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.
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.
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