CN112773888A - Application of irisin in preparation of medicine for preventing and treating bone fracture - Google Patents
Application of irisin in preparation of medicine for preventing and treating bone fracture Download PDFInfo
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- CN112773888A CN112773888A CN202110155760.XA CN202110155760A CN112773888A CN 112773888 A CN112773888 A CN 112773888A CN 202110155760 A CN202110155760 A CN 202110155760A CN 112773888 A CN112773888 A CN 112773888A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
Abstract
The invention discloses an application of Irisin in preparing a medicament for preventing and treating fracture and/or promoting fracture healing. Also discloses a pharmaceutical preparation for preventing and treating bone fracture and/or promoting bone fracture healing. Experimental results show that Irisin can remarkably promote osteogenic differentiation and mineralization processes of MSC cells, remarkably promote migration, tube formation and expression of related angiogenetic genes of HUVEC, improve bone volume fraction (BV/TV) and bone density (BMD) of callus tissues, improve vascular surface area (vascular surface) and vascular volume fraction (vascular volume fraction) of callus tissues, and improve expression of bone related protein BMP2 and angiogenesis related proteins CD31 and VEGF.
Description
Technical Field
The invention belongs to the technical field of new application of medicaments, and particularly relates to application of irisin in preparation of medicaments for preventing and treating bone fracture
Background
Irisin (Irisin) is a protein molecule which is mainly secreted by muscle tissues of human bodies and other mammals in motion and is sheared from fibronectin type III domain protein 5(FNDC5), previous researches find that Irisin plays an important role in the process of browning white fat, and brown fat can increase the fat metabolism of organisms and is considered as a potential treatment direction for diseases such as obesity and the like.
Fracture is a type of injury to the locomotor system, placing a heavy burden on society and on the patient's person. Problems in the process of fracture healing, such as delayed union and nonunion, increase with the number of attacks of fractures and the progression of aging of the population. On the basis of surgical treatment, drugs may act by promoting fracture healing.
Irisin is produced in large quantities during exercise, and in the skeletal muscle system. The role of irisin in bone tissue has been studied in recent years, which can increase bone mass of skeletal cortical bone, and as an important molecule in skeletal muscle interaction process, which is expected to have therapeutic significance in bone tissue-related diseases.
The existing fracture treatment is mainly based on internal fixation and external fixation technologies, under the braking environment, callus is rapidly formed at the fracture part, along with the development of the healing process, the callus is gradually mineralized and is changed from soft callus to hard callus, and finally, the soft callus is replaced by new bone.
Some drugs that have a promoting effect on the healing process of fractures, such as BMP-2 (approved in 2004 for treating tibial nonunion), have side effects of ectopic ossification and inflammation, and do not promote the vascular ingrowth required for the callus of fractures, which limits their clinical applications. Therefore, a drug that can promote both osteogenesis and angiogenesis is more important.
Disclosure of Invention
In view of the above-mentioned drawbacks of the prior art, the present invention aims to provide the following solutions:
the application of irisin in preparing medicine for preventing and treating fracture and/or promoting fracture healing is provided.
Further, the application of the irisin in preparing the medicine for preventing and treating bone fracture and/or promoting fracture healing is characterized in that the irisin is used for improving the body volume fraction (BV/TV) and bone density (BMD) of callus tissues.
Furthermore, the application of the irisin in preparing the medicine for preventing and treating bone fracture and/or promoting bone fracture healing is characterized in that the irisin is used for improving the vascular surface area (vascular surface) and the vascular volume fraction (vascular volume fraction) of callus tissues.
Furthermore, the application of the irisin in preparing the medicine for preventing and treating bone fracture and/or promoting bone fracture healing is characterized in that the irisin is used for improving the vascular surface area (vascular surface) and the vascular volume fraction (vascular volume fraction) of callus tissues.
Furthermore, the application of irisin in preparing the medicine for preventing and treating bone fracture and/or promoting fracture healing is characterized in that the irisin is used for improving the expression of bone related protein BMP2 and angiogenesis related proteins CD31 and VEGF.
