title: Mice with a heterozygous Lrp6 deletion have impaired fracture healing.
abstract: Bone fracture non-unions, the failure of a fracture to heal, occur in 10%-20% of fractures and are a costly and debilitating clinical problem. The Wnt/β-catenin pathway is critical in bone development and fracture healing. Polymorphisms of linking low-density lipoprotein receptor-related protein 6 (LRP6), a Wnt-binding receptor, have been associated with decreased bone mineral density and fragility fractures, although this remains controversial. Mice with a homozygous deletion of Lrp6 have severe skeletal abnormalities and are not viable, whereas mice with a heterozygous deletion have a combinatory effect with Lrp5 to decrease bone mineral density. As fracture healing closely models embryonic skeletal development, we investigated the process of fracture healing in mice heterozygous for Lrp6 (Lrp6 (+/-)) and hypothesized that the heterozygous deletion of Lrp6 would impair fracture healing. Mid-diaphyseal femur fractures were induced in Lrp6 (+/-) mice and wild-type controls (Lrp6 (+/+)). Fractures were analyzed using micro-computed tomography (μCT) scans, biomechanical testing, and histological analysis. Lrp6 (+/-) mice had significantly decreased stiffness and strength at 28 days post fracture (PF) and significantly decreased BV/TV, total density, immature bone density, and mature area within the callus on day-14 and -21 PF; they had significantly increased empty callus area at days 14 and 21 PF. Our results demonstrate that the heterozygous deletion of Lrp6 impairs fracture healing, which suggests that Lrp6 has a role in fracture healing.
authors.affiliation: Center for Cancer and Cell Biology, Program for Skeletal Disease and Tumor Microenvironment, Van Andel Research Institute , Grand Rapids, MI, USA.
authors.forename: Travis A
authors.initials: TA
authors.lastname: Burgers
authors.affiliation: Facultad de Ingenieria y Ciencias, Adolfo Ibáñez University , Viña del Mar, Chile.
authors.forename: Juan F
authors.initials: JF
authors.lastname: Vivanco
authors.affiliation: Center for Cancer and Cell Biology, Program for Skeletal Disease and Tumor Microenvironment, Van Andel Research Institute , Grand Rapids, MI, USA.
authors.forename: Juraj
authors.initials: J
authors.lastname: Zahatnansky
authors.affiliation: Padnos College of Engineering and Computing, Grand Valley State University , Grand Rapids, MI, USA.
authors.forename: Andrew J Vander
authors.initials: AJ
authors.lastname: Moren
authors.affiliation: Center for Cancer and Cell Biology, Program for Skeletal Disease and Tumor Microenvironment, Van Andel Research Institute , Grand Rapids, MI, USA.
authors.forename: James J
authors.initials: JJ
authors.lastname: Mason
authors.affiliation: Center for Cancer and Cell Biology, Program for Skeletal Disease and Tumor Microenvironment, Van Andel Research Institute , Grand Rapids, MI, USA.
authors.forename: Bart O
authors.initials: BO
authors.lastname: Williams