Irisin reduces bone fracture by facilitating osteogenesis and antagonizing TGF-β/Smad signaling in a growing mouse model of osteogenesis imperfecta
Objective: Osteogenesis imperfecta (OI) is a congenital disorder characterized by muscle defect and skeletal fragility, and no cure is yet available. Crosstalk between bone and muscle has become a new coming focus of therapeutic strategy in OI. Irisin, a secreted myokine, was found to be involved in...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-01-01
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| Series: | Journal of Orthopaedic Translation |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2214031X22001176 |
| _version_ | 1797904365021822976 |
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| author | Bin Sun Huiqiao Wu Jiajia Lu Rongcheng Zhang Xiaolong Shen Yifei Gu Changgui Shi Ying Zhang Wen Yuan |
| author_facet | Bin Sun Huiqiao Wu Jiajia Lu Rongcheng Zhang Xiaolong Shen Yifei Gu Changgui Shi Ying Zhang Wen Yuan |
| author_sort | Bin Sun |
| collection | DOAJ |
| description | Objective: Osteogenesis imperfecta (OI) is a congenital disorder characterized by muscle defect and skeletal fragility, and no cure is yet available. Crosstalk between bone and muscle has become a new coming focus of therapeutic strategy in OI. Irisin, a secreted myokine, was found to be involved in regulating bone metabolism, and may be beneficial for the treatment of OI. However, its effects in OI have yet to be determined. This study sought to determine whether Irisin therapy is capable of reducing fracture risk in OI and to investigate the potential mechanisms of action. Methods: Fibronectin type III domain containing 5 (FNDC5)/Irisin expression was assessed by enzyme-linked immunosorbent assay (ELISA) and immunohistochemical staining. In vivo, X-ray was used for fracture counting and micro-CT, dynamic histomorphometry analysis, immunohistochemistry, histomorphometry, and biomechanical test were used to evaluate the effects of Irisin on fracture frequency and bone quality in OI mouse model, oim/oim mouse. In vitro, osteogenesis-related gene expressions were determined by quantitative real-time PCR (qRT-PCR), western blot, and osteoblastogenesis assay were assessed by alkaline phosphatase (ALP) staining and alizarin red S (ARS) staining. Mechanistically, cell immunofluorescence staining, co-immunoprecipitation (co-IP) molecular docking, western blot, luciferase reporter assay, and chromatin immunoprecipitation (ChIP) assay were used for elucidating the mechanisms of how Irisin antagonized transforming growth factor-β (TGF-β)/Smad signaling in oim/oim osteoblasts and further attenuated the inhibitory effect of TGF-β1 on osteogenic differentiation. Results: Musculoskeletal system-related FNDC5/Irisin was decreased in the serum, muscle, and bone in oim/oim mice. Irisin administration reduced bone fracture and attenuated bone abnormalities by improving bone mass and strength and facilitating the expression of osteogenic differentiation markers. In vivo study and in vitro experiments showed that Irisin antagonized TGF-β/Smad signaling by interfering with TGF-β1-TGF-β receptor II (TβRII) binding. In oim/oim osteoblasts, Irisin alleviated TGF-β1-induced suppression of osteogenic differentiation through both integrin-dependent and integrin-independent mechanisms. Independent of integrin receptors, Irisin affected osteogenesis by activating ERK/p38 signaling and counteracting TGF-β/Smad2/3 signaling. In particular, Irisin alleviated TGF-β1-induced inhibition of Runx2 function at the osteocalcin promoter through decreasing Smad2/3 signaling and inducing HADC4/5 degeneration. Conclusions: Collectively, Irisin could effectively reduce bone fracture in oim/oim mice through promoting osteogenesis and counteracting TGF-β/Smad signaling. Translational potential statement: Findings from this study provided evidence for using Irisin as a potential therapeutic reagent to prevent the progression of OI. |
| first_indexed | 2024-04-10T09:47:45Z |
| format | Article |
| id | doaj.art-8b9dbb987f7349d8af7fb3abcd923686 |
| institution | Directory Open Access Journal |
| issn | 2214-031X |
| language | English |
| last_indexed | 2024-04-10T09:47:45Z |
| publishDate | 2023-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Orthopaedic Translation |
| spelling | doaj.art-8b9dbb987f7349d8af7fb3abcd9236862023-02-17T04:54:26ZengElsevierJournal of Orthopaedic Translation2214-031X2023-01-0138175189Irisin reduces bone fracture by facilitating osteogenesis and antagonizing TGF-β/Smad signaling in a growing mouse model of osteogenesis imperfectaBin Sun0Huiqiao Wu1Jiajia Lu2Rongcheng Zhang3Xiaolong Shen4Yifei Gu5Changgui Shi6Ying Zhang7Wen Yuan8Department of Orthopaedics, Changzheng Hospital, Naval Medical University, Shanghai, ChinaDepartment of Orthopaedics, Changzheng Hospital, Naval Medical University, Shanghai, ChinaDepartment of Orthopaedics, Changzheng Hospital, Naval Medical University, Shanghai, ChinaDepartment of Orthopaedics, Changzheng Hospital, Naval Medical University, Shanghai, ChinaDepartment of Orthopaedics, Changzheng Hospital, Naval Medical University, Shanghai, ChinaDepartment of Orthopaedics, Changzheng Hospital, Naval Medical University, Shanghai, ChinaCorresponding author. Department of Orthopaedics, Changzheng