Furthermore, the application of irisin in preparing the medicine for preventing and treating bone fracture and/or promoting fracture healing is characterized in that the irisin is used for promoting osteogenic differentiation and mineralization process of MSC cells and/or promoting migration, tube formation and expression of related angiogenetic genes of HUVEC.
A pharmaceutical preparation for preventing and treating bone fracture and/or promoting bone fracture healing is characterized by comprising effective dose of irisin or irisin and pharmaceutically acceptable auxiliary materials.
Further, the pharmaceutical preparation is suitable for gastrointestinal or parenteral administration.
Furthermore, the pharmaceutical preparation is a freeze-dried preparation, an injection, a tablet, a granule or a capsule.
Furthermore, the pharmaceutical preparation is a stent or microsphere carrying Irisin protein.
The invention has the beneficial effects that the invention discloses the application of Irisin in preparing the medicine for preventing and treating fracture and/or promoting fracture healing. Also discloses a pharmaceutical preparation for preventing and treating bone fracture and/or promoting bone fracture healing. Experimental results show that Irisin can remarkably promote osteogenic differentiation and mineralization processes of MSC cells, remarkably promote migration, tube formation and expression of related angiogenetic genes of HUVEC, improve bone volume fraction (BV/TV) and bone density (BMD) of callus tissues, improve vascular surface area (vascular surface) and vascular volume fraction (vascular volume fraction) of callus tissues, and improve expression of bone related protein BMP2 and angiogenesis related proteins CD31 and VEGF. Therefore, Irisin provides a new way for preventing and treating fracture.
Description of the drawings:
FIG. 1 is a diagram of the mechanism of action of Irisin in preventing and/or treating bone fracture and/or promoting fracture healing.
FIG. 2 shows the effect of Irisin on callus formation and mineralization.
FIG. 3 shows the effect of Irisin on bone volume fraction (BV/TV) and bone density (BMD) of callus.
FIG. 4 shows the effect of Irisin on vascular surface area (vascular surface) and vascular volume fraction (vascular volume fraction) of callus tissue.
FIG. 5 shows the effect of Irisin on callus formation, mineralization, expression of the protein BMP2 and the angiogenesis-related proteins CD31 and VEGF.
FIG. 6 is a graph showing the effect of Irisin on osteoblastic differentiation of MSC cells.
FIG. 7 shows the effect of Irisin on HUVEC cells.
Detailed Description
The present invention is further described below with reference to specific examples, which are only exemplary and do not limit the scope of the present invention in any way. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention, and that such changes and modifications may be made without departing from the spirit and scope of the invention.
The technical solution of the present patent will be described in further detail with reference to the following embodiments.
In the following examples, Irisin is commercially available under the trade designation (8880-IR-025, R & D, MN, USA), and the control group is a solvent control group injected with no Irisin.
Example 1 in vivo experiment of Effect of Irisin
Irisin-promoting effect on fracture healing in C57 mice
Male C57BL/6 mice, 8 weeks old, were anesthetized by intraperitoneal injection of 7% chloral hydrate, and then a stable femoral open fracture model was established with a 23-gauge intramedullary needle. After surgery, mice were randomized into control and irisin treatment groups. The mice were administered intraperitoneally, starting on the first day after surgery, with recombinant irisin (8880-IR-025, R & D, MN, USA) at a dose of 100 μ g/kg body weight every other day. The same volume of vehicle (0.9% physiological saline) was injected into control mice.
Mice were X-rayed and evaluated for fracture healing at 3, 7, 10, 15, 17d after surgery, and were harvested at 2, 3w after surgery and scanned and quantified for callus and blood vessels by Micro-CT, while histological staining was performed to observe callus growth and changes in expression of antibodies associated with osteogenesis and angiogenesis.
Effect of Irisin on callus formation and mineralization
The fractured regions of the mice were X-ray scanned 3, 7, 10, 15, 17 days after surgery and evaluated for callus formation and mineralization during Fracture healing using Fracture healing scores (fraction healing score, FHS, quantification of imaging images by three independent observers, Fracture healing scores determined by evaluating three criteria: bone formation, bone healing and bone remodeling). As shown in fig. 2, it was found that the fracture healing score of mice in the Irisin intervention group was significantly higher than that of the control group at 7d, 15d, and 17d after the operation.
