Relationship between LRP5 gene single nucleotide polymorphism and glucocorticoid-induced osteoporosis in children / 中华内分泌外科杂志

Objective:To investigate the relationship between the polymorphisms of two SNP loci (rs901823 and rs3736228) in the low density lipoprotein receptor-associated protein 5 (LRP5) gene and glucocorticoids-induced osteoporosis (GIOP) in children.Methods:87 children with GIOP who were treated in Beijing Aiyuhua Women’s and Children’s Hospital and Beijing Children’s Hospital affiliated to Capital Medical University from Jan. 2015 to Dec. 2020 were selected as the research objects, and 100 children with normal bone mass who were treated with corticosteroids in this hospital during the same period were enrolled as the control group. Capillary electrophoresis and fragment analysis (SNaPshot) technology were used to genotype SNP sites rs901823 (T>C) and rs3736228 (C>T) ; Quantitative real-time fluorescence quantitative polymerase chain reaction detection method was employed to determine the relative mRNA of LPR5 gene The amount of expression.Results:For the rs901823 locus of the LRP5 gene, the TT, TC, and CC genotype distribution differences between the GIOP group and the control group were statistically significant ( χ2=14.176, P=0.001) . Compared with the TT genotype, carriers of the TC and CC genotypes had a higher risk of GIOP, with OR values of 3.022 (1.189-6.387) and 5.483 (1.452-20.883) ; For academic significance, OR values were 3.412 (1.795-6.587) and 4.352 (1.215-15.982) . For the rs3736228 locus, the distribution of CC, CT, TT genotypes between the GIOP group and the control group was significantly different ( χ2=9.597, P=0.008) . Compared with CC carriers, CT genotype carriers had a significantly increased risk of GIOP, with an OR value of 5.125 (1.721-16.241) . The result of a dominant model was statistically significant, with an OR value of 4.165 (1.335-14.652) , while for TT there was no statistically significant difference between the carrier and the CC genotype ( P=0.512) , and the results of the recessive model also showed no significant statistical significance ( P=0.887) . There was a statistically significant difference in the frequency distribution of T and C alleles at rs901823 between the GIOP group and the control group ( χ2=17.298, P<0.001) , and the difference in the frequency distribution of C and T alleles at rs3736228 was also statistically significant ( χ2=9.356, P=0.002) . The relative expression level of LRP5 gene mRNA in children with GIOP was 1.34±0.26, which was significantly lower than the expression level of LRP5 gene mRNA in children in the control group of 3.06±0.42 ( t=8.248, P<0.001) . Among children with GIOP, the relative expression of LRP5 gene mRNA in patients with rs901823 locus TT, TC, and CC genotypes was statistically significant ( P<0.001) ; the differences in rs901823 locus CC, CT, TT genotype patients were significant. Pairwise comparison of the relative expression of LRP5 gene mRNA showed that there was no significant difference between the TT group and the CT group ( P>0.05) , but the expression of the CC group was significantly higher than that of the CT group and the TT group ( P<0.05) . Conclusion:The rs901823 and rs3736228 polymorphisms of LRP5 gene are correlated with the occurrence of GIOP and can be used as genetic markers for predicting GIOP in children.

Effect of Zuoguiwan on Wnt/β-catenin Signaling Pathway in Ovariectomized Osteoporosis Model Rats / 中国实验方剂学杂志

