Diabetes Perturbs Bone Microarchitecture and Bone Strength through Regulation of Sema3A/IGF-1/β-Catenin in Rats

Abstract

Purpose: Increasing evidence supported that semaphorin 3A (Sema3A), insulin-like growth factor (IGF)-1 and β-catenin were involved in the development of osteoporosis and diabetes. This study is aimed to evaluate whether Sema3A/IGF-1/β-catenin is directly involved in the alterations of bone microarchitecture and bone strength of diabetic rats. Methods: Diabetic rats were induced by streptozotocin and high fat diet exposure. Bone microarchitecture and strength in the femurs were evaluated by micro-CT scanning, three-point bending examination and the stainings of HE, alizarin red S and safranin O/fast green, respectively. The alterations of lumbar spines microarchitecture were also determined by micro-CT scanning. Western blot and immunohistochemical analyses were used to examine the expression of Sema3A, β-catenin, IGF-1, peroxisome proliferator-activated receptor γ (PPARγ) and cathepsin K in rat tibias. Results: Diabetic rats exhibited decreased trabecular numbers and bone formation, but an increased trabecular separation in the femurs and lumbar spines. Moreover, the increased bone fragility and decreased bone stiffness were evident in the femurs of diabetic rats. Diabetic rats also exhibited a pronounced bone phenotype which manifested by decreased expression of Sema3A, IGF-1 and β-catenin, as well as increased expression of cathepsin K and PPARγ. Conclusions: This study suggests that diabetes could perturb bone loss through the Sema3A/IGF-1/β-catenin pathway. Sema3A deficiency in bone may contribute to upregulation of PPARγ and cathepsin K expression, which further disrupts bone remodeling in diabetic rats.

Radix Salviae miltiorrhizae improves bone microstructure and strength through Wnt/β‐catenin and osteoprotegerin/receptor activator for nuclear factor‐κB ligand/cathepsin K signaling in ovariectomized rats

“…In addition, DKK1 prevents Wnt binding to the extracellular regions and accordingly inhibits Wnt signal transduction and its subsequent bone‐forming effect (Zhou et al, ). Our results also confirmed that ovariectomy inhibited Wnt/β‐catenin signaling via increasing the expression of DKK1 and decreasing LRP6 expression as well as regulating the relative ratios of p‐GSK3β to GSK3β and p‐β‐catenin to β‐catenin, which further leads to β‐catenin degradation and subsequent bone loss (Ma et al, ). Administration of RSM to OVX rats for 14 weeks significantly antagonized DKK1 expression and increased p‐LRP6 expression and the relative ratio of p‐GSK3β to GSK3β, as well as decreased the relative expression of p‐β‐catenin to β‐catenin in the rat tibias, resulting in osteoblasts differentiation and maturation as well as bone improvement.…”

“…The fixed uteri and decalcified femurs were defatted and dehydrated with xylene and graded ethanol (50–100%) and embedded in paraffin. Then 5‐μm paraffin sections were prepared by automated microtome (Leica; Wetzlar, Germany) and used for the stainings of H&E and Safranin O/Fast green according to the protocols as previously described (Guo et al, ; Ma et al, ).…”

“…After scanning, the left femur was taken for the three‐point bending assay using electronic universal testing machine (Shenzhen Reger Instrument Co. Ltd., Model RGWF4005, China) according to Ma et al's () description. The diameter of femoral stem was measured with vernier caliper.…”

Bioinspired bone therapies using naringin: applications and advances

“…This protective effect is thought to be modulated via naringin-induced increase in Semaphorin 3A expression in vivo, a local factor of the bone microenvironment that simultaneously promotes bone formation while reducing bone resorption [49]. However, Semaphorin 3A deficiency is directly implicated in the disruption of bone remodeling and subsequent bone loss in diabetic rats [50]. This might explain why naringin successfully prevented bone loss in a rat model of streptozotocin-induced diabetes [51].…”

Sustained Release of IGF-1 by 3D Mesoporous Scaffolds Promoting Cardiac Stem Cell Migration and Proliferation

“…Insulin-like growth factor-1 (IGF-1) is a peptide with a molecular mass of 7.6 kDa that is produced in the liver and secreted into the circulation [7][8]. It regulates cell survival, proliferation, differentiation, and metabolism [7], and is especially important in the circulatory system [9].…”