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.

Genetics: Mutation linked to impaired fracture healing

A gene defect linked to changes in bone mass in humans also impairs fracture healing in mouse models. The Wnt signaling pathway has emerged as a central regulator of skeletal remodeling, and some studies have found that people with mutations in one Wnt-associated gene called LRP6 have decreased bone mineral density and more fractures resulting from normal activities. To investigate the role of LRP6 in fracture healing, a team led by Bart Williams from the Van Andel Research Institute in Grand Rapids, Michigan, USA, bred mice with only one working copy of the gene. (Mice with two defective copies die before birth.) They induced fractures in the leg bone and four weeks later observed that the mutant mice had decreased density and volume in the healing bone, with fewer signs of tissue repair than normal mice.

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