CN112336863A - Application of S1P receptor inhibitor in preparation of product for preventing and treating ankylosing spondylitis - Google Patents
Application of S1P receptor inhibitor in preparation of product for preventing and treating ankylosing spondylitis Download PDFInfo
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- CN112336863A CN112336863A CN202011346592.4A CN202011346592A CN112336863A CN 112336863 A CN112336863 A CN 112336863A CN 202011346592 A CN202011346592 A CN 202011346592A CN 112336863 A CN112336863 A CN 112336863A
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
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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
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Abstract
The invention belongs to the technical field of medical biology, and particularly relates to application of an S1P receptor inhibitor in preparation of a product for preventing and treating ankylosing spondylitis, aiming at solving the problem that pathological osteogenic fusion of joints and spines of patients cannot be solved by current AS treatment.
Description
Technical Field
The invention belongs to the technical field of medical biology, and particularly relates to an application of an S1P receptor inhibitor in preparation of a product for preventing and treating ankylosing spondylitis.
Background
Ankylosing Spondylitis (AS), a seronegative spondyloarthropathy, is an autoimmune disease characterized by inflammatory involvement of the spine and sacroiliac joints. The male is frequently attacked, mainly affects young and strong years, usually attacks about 18-22 years old, and the incidence rate of China is high. Patients with AS have clinical manifestations of inflammatory low back pain, stiffness and restricted mobility, and some patients may have extra-articular manifestations such AS uveitis. Since chronic inflammation existing in vivo for a long time can affect the synovial joint, cartilage joint and tendon, ligament attached to bone, the patient can rapidly progress into bony ankylosis, which is characterized by spinal fusion and limited activity.
At present, the treatment aiming at the AS mainly aims at relieving inflammation, but AS the disease progresses, even if the inflammation is well controlled, the pathological osteogenesis in the body of a patient still cannot be blocked, and no effective method aiming at treating the excessive osteogenesis in the AS body exists. The patient shows the ankylosis and the spinal osseous fusion in the late stage, and can recover partial mobility only through surgical correction. Therefore, the clinical need is urgent to find an accurate target point which can effectively delay the pathological osteogenesis of patients.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention can effectively slow down the pathological osteogenesis and spinal fusion progress of AS focuses by inhibiting the generation of H-shaped blood vessels in the body of a patient with ankylosing spondylitis, break through the bottleneck of AS treatment and realize the control of the disease attack of the ankylosing spondylitis.
In order to achieve the purpose, the invention adopts the technical scheme that:
the invention provides application of an S1P receptor inhibitor in preparation of a product for preventing and treating ankylosing spondylitis.
Preferably, the S1P receptor inhibitors include, but are not limited to, FTY720, VPC-23019. Further, the FTY720 is S1PBody inhibitor FTY720 group (inhibiting S1P)1/3/4/5Receptor function), the VPC-23019 is the S1P receptor inhibitor VPC-23019 group (inhibiting S1P)1/3The function of the receptor).
Preferably, the prevention and treatment of ankylosing spondylitis is inhibition of H-type angiogenesis in patients with ankylosing spondylitis.
Bone formation and angiogenesis are processes that are coupled to each other. Type H vessels have recently been found to be distributed predominantly in the endosteum and long metaphysis of bone, as CD31+EMCN+Is a characteristic vascular subtype. It has been reported in the literature that this particular vascular subtype is capable of regulating skeletal vascular density, maintaining perivascular osteoprogenitor cell activity, coupling angiogenesis and bone formation, and promoting osteogenic differentiation in humans under normal physiological conditions and pathological conditions of disease.
The function of Sphingosine-1-phosphate (S1P) is closely related to H angiogenesis, the invention inhibits the generation of H-type blood vessels by inhibiting the function of S1P receptors (S1P receptor inhibitors FTY720 and VPC-23019), and the invention finds that after the H-type blood vessels are inhibited in an AS mouse model, namely an SKG mouse, the pathological osteogenesis in the mouse is effectively controlled, which indicates that the control of the H-type blood vessels generation is possibly a new target for treating the excessive osteogenesis of AS.
Preferably, the product for preventing and treating ankylosing spondylitis includes, but is not limited to, drugs for preventing and treating ankylosing spondylitis and health-care functional foods for preventing and treating ankylosing spondylitis.
