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Loss of insulin receptor in osteoprogenitor cells impairs structural strength of bone.

ABSTRACT: Type 1 diabetes mellitus (T1D) is associated with decreased bone mineral density, a deficit in bone structure, and subsequently an increased risk of fragility fracture. These clinical observations, paralleled by animal models of T1D, suggest that the insulinopenia of T1D has a deleterious effect on bone. To further examine the action of insulin signaling on bone development, we generated mice with an osteoprogenitor-selective (osterix-Cre) ablation of the insulin receptor (IR), designated OIRKO. OIRKO mice exhibited an 80% decrease in IR in osteoblasts. Prenatal elimination of IR did not affect fetal survival or gross morphology. However, loss of IR in mouse osteoblasts resulted in a postnatal growth-constricted phenotype. By 10-12 weeks of age, femurs of OIRKO mice were more slender, with a thinner diaphyseal cortex and, consequently, a decrease in whole bone strength when subjected to bending. In male mice alone, decreased metaphyseal trabecular bone, with thinner and more rodlike trabeculae, was also observed. OIRKO mice did not, however, exhibit abnormal glucose tolerance. The skeletal phenotype of the OIRKO mouse appeared more severe than that of previously reported bone-specific IR knockdown models, and confirms that insulin receptor expression in osteoblasts is critically important for proper bone development and maintenance of structural integrity.

SUBMITTER: Thrailkill K

PROVIDER: S-EPMC4052184 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Loss of insulin receptor in osteoprogenitor cells impairs structural strength of bone.

Thrailkill Kathryn K Bunn R Clay RC Lumpkin Charles C Wahl Elizabeth E Cockrell Gael G Morris Lindsey L Kahn C Ronald CR Fowlkes John J Nyman Jeffry S JS

Journal of diabetes research 20140518

Type 1 diabetes mellitus (T1D) is associated with decreased bone mineral density, a deficit in bone structure, and subsequently an increased risk of fragility fracture. These clinical observations, paralleled by animal models of T1D, suggest that the insulinopenia of T1D has a deleterious effect on bone. To further examine the action of insulin signaling on bone development, we generated mice with an osteoprogenitor-selective (osterix-Cre) ablation of the insulin receptor (IR), designated OIRKO. ...[more]

PMID: 24963495

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Project description:BackgroundManaging massive bone defects, a great challenge to orthopaedics reconstructive surgery. The problem arise is the supply of suitable bone is limited with many complications. Tissue-engineered hydroxyapatite bone (TEHB) scaffold impregnated with osteoprogenitor cells developed as an alternative to promote bone regeneration.MethodsThis animal protocol has been approved by Universiti Kebangsaan Malaysia Animal Ethical Committee. The TEHB scaffold prepared from hydroxyapatite using gel casting method. A total of six adolescent female sheep were chosen for this study. Later, all the sheep were euthanized in a proper manner and the bone harvested for biomechanical study. Bone marrow was collected from iliac crest of the sheep and bone marrow stem cells (BMSCs) isolated and cultured. BMSCs then cultured in osteogenic medium for osteoprogenitor cells development and the plasma collected was seeded with osteoprogenitor cells mixed with calcium chloride. Bone defect of 3 cm length of tibia bone created from each sheep leg and implanted with autologous and TEHB scaffold in 2 different groups of sheep. Wound site was monitored weekly until the wound completely healed and conventional X-ray performed at week 1 and 24. Shear test was conducted to determine the shear force on the autologous bone and TEHB scaffold after implantation for 24 weeks.ResultsAll of the sheep survived without any complications during the study period and radiograph showed new bone formation. Later, the bone harvested was for biomechanical study. The highest shear force for the autologous group was 13 MPa and the lowest was 5 MPa while for the scaffold group, the highest was 10 MPa and the lowest was 3 MPa. Although, proximal and distal interface of autologous bone graft shows higher shear strength compared to the TEHB scaffold but there is no significant difference in both groups, p value > 0.05. Histologically in both proximal and distal interface in both arms shows bone healing and woven bone formation.ConclusionTEHB scaffold impregnated with osteoprogenitor cells has the potential to be developed as a bone substitute in view of its strength and capability to promote bone regeneration.

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Loss of insulin receptor in osteoprogenitor cells impairs structural strength of bone.

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Loss of insulin receptor in osteoprogenitor cells impairs structural strength of bone.

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