Adolescent idiopathic scoliosis(AIS),a complex early-onset three-dimensional spinal deformity,remains etiologically ambiguous despite extensive ongoing investigations.Currently,braces and surgeries are primary treatme...Adolescent idiopathic scoliosis(AIS),a complex early-onset three-dimensional spinal deformity,remains etiologically ambiguous despite extensive ongoing investigations.Currently,braces and surgeries are primary treatments of AIS,which come with inherent risks and costs.Therefore,there is an urgent need for biotherapeutic targets for AIS.Using human specimens obtained from the clinic,we discovered that ORM1 was expressed in AIS bone tissues.Also,immune cells were found to interact with osteoclasts through the LTB-LTBR pathway,resulting in elevated ORM1 expression,proliferation promotion and differentiation of monocytes/osteoclasts.Protein analysis showed that in ORM1-positive AIS patient-derived osteoblasts,there was an increased expression of RANKL,decreased expression of OPG,and an increased RANKL/OPG ratio.Furthermore,osteoclasts overexpressing ORM1 promoted their own differentiation while inhibiting osteoblast proliferation and function.ORM1 knockdown osteoclasts co-cultured with osteoblasts,along with the addition of leptin,significantly inhibited osteoclast differentiation while promoting osteoblast proliferation and function-related protein expression.In conclusion,ORM1 acts as a detrimental factor in the pathogenesis of Adolescent Idiopathic Scoliosis(AIS)by promoting osteoclast differentiation and inhibiting both the proliferation and function of osteoblasts.This suggests that ORM1 may represent a valuable therapeutic target for AIS.展开更多
目的研究人源血清类粘蛋白1(orosomucoid 1,ORM1)通过丝氨酸棕榈酰转移酶长链碱基亚基1(serine palmitoyltransferase long chain base subunit 1,SPTLC1)对干眼症鞘脂代谢的影响,为干眼症的发病机制提供新的研究方向。方法通过皮下注...目的研究人源血清类粘蛋白1(orosomucoid 1,ORM1)通过丝氨酸棕榈酰转移酶长链碱基亚基1(serine palmitoyltransferase long chain base subunit 1,SPTLC1)对干眼症鞘脂代谢的影响,为干眼症的发病机制提供新的研究方向。方法通过皮下注射氢溴酸东莨菪碱构建干眼症模型,通过晶状体注射腺相关病毒过表达ORM1。行泪液分泌量检测,杯状细胞检测,角膜荧光素染色,泪膜破裂时间检测,HE检测评估角膜结膜损伤,泪液质量,以及组织病理变化。通过生化试剂盒检测神经酰胺和鞘磷脂含量,通过qPCR和WB检测ORM1和SPTLC1的表达。结果(1)ORM1可增加干眼症模型的泪液分泌(P<0.0001);(2)ORM1可增加干眼症模型的眼表泪膜稳定性(P<0.001);(3)ORM1可改善干眼症模型的角膜上皮损伤(P<0.0001);(4)ORM1可增加干眼症模型的角膜组织中杯状细胞数量(P<0.001);(5)过表达ORM1后,角膜组织上皮层变厚,基底层细胞排列较为紧密,细胞层数变多,空泡减少;(6)ORM1可抑制干眼症模型的炎症基因表达(P<0.01);(7)ORM1可促进总神经酰胺和鞘磷脂含量(P<0.01);(8)ORM1可促进SPTLC1的mRNA和蛋白表达(P<0.001)。结论ORM1可通过调控SPTLC1参与调控干眼症鞘脂代谢,为探讨干眼症的发生发展机制和寻找有效且安全的治疗方案提供新的视角。展开更多
基金supported by National Natural Science Foundation of China(82102525 and 81972035)Natural Science Foundation of Shanghai Municipality(21ZR1478600)Naval Medical University Deep Blue Medical Talent Program。
文摘Adolescent idiopathic scoliosis(AIS),a complex early-onset three-dimensional spinal deformity,remains etiologically ambiguous despite extensive ongoing investigations.Currently,braces and surgeries are primary treatments of AIS,which come with inherent risks and costs.Therefore,there is an urgent need for biotherapeutic targets for AIS.Using human specimens obtained from the clinic,we discovered that ORM1 was expressed in AIS bone tissues.Also,immune cells were found to interact with osteoclasts through the LTB-LTBR pathway,resulting in elevated ORM1 expression,proliferation promotion and differentiation of monocytes/osteoclasts.Protein analysis showed that in ORM1-positive AIS patient-derived osteoblasts,there was an increased expression of RANKL,decreased expression of OPG,and an increased RANKL/OPG ratio.Furthermore,osteoclasts overexpressing ORM1 promoted their own differentiation while inhibiting osteoblast proliferation and function.ORM1 knockdown osteoclasts co-cultured with osteoblasts,along with the addition of leptin,significantly inhibited osteoclast differentiation while promoting osteoblast proliferation and function-related protein expression.In conclusion,ORM1 acts as a detrimental factor in the pathogenesis of Adolescent Idiopathic Scoliosis(AIS)by promoting osteoclast differentiation and inhibiting both the proliferation and function of osteoblasts.This suggests that ORM1 may represent a valuable therapeutic target for AIS.
文摘目的研究人源血清类粘蛋白1(orosomucoid 1,ORM1)通过丝氨酸棕榈酰转移酶长链碱基亚基1(serine palmitoyltransferase long chain base subunit 1,SPTLC1)对干眼症鞘脂代谢的影响,为干眼症的发病机制提供新的研究方向。方法通过皮下注射氢溴酸东莨菪碱构建干眼症模型,通过晶状体注射腺相关病毒过表达ORM1。行泪液分泌量检测,杯状细胞检测,角膜荧光素染色,泪膜破裂时间检测,HE检测评估角膜结膜损伤,泪液质量,以及组织病理变化。通过生化试剂盒检测神经酰胺和鞘磷脂含量,通过qPCR和WB检测ORM1和SPTLC1的表达。结果(1)ORM1可增加干眼症模型的泪液分泌(P<0.0001);(2)ORM1可增加干眼症模型的眼表泪膜稳定性(P<0.001);(3)ORM1可改善干眼症模型的角膜上皮损伤(P<0.0001);(4)ORM1可增加干眼症模型的角膜组织中杯状细胞数量(P<0.001);(5)过表达ORM1后,角膜组织上皮层变厚,基底层细胞排列较为紧密,细胞层数变多,空泡减少;(6)ORM1可抑制干眼症模型的炎症基因表达(P<0.01);(7)ORM1可促进总神经酰胺和鞘磷脂含量(P<0.01);(8)ORM1可促进SPTLC1的mRNA和蛋白表达(P<0.001)。结论ORM1可通过调控SPTLC1参与调控干眼症鞘脂代谢,为探讨干眼症的发生发展机制和寻找有效且安全的治疗方案提供新的视角。