The invention also provides a medicine for preventing and treating ankylosing spondylitis, which comprises an S1P receptor inhibitor.
Preferably, in order to improve the application range of the medicine, the medicine also comprises a pharmaceutically acceptable carrier and/or an auxiliary material. Such as acidulants, toners, flavorants, sweeteners, or combinations thereof.
Preferably, the dosage form of the ankylosing spondylitis prevention and treatment drug comprises but is not limited to oral liquid, granules, capsules, tablets, granules, pills, paste and injections.
The invention also provides a health-care functional food for preventing and treating ankylosing spondylitis, which is characterized by comprising an S1P receptor inhibitor.
Preferably, in order to improve the application range of the health functional food, the health functional food further comprises a carrier and/or an auxiliary material acceptable on the food. Such as diluents, excipients, fillers, binders, humectants, disintegrants, absorption enhancers, sweeteners, flavorants, or combinations thereof.
Preferably, the dosage form of the health-care functional food for preventing and treating ankylosing spondylitis includes, but is not limited to, liquid preparations, tablets and powders.
Compared with the prior art, the invention has the beneficial effects that:
because the existing AS treatment methods cannot solve the problem of pathological osteogenic fusion of joints and spines of patients, the invention provides the application of an S1P receptor inhibitor in preparing products for preventing and treating ankylosing spondylitis, the method of inhibiting H angiogenesis is taken, the pathological osteogenesis is inhibited by the function discovery of inhibiting S1P receptors, and the spine fusion is delayed, so that a new AS treatment target is discovered, and a new direction is provided for preventing and treating ankylosing spondylitis.
Drawings
FIG. 1 is a flow chart of an animal experiment;
FIG. 2 is a graph comparing H-type angiogenesis at the lesion site before and after treatment of SKG mice;
FIG. 3 is a comparison graph of OCN expression of the osteogenic marker protein at the lesion site before and after treatment of SKG mice;
FIG. 4 is a Micro-CT contrast chart of spinal fusion and osteophyte generation before and after treatment of SKG mice.
Detailed Description
The following further describes the embodiments of the present invention. It should be noted that the description of the embodiments is provided to help understanding of the present invention, but the present invention is not limited thereto. In addition, the technical features involved in the embodiments of the present invention described below may be combined with each other as long as they do not conflict with each other.
The experimental procedures in the following examples were carried out by conventional methods unless otherwise specified, and the test materials used in the following examples were commercially available by conventional methods unless otherwise specified.
Example 1 animal experiments: effect of S1P receptor inhibitor on pathological osteogenesis and spinal fusion conditions of mice
The flow of the animal experiment is shown in figure 1:
(1) mouse model
SKG mice were developed by CLEA corporation of Japan and had genetic mutations in the SH2 domain of ZAP-70, a key signaling molecule in T cells. Due to the T cell signal transduction disorder, the inflammatory T cells in SKG mice are hyperproliferated, so that systemic chronic arthritis and extraarticular manifestations are caused. The mouse can have systemic polyarthritis and bone metabolism abnormality after being induced by curdlan for about 2 weeks, and can develop into spinal bone fusion after being induced for about 8 weeks. The phenotype is similar to the clinical manifestation of AS patients, so the method is widely applied to AS disease models.
SKG mice used in this experiment were purchased from CLEA, Japan, and were induced to develop disease by intraperitoneal injection of 3mg of curdlan (purchased from Wako Chemicals) at 10 weeks of age.
(2) Group administration
SKG mice were randomly divided into 4 groups of 10 mice each, including control group 1 and S1P receptor inhibitor FTY720 group (inhibiting S1P)1/3/4/5Receptor function), control 2 and S1P receptor inhibitors VPC-23019 (inhibiting S1P)1/3Receptor function). The specific medication scheme is as follows:
oral FTY720 group: FTY720 (purchased from ApexBio Technology) was dissolved in DMSO solvent, and the disease was induced by intraperitoneal injection of 3mg curdlan at week 10, and received 4 consecutive weeks of experimental drinking water (free drink) from week 19 to week 22, and an aqueous solution (1mg/kg) containing FTY720 was drunk, and mice in control group 1 were drunk with double distilled water.