Objective:To observe the effect of Zuoguiwan on bone metabolism and Wnt/<italic>β</italic>-catenin signaling pathway in ovariectomized osteoporotic rats model， and to explore the molecular biological mechanism of Zuoguiwan in the prevention and treatment of osteoporosis. Method:The rat model of postmenopausal osteoporosis was established by bilateral ovariectomy， 60 female SD rats were randomly divided into sham operation group， model group， positive group （estradiol valerate tablet 0.05 mg·kg^-1·d^-1） and low， middle and high dose groups of Zuoguiwan （5.5，11，22 g·kg^-1·d^-1）.After successful establishment of the model in the 13^th week， intragastric administration （<italic>ig</italic>） was given once a day for a total of 12 weeks. After administration， the histomorphological changes of femur in rats were observed by hematoxylin-eosin （HE） staining， the bone mineral density （BMD） and bone mineral content（BMC） of femur were measured by dual energy X-ray apparatus， and the biomechanical properties of bone were measured by MTS Acumen3 biomechanical testing system. The contents of bone alkaline phosphatase （BALP）， bone glaprotein（BGP），estradiol （E₂） ，and tartrate-resistant acid phosphatase （TRAP）， type Ⅰ procollagen N-terminal propeptide （PINP） in serum were detected by enzyme-linked immunosorbent assay （ELISA）. Western blot was used to detect the protein level of Wnt2，<italic>β</italic>-catenin，low density lipoprotein related receptor protein 5 （LRP5） and the phosphorylation level of glycogen synthase kinase-3<italic>β</italic>（GSK-3<italic>β</italic>） in rat tibia. Result:Compared with sham operation group， the maximum load and stiffness of BMD，BMC， in the model group decreased significantly（<italic>P</italic><0.01）， the contents of E₂ and PINP in serum decreased significantly（<italic>P</italic><0.01）， the content of BALP，BGP，TRAP increased significantly（<italic>P</italic><0.01）， the expression levels of Wnt2，p-GSK-3<italic>β </italic>Ser9，LRP5 and <italic>β</italic>-catenin protein in bone tissue decreased significantly（<italic>P</italic><0.01）， the trabecula of femur became thinner and thinner， the number of bone trabeculae decreased. Compared with model group， the maximum load and stiffness of BMD，BMC， in estradiol group and Zuoguiwan group were significantly increased （<italic>P</italic><0.05，<italic>P</italic><0.01）， the contents of serum E₂ and PINP were significantly increased （<italic>P</italic><0.05，<italic>P</italic><0.01）， the content of BALP，BGP，TRAP was significantly decreased （<italic>P</italic><0.01）， and the expression level of Wnt2，p-GSK-3<italic>β</italic> Ser9，LRP5， <italic>β</italic>-catenin protein in bone tissue was significantly increased （<italic>P</italic><0.05，<italic>P</italic><0.01） ， the trabeculae of femur became thicker， the number increased， the structure was basically clear. Conclusion:Zuoguiwan has a certain preventive and therapeutic effect on osteoporosis in ovariectomized rats， and its mechanism may be related to increasing the level of estrogen， activating Wnt/<italic>β</italic>-catenin signaling pathway， up-regulating the expression of Wnt2 and LRP5 protein， inhibiting the activity of GSK-3<italic>β</italic>， reducing the degradation of <italic>β</italic>-catenin， coordinating the dynamic coupling balance between bone formation and bone resorption， correcting the disorder of bone metabolism and improving bone morphology.

The low-density lipoprotein receptor-related protein 5 (LRP5) 4037C>T polymorphism: candidate for susceptibility to type 1 diabetes mellitus

ABSTRACT Objective: The present study has investigated the association between low-density lipoprotein receptor-related protein 5 (LRP5) 4037C>T polymorphism and type 1 diabetes mellitus (T1DM) susceptibility in a Brazilian population. Subjects and methods: A total number of 134 T1DM patients and 180 normoglycemic individuals (NG) aged 6-20 years were studied. Glycated hemoglobin and glucose levels were determined. Genotyping of LRP5 4037C>T (rs3736228) was performed. Results: T1DM patients showed poor glycemic control. Genotypes in the codominant (CT: OR = 2.99 [CI 95%: 1.71-5.24], p < 0.001; TT: OR = 5.34 [CI 95%: 1.05-2702], p < 0.001), dominant (CT + TT: OR = 3.16 [CI 95%: 1.84-5.43], p < 0.001) and log-additive (OR = 2.78 [CI 95%: 1.70-4.52], p < 0.001) models, and LRP5 4037T allele (OR = 2.88, [CI 95%: 1.78-4.77], p < 0.001) were associated with an increased risk of developing T1DM. LRP5 4037CT and CT+TT carriers in T1DM group showed higher concentrations of serum glucose and glycated hemoglobin when compared with CC carriers. Conclusion: The LRP5 4037C>T may represent a candidate for T1DM susceptibility, as well as poor glycemic control.

