Mutations in Lrp5 improve bone properties in a mouse model of Osteogenesis Imperfecta. C. M. Jacobsen1,2,3,4, L. A. Barber3, U. M. Ayturk3,5, H. J. Roberts3, M. A. Schwartz3, M. Weis6, D. Eyre6, D. Zurakowski7, A. G. Robling8, M. L. Warman3,5,9 1) Division of Endocrinology, Boston Children's Hospital, Boston, MA; 2) Division of Genetics, Boston Children's Hospital, Boston, MA; 3) Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, Boston Children's Hospital, Boston, MA; 4) Department of Pediatrics, Harvard Medical School, Boston, MA; 5) Department of Genetics, Harvard Medical School, Boston, MA; 6) Department of Orthopedics and Sports Medicine, University of Washington, Seattle, WA; 7) Department of Anesthesia, Children's Hospital Boston, Boston, MA; 8) Department of Anatomy and Cell Biology, Indiana University, Indianapolis, IN; 9) Howard Hughes Medical Institute, Boston, MA.
The cell surface receptor, low-density lipoprotein receptor-related protein 5 (LRP5) has emerged as a key regulator of bone mass and strength. Heterozygous missense mutations in LRP5 can increase bone mass and strength in humans. These mutations reduce binding to LRP5 by its endogenous inhibitors. Mice with a Lrp5 missense mutation that is orthologous to a human high bone mass (HBM) causing mutation have increased bone formation and as a consequence increased bone mass and bone strength. Osteogenesis Imperfecta (OI), a disorder most frequently caused by mutations in Type I collagen, is characterized by increased skeletal fragility which can lead to deformity, pain, and disability. Therapies are needed that can reduce fractures and improve bone health in patients with OI.
We mated mice with a dominant Lrp5 HBM-causing knockin allele to mice with a dominant OI-causing Col1a2 allele. We evaluated the offspring at 12-weeks-old. We analyzed skeletal properties by DEXA, CT, whole-bone 3-point bending and quantitative histomorphometry. As expected, offspring with OI alone have lower bone density and weaker bones than wild-type siblings, and mice with a HBM allele alone have higher bone density and stronger bones than wild-type siblings. Compared to siblings with OI alone, siblings with OI and a HBM allele have significantly increased bone density and bone strength (p <0.05). RNAseq and collagen analysis from the bones of mice with OI and a HBM allele demonstrated that the improved bone properties were not due to altered mRNA expression of type I collagen or its chaperones, nor were they due to changes in mutant type I collagen secretion.
Increased LRP5 signaling improves bone density and strength in a mouse model of moderate OI. This proof of principle experiment indicates that promoting bone anabolism may benefit patients with OI, even though the underlying collagen defect responsible for their skeletal fragility is unchanged. Therefore, therapies that target the LRP5 signaling pathway could be effective in improving outcomes for patients with OI.
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