). (B) Locations of the HBM mutations modeled around the three-dimensional structure of the EGF-like domain name of the low-density-lipoprotein receptor (14) by using the RasMol molecular graphics visualization tool (version 2.6, September 1996 update [http://www.umass.edu/microbio/rasmol/getras.htm]; R. Sayle, Stevanage, United Kingdom). Note that all mutations affect residues near the top surface (side view) and central region (top view) of the -propeller structure within the EGF-like domain name. The types.