Enhanced Wnt signaling improves bone mass and strength, but not brittleness, in the Col1a1(+/mov13) mouse model of type I Osteogenesis Imperfecta.
Osteogenesis Imperfecta (OI) comprises a group of genetic skeletal fragility disorders. The mildest form of OI, Osteogenesis Imperfecta type I, is frequently caused by haploinsufficiency mutations in COL1A1, the gene encoding the α1(I) chain of type 1 collagen. Children with OI type I have a 95-fold higher fracture rate compared to unaffected children. Therapies for OI type I in the pediatric population are limited to anti-catabolic agents. In adults with osteoporosis, anabolic therapies that enhance Wnt signaling in bone improve bone mass, and ongoing clinical trials are determining if these therapies also reduce fracture risk. We performed a proof-of-principle experiment in mice to determine whether enhancing Wnt signaling in bone could benefit children with OI type I. We crossed a mouse model of OI type I (Col1a1(+/Mov13)) with a high bone mass (HBM) mouse (Lrp5(+/p.A214V)) that has increased bone strength from enhanced Wnt signaling. Offspring that inherited the OI and HBM alleles had higher bone mass and strength than mice that inherited the OI allele alone. However, OI+HBM and OI mice still had bones with lower ductility compared to wild-type mice. We conclude that enhancing Wnt signaling does not make OI bone normal, but does improve bone properties that could reduce fracture risk. Therefore, agents that enhance Wnt signaling are likely to benefit children and adults with OI type 1.
Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, Boston Children's Hospital, Boston, MA, United States; Division of Endocrinology, Boston Children's Hospital, Boston, MA, United States; Division of Genetics, Boston Children's Hospital, Boston, MA, United States; Department of Pediatrics, Harvard Medical School, Boston, MA, United States. Electronic address: Christina.Jacobsen@childrens.harvard.edu.
Christina M
CM
Jacobsen
Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, Boston Children's Hospital, Boston, MA, United States.
Marissa A
MA
Schwartz
Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, Boston Children's Hospital, Boston, MA, United States.
Heather J
HJ
Roberts
Department of Anatomy and Cell Biology, Indiana University, Indianapolis, IN, United States.
Kyung-Eun
KE
Lim
Mineralized Tissues Laboratory, Hospital for Special Surgery, New York, NY, United States.
Lyudmila
L
Spevak
Mineralized Tissues Laboratory, Hospital for Special Surgery, New York, NY, United States; Weill Cornel Medical College, New York, NY, United States.
Adele L
AL
Boskey
Department of Anesthesia, Boston Children's Hospital, Boston, MA, United States.
David
D
Zurakowski
Department of Anatomy and Cell Biology, Indiana University, Indianapolis, IN, United States.
Alexander G
AG
Robling
Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, Boston Children's Hospital, Boston, MA, United States; Department of Genetics, Harvard Medical School, Boston, MA, United States; Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA, United States.
Matthew L
ML
Warman
D000483:Alleles; D000818:Animals; D001696:Biomechanical Phenomena; D015519:Bone Density; D001857:Bone Matrix / Q000473:pathology; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D002113:Calcification, Physiologic; D000071556:Cancellous Bone / Q000000981:diagnostic imaging / Q000473:pathology / Q000503:physiopathology; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism*; D000090602:Collagen Type I, alpha 1 Chain; D000071538:Cortical Bone / Q000000981:diagnostic imaging / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D005260:Female; D005269:Femur / Q000000981:diagnostic imaging / Q000473:pathology / Q000503:physiopathology; D060492:Low Density Lipoprotein Receptor-Related Protein-5 / Q000378:metabolism; D008159:Lumbar Vertebrae / Q000000981:diagnostic imaging / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008810:Mice, Inbred C57BL; D009929:Organ Size; D010013:Osteogenesis Imperfecta / Q000473:pathology* / Q000503:physiopathology*; D060449:Wnt Signaling Pathway; D055114:X-Ray Microtomography
D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D060492:Low Density Lipoprotein Receptor-Related Protein-5; C555483:Lrp5 protein, mouse
Lrp5; Mov13; Osteogenesis Imperfecta; Wnt signaling