BONE
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2024
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IF 3.5
Xueting Wang,Hui Zhang,Ling Hu,Jin He,Qifeng Jiang,Lingfei Ren,Ke Yu,Mengdie Fu,Zhikun Li,Zhixu He,Junhao Zhu,Ying Wang,Zhiwei Jiang,Guoli Yang
Gain-of-function mutations in the low-density lipoprotein receptor-related protein 5 (LRP5) can cause high-bone-mass (HBM) phenotype, with 19 identified mutations so far. The A242T mutation in LRP5 has been found in 9 families, making it one of the most prevalent mutations. However, the correlation between the A242T mutation and HBM phenotype remains unverified in animal models. This study aimed to investigate the bone properties in a new transgenic mouse model carrying the LRP5 A241T missense mutation, equivalent to A242T in humans. Heterozygous Lrp5 A241T mice were generated using CRISPR/Cas9 genome editing. Body weight increased with age from 4 to 16 weeks, higher in males than females, with no difference between Lrp5 A241T mice and wild-type control. Micro-CT showed slightly longer femur and notably elevated trabecular bone mass of the femur and fifth lumbar spine with higher bone mineral density, bone volume fraction, and trabecular thickness in Lrp5 A241T mice compared to wild-type mice. Additionally, increased cortical bone thickness and volume of the femur shaft and skull were observed in Lrp5 A241T mice. Three-point bending tests of the tibia demonstrated enhanced bone strength properties in Lrp5 A241T mice. Histomorphometry confirmed that the A241T mutation increased bone formation without affecting osteoblast number and reduced resorption activities in vivo . In vitro experiments indicated that the LRP5 A241T mutation enhanced osteogenic capacity of osteoblasts with upregulation of the Wnt signaling pathway, with no significant impact on the resorptive activity of osteoclasts . In summary, mice carrying the LRP5 A241T mutation displayed high bone mass and quality due to enhanced bone formation and reduced bone resorption in vivo , potentially mediated by the augmented osteogenic potential of osteoblasts. Continued investigation into the regulatory mechanisms of its bone metabolism and homeostasis may contribute to the advancement of novel therapeutic strategies for bone disorders.
研究领域:
遗传学
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分子生物学
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骨生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ORAL DISEASES
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2025
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IF 2.9
Danhong Zhou,Xueting Wang,Hui Zhang,Qifeng Jiang,Qinmeng Zhang,Xiaoyan Miao,Ying Wang,Guoli Yang,Zhiwei Jiang
Objectives This study aimed to assess the effect of the low-density lipoprotein receptor-related protein 5 (Lrp5) A241T gain-of-function mutation, which induces a high-bone-mass phenotype, on implant osseointegration in a murine model. Methods Heterozygous Lrp5 A241T mutant ( Lrp5 A/+ ) and wild-type (WT) littermate male mice on a C57BL/6J background were used. Micro-computed tomography (micro-CT) was performed to assess tibial trabecular bone architecture. Sandblasted and acid-etched (SLA) titanium implants were surgically inserted into the proximal tibiae, and samples were harvested after 4 weeks for micro-CT and histological analysis. Primary osteoblasts were seeded onto SLA titanium sheets and induced for osteogenesis for 7 days. Osteogenic marker expression was assessed by quantitative real-time polymerase chain reaction and western blotting. Results The Lrp5 A/+ group exhibited significantly improved trabecular bone architecture compared to WT controls. At 4 weeks post-implantation, micro-CT revealed greater peri-implant bone formation in the Lrp5 A/+ group, while hard tissue sections showed increased bone area and bone-implant contact. HE and Masson staining further confirmed greater new bone formation. After 7 days of in vitro osteogenic induction, Lrp5, Runx2, and Sp7 were significantly upregulated in the Lrp5 A/+ group. Conclusions The Lrp5 A241T mutation significantly enhanced implant osseointegration in a transgenic murine model.
研究领域:
骨生物学
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分子骨病学
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生物材料学
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口腔种植学
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转化医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF CELLULAR PHYSIOLOGY
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2024
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IF 4.5
Zhiguang Chen,Qi Zhao,Lianghong Chen,Songlan Gao,Lingshuai Meng,Yingjie Liu,Yu Wang,Tiegang Li,Jinqi Xue
Osteogenic differentiation is important for fracture healing. Microfibrial-associated glycoprotein 2 (MAGP2) is found to function as a proangiogenic regulator in bone formation; however, its role in osteogenic differentiation during bone repair is not clear. Here, a mouse model of critical-sized femur fracture was constructed, and the adenovirus expressing MAGP2 was delivered into the fracture site. Mice with MAGP2 overexpression exhibited increased bone mineral density and bone volume fraction (BV/TV) at Day 14 postfracture. Within 7 days postfracture, overexpression of MAGP2 increased collagen I and II expression at the fracture callus, with increasing chondrogenesis. MAGP2 inhibited collagen II level but elevated collagen I by 14 days following fracture, accompanied by increased endochondral bone formation. In mouse osteoblast precursor MC3T3-E1 cells, MAGP2 treatment elevated the expression of osteoblastic factors (osterix, BGLAP and collagen I) and enhanced ALP activity and mineralization through activating β-catenin signaling after osteogenic induction. Besides, MAGP2 could interact with lipoprotein receptor-related protein 5 (LRP5) and upregulated its expression. Promotion of osteogenic differentiation and β-catenin activation mediated by MAGP2 was partially reversed by LRP5 knockdown. Interestingly, β-catenin/transcription factor 4 (TCF4) increased MAGP2 expression probably by binding to MAGP2 promoter. These findings suggest that MAGP2 may interact with β-catenin/TCF4 to enhance β-catenin/TCF4's function and activate LRP5-activated β-catenin signaling pathway, thus promoting osteogenic differentiation for fracture repair. mRNA sequencing identified the potential targets of MAGP2, providing novel insights into MAGP2 function and the directions for future research.
研究领域:
骨骼生物学
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骨科
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分子生物学
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细胞生物学
✓ 已验证
DOI
PubMed
高影响因子
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