title: Salidroside accelerates fracture healing through cell-autonomous and non-autonomous effects on osteoblasts.
abstract: Salidroside (SAL), a major active component of Rhodiola rosea L., exhibits diverse pharmacological effects. However, the direct roles of SAL in fracture healing remain largely unknown. Here, we demonstrate that SAL significantly promotes proliferation by altering the cell-cycle distribution of osteoblastic cells. SAL also greatly stimulates osteoblast differentiation and mineralization by inducing the expression of Runx2 and Osterix. In addition to its osteoblast-autonomous effects, SAL can activate the HIF-1α pathway coupling of angiogenesis and osteogenesis through cell-non-autonomous effects. Our in vitro results suggest that SAL significantly up-regulates HIF-1α expression at the mRNA and protein levels. Furthermore, the nuclear translocation and transcriptional activity of HIF-1α and the HIF-responsive gene VEGF increase following SAL treatment. Our mechanistic study revealed that the regulation of osteoblastic proliferation and HIF-1α expression partly involves MAPK/ERK and PI3K/Akt signaling. Our in vivo analysis also demonstrated that SAL can promote angiogenesis within the callus and accelerate fracture healing. Thus, SAL promotes skeletal regeneration in cell-autonomous and cell-non-autonomous ways and might be a potential therapy for accelerating fracture healing.
authors.affiliation: Tianjin Key Laboratory for Prevention and Control of Occupational and Environmental Hazards, Tianjin, People's Republic of China.|Department of Pathogenic Biology and Immunology, Logistics College of Chinese People's Armed Police Forces, Dongli District, Huizhi Ring Road, No. 1, Tianjin, 300309, People's Republic of China.
authors.forename: Xiao Qin
authors.initials: XQ
authors.lastname: Guo
authors.affiliation: Department of Pathogenic Biology and Immunology, Logistics College of Chinese People's Armed Police Forces, Dongli District, Huizhi Ring Road, No. 1, Tianjin, 300309, People's Republic of China.
authors.forename: Lin
authors.initials: L
authors.lastname: Qi
authors.affiliation: Department of Pathogenic Biology and Immunology, Logistics College of Chinese People's Armed Police Forces, Dongli District, Huizhi Ring Road, No. 1, Tianjin, 300309, People's Republic of China.
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.affiliation: Tianjin Key Laboratory for Prevention and Control of Occupational and Environmental Hazards, Tianjin, People's Republic of China. wangyue6808@126.com.|Department of Pathogenic Biology and Immunology, Logistics College of Chinese People's Armed Police Forces, Dongli District, Huizhi Ring Road, No. 1, Tianjin, 300309, People's Republic of China. wangyue6808@126.com.
authors.forename: Yue
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Stomatology, Affiliated Hospital of Logistics College of Chinese People's Armed Police Forces, Tianjin, People's Republic of China.
authors.forename: Chuan
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Pathogenic Biology and Immunology, Logistics College of Chinese People's Armed Police Forces, Dongli District, Huizhi Ring Road, No. 1, Tianjin, 300309, People's Republic of China.
authors.forename: Zong Min
authors.initials: ZM
authors.lastname: Li
authors.affiliation: Department of Pharmacology, Logistics College of Chinese People's Armed Police Forces, Tianjin, People's Republic of China.
authors.forename: Ling
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Pathogenic Biology and Immunology, Logistics College of Chinese People's Armed Police Forces, Dongli District, Huizhi Ring Road, No. 1, Tianjin, 300309, People's Republic of China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Qu
authors.affiliation: Department of Pathogenic Biology and Immunology, Logistics College of Chinese People's Armed Police Forces, Dongli District, Huizhi Ring Road, No. 1, Tianjin, 300309, People's Republic of China.
authors.forename: Dan
authors.initials: D
authors.lastname: Wang
authors.affiliation: Department of Stomatology, Affiliated Hospital of Logistics College of Chinese People's Armed Police Forces, Tianjin, People's Republic of China. 6666665901@sina.com.
authors.forename: Ze Min
authors.initials: ZM
authors.lastname: Han
mesh_terms: D000818:Animals; D002113:Calcification, Physiologic / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D050659:Core Binding Factor Alpha 1 Subunit / Q000378:metabolism; D004195:Disease Models, Animal; D017102:Fracture Healing / Q000187:drug effects*; D005960:Glucosides / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D051379:Mice; D010006:Osteoblasts / Q000187:drug effects / Q000473:pathology*; D010012:Osteogenesis / Q000187:drug effects; D010636:Phenols / Q000737:chemistry / Q000494:pharmacology*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D000076182:Sp7 Transcription Factor; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; D005960:Glucosides; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D010636:Phenols; D019408:Platelet Endothelial Cell Adhesion Molecule-1; C493709:RUNX2 protein, human; D000076182:Sp7 Transcription Factor; C478163:SP7 protein, human; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; C009172:rhodioloside
keywords: Fracture; Hypoxia-inducible factor-1α (HIF-1α); Osteoblast; Salidroside; Vascular endothelial growth factor (VEGF)