A non-synonymous SNP in the LRP5 gene was associated with decreased bone mineral density (rs3736228, p=6.3x10(-12) for lumbar spine and p=1.9x10(-4) for femoral neck) and an increased risk of both osteoporotic fractures (odds ratio [OR] 1.3, 95% CI 1.09-1.52, p=0.002) and osteoporosis (OR 1.3, 1.08-1.63, p=0.008).
Association of a single-nucleotide variation (A1330V) in the low-density lipoprotein receptor-related protein 5 gene (LRP5) with bone mineral density in adult Japanese women.
As loss-of-function mutations in the SOST gene are associated with Sclerosteosis, another disorder of excessive bone growth, our study suggests that the SOST-LRP5 antagonistic interaction plays a central role in bone mass regulation and may represent a nodal point for therapeutic intervention for osteoporosis and other bone diseases.
As loss-of-function mutations in the SOST gene are associated with Sclerosteosis, another disorder of excessive bone growth, our study suggests that the SOST-LRP5 antagonistic interaction plays a central role in bone mass regulation and may represent a nodal point for therapeutic intervention for osteoporosis and other bone diseases.
In this article, we present the extensive genetic and functional data indicating that the LRP5 gene and the Wnt signalling pathway are key players in bone formation and the risk of osteoporosis, and that LRP5 signalling is essential for normal morphology, developmental processes and bone health.
In humans, loss of LRP5 function causes osteoporosis-pseudoglioma syndrome, which is characterized by congenital blindness and extremely severe childhood-onset osteoporosis (lumbar spine Z-score often < -4) with fractures.
Genome-wide mapping efforts have identified the low-density lipoprotein receptor-related protein 5, bone morphogenetic protein 2, and 15-lipoxygenase as potential susceptibility genes for osteoporosis in the past few years, providing a rich new base for understanding bone biology.
The importance of LDL receptor-related protein 5 (LRP5) for the regulation of bone mass has recently been established, where loss of function mutations is followed by severe osteoporosis and gain of function is related to increased bone mass.
Understanding how complex interactions between agonistic and inhibitory factors in the Wnt-LRP5 canonical pathway influence osteoblast functions has the potential of providing new anabolic treatments for osteoporosis.
Here we analyzed COL1A1, COL1A2, and LRP5 for mutations in 20 pediatric patients with primary osteoporosis characterized by low BMD, recurrent fractures, and absent extraskeletal manifestations.
Mutations in the LRP5 gene on chromosome 11q12-13 have been associated with rare syndromes characterized by extremely low or high BMD, but little is known about the contribution of this gene to the development of osteoporosis and determination of BMD in a normal population.
The risk of osteoporosis in the VDR-rs2228570 polymorphism T-allele carriers was significantly higher than that in CC (CT/TT versus CC) individuals (adjusted odds ratio [OR] [95% confidence interval (CI)] = 1.76 [1.33-2.22]).
Human genetic evidence demonstrates that WNT1 mutations cause osteogenesis imperfecta (OI) and early-onset osteoporosis, implicating WNT1 as a major regulator of bone metabolism.