Effect of Irisin on bone volume fraction (BV/TV) and bone Density (BMD) of callus
As shown in FIG. 3, the callus tissues of mice at 2w and 3w after surgery were scanned and quantified using Micro-CT, and the callus tissues of mice in Irisin group were found to have higher bone volume fraction (BV/TV) and bone density (BMD).
Effect of Irisin on vascular surface area (vessel surface) and vascular volume fraction (vessel volume fraction) of callus tissue.
As shown in FIG. 4, the blood vessels in the callus tissue of mice at 2w and 3w after surgery were scanned and quantified by Micro-CT, and the callus tissue of the Irisin group mice was found to have higher vascular surface area (vascular surface) and vascular volume fraction (vascular volume fraction).
Effect of Irisin on callus formation, mineralization, expression of the protein BMP2 and the angiogenesis-related proteins CD31 and VEGF
As shown in fig. 5, callus formation was observed by bone tissue staining, and it was found that there was no abnormality in callus formation and mineralization in irisin group, and that expression of osteogenic-related protein BMP2 and angiogenetic-related proteins CD31 and VEGF was significantly increased by immunohistochemistry compared to control group.
Example 2 in vitro experiment of the Effect of Irisin
Effect of Irisin on osteogenic differentiation of MSC cells
The culture medium of the mouse primary MSC was 10% FBS DMEM. Culture medium for osteogenic induced differentiation: osteogenesis induction medium was supplemented with 10nM dexamethasone, 10mM b-glycerophosphate and 0.05mM l-ascorbic acid-2-phosphate on the basis of the medium to induce osteogenesis.
Irisin with a concentration of 100ng/ml is used for stimulating primary MSC cells of mice and simultaneously inducing osteogenic differentiation of the cells, and as shown in FIG. 6, it is found that irisin can remarkably promote the osteogenic differentiation and mineralization process of the cells.
Effect of Irisin on HUVEC cells
HUVEC used 10% FBS alpha-MEM culture medium, cell migration experiment using scratch test evaluation, its specific method is: HUVECs were seeded at a density of 1X 106 cells/well in 6-well plates. After growth to 85% -90% confluence, the wound was scratched by scraping the cells with a sterile disposable pipette tip to form a horizontal line. Then, cells were washed twice with PBS and incubated in 2% FBS α -MEM with 2% FBS and 100ng/mL irisin or the same volume of PBS. After 12 and 24 hours of incubation, cells that had migrated to the wound area were photographed with an inverted phase microscope (olympus, japan) and the relative percentage of wound healing was calculated using ImageJ (NIH, usa). Tube formation analysis was performed in matrigel (bd biosciences) according to the manufacturer's guidelines. HUVEC were suspended in 2% FBS DMEM containing 2% FBS and 100ng/mL Irisin or the same volume of PBS. HUVECs (1.5X 104) were plated onto Matrigel-coated 96-well plates. The plates were incubated at 37 ℃ in 5% CO 2 for 6 hours. The cells were then stained with calcein-AM solution (Yeason, shanghai, china) and 4, 6-dimido-2-phenylindole (DAPI). The formation of the tube was photographed under a fluorescent microscope (Olympus Corporation, Japan).
HUVECs were stimulated with irisin at a concentration of 100ng/ml, and it was found that irisin significantly promoted HUVEC migration, tubulation, and expression of the associated angiogenie genes, as shown in fig. 7.
In summary, the following conclusions are drawn from the above results:
(1) the following results were obtained by in vitro experiments: irisin can remarkably promote osteogenic differentiation and mineralization processes of MSC cells, and remarkably promote migration, tube formation and expression of related angiogenetic genes of HUVEC.
