IADR Abstract Archives
OPTN knockout mouse as a novel model for Paget’s Disease of Bone
Objectives: Paget’s disease of the bone (PDB) is characterized by increased bone turnover and disorganized bone remodeling. Recent genome wide-association studies implicated optineurin (OPTN) is genetically related to PDB patients. However, the mechanism of how OPTN influence bone remodeling is poorly understood. We hypothesize that Optineurin is critical for bone homeostasis, and depletion of OPTN may cause Pagetoid phenotype. In order to test our hypothesis, we generated floxed (flanked by LoxP) OPTN mouse in which OPTN expression can be knocked out when Cre recombinase is introduced. The goal of this study was to establish this mouse as a novel in vivo model to study PDB and bone remodeling. We identified and performed detailed phenotypic characterization for Pagetoid bone structural changes.
Methods: The floxed OPTN mouse was crossed to a CMV-Cre mouse. Offsprings were genotyped through PCR and characterized for ubiquitous genetic deletion of OPTN protein expression. We identified Pagetic lesions by micro-CT in aged, 22-month old OPTN mice and measured bone mineral density using dual energy X-ray absorptiometry.
Results: Micro-CT scanning revealed that OPTN knockout mice developed Pagetic lesions in the femur, tibia, lumbar spine and pelvis, which was not observed in control mice (n=5 animals per genotype). Furthermore, osteolytic lesions and irregular hypertrophic lesion were significantly different (a total of 18 of lesions in 5 OPTN knockout mice compared to no lesion in control, p<0.05) Finally, significantly lower bone mineral density was observed in femur (0.046 ± 0.0033 g/cm2) and lumbar spine (0.039 ± 0.0026 g/cm2) compared to femur (0.056 ± 0.0016 g/cm2) and lumbar spine in the control mice (0.047±0.0004 g/cm2) (p<0.05).
Conclusions: Aged, OPTN knockout mice exhibited abnormal bone remodeling consistent with a PDB phenotype. These mice will be useful for mechanistic study of bone remodeling in PDB and future therapeutic development.
Methods: The floxed OPTN mouse was crossed to a CMV-Cre mouse. Offsprings were genotyped through PCR and characterized for ubiquitous genetic deletion of OPTN protein expression. We identified Pagetic lesions by micro-CT in aged, 22-month old OPTN mice and measured bone mineral density using dual energy X-ray absorptiometry.
Results: Micro-CT scanning revealed that OPTN knockout mice developed Pagetic lesions in the femur, tibia, lumbar spine and pelvis, which was not observed in control mice (n=5 animals per genotype). Furthermore, osteolytic lesions and irregular hypertrophic lesion were significantly different (a total of 18 of lesions in 5 OPTN knockout mice compared to no lesion in control, p<0.05) Finally, significantly lower bone mineral density was observed in femur (0.046 ± 0.0033 g/cm2) and lumbar spine (0.039 ± 0.0026 g/cm2) compared to femur (0.056 ± 0.0016 g/cm2) and lumbar spine in the control mice (0.047±0.0004 g/cm2) (p<0.05).
Conclusions: Aged, OPTN knockout mice exhibited abnormal bone remodeling consistent with a PDB phenotype. These mice will be useful for mechanistic study of bone remodeling in PDB and future therapeutic development.