TY - JOUR
T1 - Type 1 diabetic Akita mice have low bone mass and impaired fracture healing
AU - Hu, Pei
AU - McKenzie, Jennifer A.
AU - Buettmann, Evan G.
AU - Migotsky, Nicole
AU - Gardner, Michael J.
AU - Silva, Matthew J.
N1 - Funding Information:
Supported by grants from the Orthopaedic Research and Education Foundation ( OREF ) and the NIH / NIAMS ( R21 AR066798 , R01 AR050211 ). We thank Mr. Daniel Leib, Ms. Crystal Idleburg and Ms. Samantha Coleman for their assistance with microCT and histology, supported by the Washington University Musculoskeletal Research Center ( NIH P30 AR057235 and AR074992 , and S10 RR023660 ). We acknowledge support from the Hope Center Alafi Neuroimaging Lab ( NCRR 1S10RR027552 ) and a Neuroscience Blueprint Interdisciplinary Center Core . We thank the Genome Technology Access Center in the Department of Genetics at Washington University School of Medicine for assistance with qPCR; the Center is partially supported by NCI Cancer Center Support Grant P30 CA91842 to the Siteman Cancer Center, and by ICTS/CTSA Grant# UL1TR002345 from the National Center for Advancing Translational Sciences (NCATS). We thank Core Laboratory for Clinical Studies (CLCS) at Washington University School of Medicine for serum testing.
Funding Information:
Supported by grants from the Orthopaedic Research and Education Foundation (OREF) and the NIH/NIAMS (R21 AR066798, R01 AR050211). We thank Mr. Daniel Leib, Ms. Crystal Idleburg and Ms. Samantha Coleman for their assistance with microCT and histology, supported by the Washington University Musculoskeletal Research Center (NIH P30 AR057235 and AR074992, and S10 RR023660). We acknowledge support from the Hope Center Alafi Neuroimaging Lab (NCRR 1S10RR027552) and a Neuroscience Blueprint Interdisciplinary Center Core. We thank the Genome Technology Access Center in the Department of Genetics at Washington University School of Medicine for assistance with qPCR; the Center is partially supported by NCI Cancer Center Support Grant P30 CA91842 to the Siteman Cancer Center, and by ICTS/CTSA Grant# UL1TR002345 from the National Center for Advancing Translational Sciences (NCATS). We thank Core Laboratory for Clinical Studies (CLCS) at Washington University School of Medicine for serum testing.
Publisher Copyright:
© 2021 The Authors
PY - 2021/6
Y1 - 2021/6
N2 - Type 1 diabetes (T1DM) impairs bone formation and fracture healing in humans. Akita mice carry a mutation in one allele of the insulin-2 (Ins2) gene, which leads to pancreatic beta cell dysfunction and hyperglycemia by 5–6 weeks age. We hypothesized that T1DM in Akita mice is associated with decreased bone mass, weaker bones, and impaired fracture healing. Ins2 ± (Akita) and wildtype (WT) males were subjected to femur fracture at 18-weeks age and healing assessed 3–21 days post-fracture. Non-fractured left femurs were assessed for morphology (microCT) and strength (bending or torsion) at 19–21 weeks age. Fractured right femurs were assessed for callus mechanics (torsion), morphology and composition (microCT and histology) and gene expression (qPCR). Both Akita and WT mice gained weight from 3 to 18 weeks age, but Akita mice weighed less starting at 5 weeks (−5.2%, p < 0.05). At 18–20 weeks age Akita mice had reduced serum osteocalcin (−30%), cortical bone area (−16%), and thickness (−17%) compared to WT, as well as reduced cancellous BV/TV (−39%), trabecular thickness (−23%) and vBMD (−31%). Mechanical testing of non-fractured femurs showed decreased structural (stiffness, ultimate load) and material (ultimate stress) properties of Akita bones. At 14 and 21 days post fracture Akita mice had a significantly smaller callus than WT mice (~30%), with less cartilage and bone area. Assessment of torsional strength showed a weaker callus in Akita mice with lower stiffness (−42%), maximum torque (−44%) and work to fracture (−44%). In summary, cortical and cancellous bone mass were reduced in Akita mice, with lower bone mechanical properties. Fracture healing in Akita mice was impaired by T1DM, with a smaller, weaker fracture callus due to decreased cartilage and bone formation. In conclusion, the Akita mouse mimics some of the skeletal features of T1DM in humans, including osteopenia and impaired fracture healing, and may be useful to test interventions.
AB - Type 1 diabetes (T1DM) impairs bone formation and fracture healing in humans. Akita mice carry a mutation in one allele of the insulin-2 (Ins2) gene, which leads to pancreatic beta cell dysfunction and hyperglycemia by 5–6 weeks age. We hypothesized that T1DM in Akita mice is associated with decreased bone mass, weaker bones, and impaired fracture healing. Ins2 ± (Akita) and wildtype (WT) males were subjected to femur fracture at 18-weeks age and healing assessed 3–21 days post-fracture. Non-fractured left femurs were assessed for morphology (microCT) and strength (bending or torsion) at 19–21 weeks age. Fractured right femurs were assessed for callus mechanics (torsion), morphology and composition (microCT and histology) and gene expression (qPCR). Both Akita and WT mice gained weight from 3 to 18 weeks age, but Akita mice weighed less starting at 5 weeks (−5.2%, p < 0.05). At 18–20 weeks age Akita mice had reduced serum osteocalcin (−30%), cortical bone area (−16%), and thickness (−17%) compared to WT, as well as reduced cancellous BV/TV (−39%), trabecular thickness (−23%) and vBMD (−31%). Mechanical testing of non-fractured femurs showed decreased structural (stiffness, ultimate load) and material (ultimate stress) properties of Akita bones. At 14 and 21 days post fracture Akita mice had a significantly smaller callus than WT mice (~30%), with less cartilage and bone area. Assessment of torsional strength showed a weaker callus in Akita mice with lower stiffness (−42%), maximum torque (−44%) and work to fracture (−44%). In summary, cortical and cancellous bone mass were reduced in Akita mice, with lower bone mechanical properties. Fracture healing in Akita mice was impaired by T1DM, with a smaller, weaker fracture callus due to decreased cartilage and bone formation. In conclusion, the Akita mouse mimics some of the skeletal features of T1DM in humans, including osteopenia and impaired fracture healing, and may be useful to test interventions.
KW - Akita diabetic mouse
KW - Bone formation
KW - Bone strength
KW - Cartilage
KW - Fracture healing
UR - http://www.scopus.com/inward/record.url?scp=85102373215&partnerID=8YFLogxK
U2 - 10.1016/j.bone.2021.115906
DO - 10.1016/j.bone.2021.115906
M3 - Article
C2 - 33662611
AN - SCOPUS:85102373215
SN - 8756-3282
VL - 147
JO - Bone
JF - Bone
M1 - 115906
ER -