(2) The following results are obtained through in vivo experiments: irisin can promote fracture healing, increase bone volume fraction (BV/TV) and bone density (BMD) of callus, increase vascular surface area (vascular surface) and vascular volume fraction (vascular volume fraction) of callus, and increase expression of bone related protein BMP2 and angiogenesis related proteins CD31 and VEGF
By combining the experimental results in vitro and in vivo, Irisin can be used as a medicine for promoting fracture healing, relieving the state of illness and achieving the purpose of treatment.
Claims (10)
1. The application of irisin in preparing medicine for preventing and treating fracture and/or promoting fracture healing is provided.
2. The use of irisin in the preparation of a medicament for the prevention and/or treatment and/or promotion of healing of bone fractures according to claim 1, wherein irisin is used to increase body mass score (BV/TV) and bone density (BMD) of callus tissue.
3. The use of irisin in the preparation of a medicament for the prevention and/or treatment of bone fractures and/or for promoting healing of bone fractures according to claim 1, wherein irisin is used to increase vascular surface area (vascular surface) and vascular volume fraction (vascular volume fraction) of callus tissue.
4. The use of irisin in the preparation of a medicament for the prevention and/or treatment of bone fractures and/or for promoting healing of bone fractures according to claim 1, wherein irisin is used to increase vascular surface area (vascular surface) and vascular volume fraction (vascular volume fraction) of callus tissue.
5. The use of irisin in the preparation of a medicament for the prevention and/or treatment of bone fractures and/or the promotion of fracture healing according to claim 1, wherein irisin is used to increase the expression of bone-related protein BMP2 and the angiogenesis-related proteins CD31 and VEGF.
6. The use of irisin in the manufacture of a medicament for the prevention and treatment and/or promotion of fracture healing according to claim 1, wherein irisin is used to promote osteogenic differentiation and mineralization of MSC cells and/or to promote migration, vascularization and expression of relevant angiogenie genes of HUVECs.
7. A pharmaceutical preparation for preventing and treating bone fracture and/or promoting bone fracture healing is characterized by comprising effective dose of irisin or irisin and pharmaceutically acceptable auxiliary materials.
8. The pharmaceutical formulation of claim 7, wherein the pharmaceutical formulation is suitable for gastrointestinal or parenteral administration.
9. The pharmaceutical preparation of claim 7, wherein the pharmaceutical preparation is a lyophilized preparation, an injection, a tablet, a granule or a capsule.
10. The pharmaceutical formulation of claim 7, wherein the pharmaceutical formulation is an Irisin protein loaded scaffold or microsphere.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20180153960A1 (en) * | 2015-04-16 | 2018-06-07 | Universita' Degli Studi Di Bari | Irisin for care and prevention of osteoporosis |
| CN111000986A (en) * | 2019-12-10 | 2020-04-14 | 上海交通大学医学院附属第九人民医院 | Application of irisin in preparing medicine for preventing and treating osteoarthritis |
| US20200289625A1 (en) * | 2017-10-25 | 2020-09-17 | Texas A&M University System | Uses of Irisin |
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- 2021-02-04 CN CN202110155760.XA patent/CN112773888A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20180153960A1 (en) * | 2015-04-16 | 2018-06-07 | Universita' Degli Studi Di Bari | Irisin for care and prevention of osteoporosis |
| US20200289625A1 (en) * | 2017-10-25 | 2020-09-17 | Texas A&M University System | Uses of Irisin |
| CN111000986A (en) * | 2019-12-10 | 2020-04-14 | 上海交通大学医学院附属第九人民医院 | Application of irisin in preparing medicine for preventing and treating osteoarthritis |
Non-Patent Citations (3)
| Title |
|---|
| 吴菲: "（一）重组Irisin蛋白诱导内皮细胞迁移和血管新生及其机制研究 （二）二氢杨梅素对顺铂引起肾损伤的保护性作用及其机制研究", 《中国博士学位论文全文数据库 医药卫生科技辑》 * |
| 席梦莹等: "鸢尾素促进大鼠胫骨骨折愈合的研究", 《重庆医科大学学报》 * |
| 田梦婷等: "鸢尾素对大鼠骨髓间充质干细胞Sost基因表达及成骨分化的影响", 《中华口腔医学研究杂志（电子版）》 * |
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Application publication date: 20210511 |