Injection of VPC-23019 group: VPC-23019 (purchased from Avanti Polar Lipids, Inc.) was dissolved in DMSO solvent, 3mg of curdlan was intraperitoneally injected at week 10 to induce morbidity, and VPC-23019 antagonist (0.75mg/kg, twice daily, morning/evening) was intraperitoneally injected for 9 consecutive days beginning at week 19, and mice in control group 2 were intraperitoneally injected with an equal amount of physiological saline.
(3) Detecting H-type angiogenesis and spinal fusion conditions of mice
After 4 weeks of oral FTY720 drug administration or 9 days of VPC-23019 drug injection, mice were sacrificed by overdose anesthesia and then measured for the following:
1) scanning the spine of the mouse by adopting a Micro-computed tomography (Micro-CT) method, and detecting and evaluating the spine bone fusion condition of the mouse;
2) taking 3 rd to 5 th lumbar vertebra segments of a vertebral column of a mouse, and carrying out xylem-eosin staining (HE) staining after fixing, decalcification, paraffin embedding and slicing treatment in sequence;
3) bone neogenesis of the spinal column of mice was assessed by detection of Osteocalcin (OCN) by Immunohistochemical (IHC) staining;
4) grinding the femoral head of a mouse by liquid nitrogen, separating living cells for flow cytometry analysis, and detecting the H-type angiogenesis condition of the mouse.
(4) Results
With CD31+EMCN+The cells were detected by flow cytometry as surface markers specific to type H blood vessels. Type H angiogenesis at the femoral head of mice was reduced following treatment with S1P receptor inhibitor compared to control (figure 2).
The IHC results showed that the mouse spinal OCN protein expression was reduced and osteogenesis was reduced after treatment with S1P receptor inhibitor compared to the control group (fig. 3).
The spine of the mice was scanned by micro-CT and it was found that pathological osteogenesis and spinal fusion of the mice were reduced after treatment with S1P receptor inhibitor compared to the control group (fig. 4).
Taken together, the results above, treatment of SKG mice with S1P receptor inhibitor inhibited H-type angiogenesis, resulting in reduced spinal fusion. All mice have no side effects such as abnormal death or infection.
The embodiments of the present invention have been described in detail, but the present invention is not limited to the described embodiments. It will be apparent to those skilled in the art that various changes, modifications, substitutions and alterations can be made in these embodiments without departing from the principles and spirit of the invention, and the scope of protection is still within the scope of the invention.
Claims (10)
- Application of an S1P receptor inhibitor in preparing a product for preventing and treating ankylosing spondylitis.
- 2. The use of claim 1, wherein the S1P receptor inhibitor includes, but is not limited to, FTY720, VPC-23019.
- 3. The use of claim 1, wherein the prevention and treatment of ankylosing spondylitis is inhibition of H-angiogenesis in patients with ankylosing spondylitis.
- 4. The use according to claim 1, wherein the products for preventing and treating ankylosing spondylitis include, but are not limited to, drugs for preventing and treating ankylosing spondylitis and health-care functional foods for preventing and treating ankylosing spondylitis.
- 5. A medicament for preventing and treating ankylosing spondylitis, which is characterized by comprising an S1P receptor inhibitor.
- 6. The medicament for preventing and treating ankylosing spondylitis according to claim 5, further comprising a pharmaceutically acceptable carrier and/or adjuvant.
- 7. The drug for preventing and treating ankylosing spondylitis according to claim 5, wherein the dosage form of the drug for preventing and treating ankylosing spondylitis includes but is not limited to oral liquid, granules, capsules, tablets, granules, pills, paste and injections.
- 8. A health functional food for preventing and treating ankylosing spondylitis is characterized by comprising an S1P receptor inhibitor.
- 9. The health-care functional food for preventing and treating ankylosing spondylitis of claim 8, further comprising a food-acceptable carrier and/or an auxiliary material.
- 10. The health-care functional food for preventing and treating ankylosing spondylitis of claim 8, wherein dosage forms of the health-care functional food for preventing and treating ankylosing spondylitis include, but are not limited to, liquid preparations, tablets and powders.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN113425723A (en) * | 2021-07-26 | 2021-09-24 | 中山大学附属第八医院（深圳福田） | Application of Pim1 small-molecule inhibitor in preparation of product for preventing and treating ankylosing spondylitis |
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