New Avenues in the LRP5-mediated Bone Mass Acquisition

Lipoprotein receptor-related protein (LRP5) signaling is well correlated with the bone mass in both human and mice. Loss-of-function mutations of LRP5 result in osteopenia or osteoporosis. In contrast, gain-of-function mutations show high bone mass phenotype. To elucidate the molecular mechanism of the LRP5-mediated bone mass acquisition, several groups have genetically dissected the Wingless and Int-1 (Wnt)beta-catenin signaling pathway using osteoblast-lineage specific Cre mice. Key players for LRP5-mediated bone mass acquisition turn out to be different molecules with respect to the expressing tissue and action mode of these molecules. One is serotonin, a tryptophan metabolite that originates from duodenum, which acts as a negative regulator for bone formation. LRP5 suppresses serotonin biosynthesis by inhibiting the expression of tryptophan hydroxylase 1 in the gut. The other is sclerostin, an osteocyte-producing antagonist for LRP5 signaling. Here is a summary of recent findings about these two molecules, providing a chance to speculate new avenues in the LRP5-mediated bone mass acquisition.

New Avenues in the LRP5-mediated Bone Mass Acquisition

Lipoprotein receptor-related protein (LRP5) signaling is well correlated with the bone mass in both human and mice. Loss-of-function mutations of LRP5 result in osteopenia or osteoporosis. In contrast, gain-of-function mutations show high bone mass phenotype. To elucidate the molecular mechanism of the LRP5-mediated bone mass acquisition, several groups have genetically dissected the Wingless and Int-1 (Wnt)beta-catenin signaling pathway using osteoblast-lineage specific Cre mice. Key players for LRP5-mediated bone mass acquisition turn out to be different molecules with respect to the expressing tissue and action mode of these molecules. One is serotonin, a tryptophan metabolite that originates from duodenum, which acts as a negative regulator for bone formation. LRP5 suppresses serotonin biosynthesis by inhibiting the expression of tryptophan hydroxylase 1 in the gut. The other is sclerostin, an osteocyte-producing antagonist for LRP5 signaling. Here is a summary of recent findings about these two molecules, providing a chance to speculate new avenues in the LRP5-mediated bone mass acquisition.

Association of LRP5 gene polymorphisms with bone mineral density and bone responsiveness to hormone therapy in postmenopausal Korean women / 대한산부인과학회지

OBJECTIVE: To evaluate the association of LRP5 gene polymorphisms with bone mineral density (BMD) and bone responsiveness to hormone therapy (HT) in postmenopausal women. DESIGN AND METHODS: The LRP5 gene polymorphisms were analyzed by restriction fragment length polymorphism (RFLP) in 229 postmenopausal women receiving HT for 1 year. The BMD before HT was check using dual-energy x-ray absorptiometer (DEXA) at lumar spine, femur neck, Ward's triangle, and greater trochanter of femur, and women in the study were classificed into 3 group, normal, osteopenia and osteroporosis according to their BMD. RESULTS: The frequency of genotype C/C of C1677A was significanty high in osteoporosis group, and that of C/A was much low in osteoporosis group. The frequency of genotype T/C of T2268C was high in osteoporosis group, while that of C/C was low in the same group. There was no significant relationship between LRP5 polymorphisms and BMD before HT. In patients whose genotype was A/A of C3405G, C/C of T2268C, or C/C of T4037C had meaningful responsiveness to HT at the lumbar spine, regardless of their initial BMD. The Genotype C/A of C1677A also had great responsiveness to HT at the greater trochanter of femur in both osteopenia and osteoporis group. CONCLUSION: The LRP5 gene polymorphisms were not associated with the BMD before HT, but there were some reponsiveness to HT at specific site according to genotypes of the gene.