Hospital, Naval Medical University, 415 Fengyang Road, Shanghai, 200003, People's Republic of China.; Department of Orthopaedics, Changzheng Hospital, Naval Medical University, Shanghai, ChinaCorresponding author. Department of Orthopaedics, Changzheng Hospital, Naval Medical University, 415 Fengyang Road, Shanghai, 200003, People's Republic of China.; Department of Orthopaedics, Changzheng Hospital, Naval Medical University, Shanghai, ChinaCorresponding author. Department of Orthopaedics, Changzheng Hospital, Naval Medical University, 415 Fengyang Road, Shanghai, 200003, People's Republic of China.; Department of Orthopaedics, Changzheng Hospital, Naval Medical University, Shanghai, ChinaObjective: Osteogenesis imperfecta (OI) is a congenital disorder characterized by muscle defect and skeletal fragility, and no cure is yet available. Crosstalk between bone and muscle has become a new coming focus of therapeutic strategy in OI. Irisin, a secreted myokine, was found to be involved in regulating bone metabolism, and may be beneficial for the treatment of OI. However, its effects in OI have yet to be determined. This study sought to determine whether Irisin therapy is capable of reducing fracture risk in OI and to investigate the potential mechanisms of action. Methods: Fibronectin type III domain containing 5 (FNDC5)/Irisin expression was assessed by enzyme-linked immunosorbent assay (ELISA) and immunohistochemical staining. In vivo, X-ray was used for fracture counting and micro-CT, dynamic histomorphometry analysis, immunohistochemistry, histomorphometry, and biomechanical test were used to evaluate the effects of Irisin on fracture frequency and bone quality in OI mouse model, oim/oim mouse. In vitro, osteogenesis-related gene expressions were determined by quantitative real-time PCR (qRT-PCR), western blot, and osteoblastogenesis assay were assessed by alkaline phosphatase (ALP) staining and alizarin red S (ARS) staining. Mechanistically, cell immunofluorescence staining, co-immunoprecipitation (co-IP) molecular docking, western blot, luciferase reporter assay, and chromatin immunoprecipitation (ChIP) assay were used for elucidating the mechanisms of how Irisin antagonized transforming growth factor-β (TGF-β)/Smad signaling in oim/oim osteoblasts and further attenuated the inhibitory effect of TGF-β1 on osteogenic differentiation. Results: Musculoskeletal system-related FNDC5/Irisin was decreased in the serum, muscle, and bone in oim/oim mice. Irisin administration reduced bone fracture and attenuated bone abnormalities by improving bone mass and strength and facilitating the expression of osteogenic differentiation markers. In vivo study and in vitro experiments showed that Irisin antagonized TGF-β/Smad signaling by interfering with TGF-β1-TGF-β receptor II (TβRII) binding. In oim/oim osteoblasts, Irisin alleviated TGF-β1-induced suppression of osteogenic differentiation through both integrin-dependent and integrin-independent mechanisms. Independent of integrin receptors, Irisin affected osteogenesis by activating ERK/p38 signaling and counteracting TGF-β/Smad2/3 signaling. In particular, Irisin alleviated TGF-β1-induced inhibition of Runx2 function at the osteocalcin promoter through decreasing Smad2/3 signaling and inducing HADC4/5 degeneration. Conclusions: Collectively, Irisin could effectively reduce bone fracture in oim/oim mice through promoting osteogenesis and counteracting TGF-β/Smad signaling. Translational potential statement: Findings from this study provided evidence for using Irisin as a potential therapeutic reagent to prevent the progression of OI.http://www.sciencedirect.com/science/article/pii/S2214031X22001176IrisinTGF-βBone fractureOsteogenesis imperfectaOsteogenesis |
| spellingShingle | Bin Sun Huiqiao Wu Jiajia Lu Rongcheng Zhang Xiaolong Shen Yifei Gu Changgui Shi Ying Zhang Wen Yuan Irisin reduces bone fracture by facilitating osteogenesis and antagonizing TGF-β/Smad signaling in a growing mouse model of osteogenesis imperfecta Journal of Orthopaedic Translation Irisin TGF-β Bone fracture Osteogenesis imperfecta Osteogenesis |
| title | Irisin reduces bone fracture by facilitating osteogenesis and antagonizing TGF-β/Smad signaling in a growing mouse model of osteogenesis imperfecta |
| title_full | Irisin reduces bone fracture by facilitating osteogenesis and antagonizing TGF-β/Smad signaling in a growing mouse model of osteogenesis imperfecta |
| title_fullStr | Irisin reduces bone fracture by facilitating osteogenesis and antagonizing TGF-β/Smad signaling in a growing mouse model of osteogenesis imperfecta |
| title_full_unstemmed | Irisin reduces bone fracture by facilitating osteogenesis and antagonizing TGF-β/Smad signaling in a growing mouse model of osteogenesis imperfecta |
| title_short | Irisin reduces bone fracture by facilitating osteogenesis and antagonizing TGF-β/Smad signaling in a growing mouse model of osteogenesis imperfecta |
| title_sort | irisin reduces bone fracture by facilitating osteogenesis and antagonizing tgf β smad signaling in a growing mouse model of osteogenesis imperfecta |
| topic | Irisin TGF-β Bone fracture Osteogenesis imperfecta Osteogenesis |
| url | http://www.sciencedirect.com/science/article/pii/S2214031X22001176 |
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