RESUMEN
The effects of kinin B1 receptor (B1 R) deletion were examined on femur bone regeneration in streptozotocin (STZ)-type 1 diabetes. Diabetes induction in wild-type C57/BL6 (WTC57BL6) mice led to decrease in body weight and hyperglycemia, compared to the non-diabetic group of the same strain. The lack of B1 R did not affect STZ-elicited body weight loss, but partially prevented hyperglycemia. Diabetic mice had a clear delay in bone regeneration, and displayed large areas of loose connective tissue within the defects, with a reduced expression of the mineralization-related protein osteonectin, when compared to the non-diabetic WTC57/BL6. The non-diabetic and diabetic B1 R knockout (B1 RKO) mice had bone regeneration levels and osteonectin expression comparable to that seen in control WTC57/BL6 mice. WTC57/BL6 STZ-diabetic mice also showed a marked reduction of collagen contents, with increased immunolabeling for the apoptosis marker caspase-3, whereas diabetic B1 RKO had collagen levels and caspase-3 activity comparable to those observed in non-diabetic WTC57/BL6 or B1 RKO mice. No significant difference was detected in the number of tartrate-resistant acid phosphatase (TRAP)-stained cells, or in RANK/RANKL/OPG system immunolabeling throughout the experimental groups. Data bring novel evidence on the relevance of kinin B1 R under type 1 diabetes with regards to its role in bone regeneration.
Asunto(s)
Regeneración Ósea , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Fracturas del Fémur/metabolismo , Fémur/metabolismo , Curación de Fractura , Receptor de Bradiquinina B1/deficiencia , Animales , Apoptosis , Caspasa 3/metabolismo , Colágeno/metabolismo , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/patología , Diabetes Mellitus Experimental/fisiopatología , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/patología , Diabetes Mellitus Tipo 1/fisiopatología , Fracturas del Fémur/genética , Fracturas del Fémur/patología , Fracturas del Fémur/fisiopatología , Fémur/patología , Fémur/fisiopatología , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Osteonectina/metabolismo , Receptor de Bradiquinina B1/genética , Transducción de Señal , Factores de TiempoRESUMEN
AIM: This study set forth a question: are there any differences in bone responses to insulin and/or vitamin D3 treatment in female and male type 1 diabetic (T1D) mice? MAIN METHODS: To address this issue, a non-critical sized femur defect was created in streptozotocin (STZ)-T1D mice. Control non-diabetic and T1D female and male mice received: saline; vitamin D3; insulin; or vitamin D3 plus insulin, for 21 days. KEY FINDINGS: Female and male T1D mice showed impaired bone healing, as indicated by histological and micro-computed tomography (micro-CT) analysis. Vitamin D3 or insulin improved the bone regeneration in T1D mice, irrespective of sex. Vitamin D3 plus insulin did not exhibit any additional effects. There were no differences regarding the numbers of TRAP-stained osteoclasts in either evaluated groups. The osteoblast-related gene osterix was upregulated in vitamin D3-treated male T1D mice, as revealed by RT-qPCR. Female T1D mice treated with vitamin D3, insulin, or vitamin D3 plus insulin presented an increased expression of insulin growth factor-1 (IGF-1) mRNA. Conversely, IGF-1 mRNA levels were reduced by the same treatments in male TD1 mice. SIGNIFICANCE: Altogether, the results suggested that T1D similarly delayed the osseous healing in female and male mice, with beneficial effects for either vitamin D3 or insulin in T1D mice of both sexes. However, data indicated marked sex differences regarding the expression of genes implicated in bone formation, in T1D mice treated with vitamin D3 and/or insulin.