Use of PT-129 in the preparation of a medicament for treating rheumatoid arthritis

Abstract

This invention discloses the application of PT-129 in the preparation of drugs for treating rheumatoid arthritis (RA), belonging to the field of RA treatment. This invention is the first to demonstrate that the compound PT-129 can target and intervene in the synovial microenvironment, effectively inhibiting the abnormal activation behaviors of RA fibroblast-like synovial cells (FLS) such as proliferation, migration, and invasion, and downregulating the expression of N-cadherin and MMP3 proteins in synovial tissue. This invention provides a combined drug formulation containing PT-129 and RGFP966. This composition exhibits a significant synergistic effect in vivo, effectively relieving joint swelling, increasing bone density and trabecular bone thickness, reducing trabecular bone separation, thereby inhibiting cartilage degradation and bone destruction. This invention provides a novel targeted drug and combination therapy with definite efficacy for the clinical intervention of RA, possessing extremely high clinical application development value.

Description

Technical Field

[0001] This invention belongs to the field of rheumatoid arthritis treatment, specifically involving the application of PT-129 in the preparation of drugs for treating rheumatoid arthritis. Background Technology

[0002] Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic synovial inflammation and progressive joint damage. Epidemiological data shows that the prevalence of RA in my country is approximately 0.28%, with nearly half of patients experiencing work impairment due to disease progression, placing a heavy burden on individuals, families, and the social healthcare system. The pathological process of RA involves multiple stages, including immune cell infiltration, synovial tissue proliferation, cartilage degradation, and bone erosion, and its pathogenesis is not yet fully understood.

[0003] Fibroblast-like synoviocytes (FLSs) are the main stromal cells in the synovial tissue of joints. In the inflammatory microenvironment of rheumatoid arthritis (RA), FLSs undergo phenotypic transformation and acquire invasive biological behaviors: on the one hand, they exhibit uncontrolled proliferation and resistance to apoptosis; on the other hand, they directly degrade cartilage matrix and promote osteoclast differentiation and activation by secreting effector molecules such as matrix metalloproteinases (MMPs) and RANKL, mediating joint bone destruction. Simultaneously, activated FLSs release large amounts of pro-inflammatory cytokines such as IL-6 and IL-8, as well as chemokines, continuously recruiting macrophages, T cells, and other immune cells to infiltrate the synovial tissue, forming a positive feedback loop of inflammation, ultimately leading to synovial pannus formation and irreversible joint structural damage. These pathological processes suggest that abnormal FLS activation is not only a key link in maintaining synovial inflammation in RA but also a direct driver of joint structural destruction. Based on this, targeted regulation of FLS function and its activation pathways has become an important direction in the development of RA treatment strategies, and the application of drugs such as JAK inhibitors and MMP inhibitors is providing new ideas for improving the clinical prognosis of RA.

[0004] There are currently no reports on the use of PT-129 in the preparation of drugs for the treatment of rheumatoid arthritis. Summary of the Invention

[0005] In view of the shortcomings of the prior art, the purpose of this invention is to provide the application of PT-129 in the preparation of drugs for treating rheumatoid arthritis, thereby solving the problems in the prior art.

[0006] The objective of this invention can be achieved through the following technical solutions: Application of PT-129 in the preparation of drugs for treating rheumatoid arthritis.

[0007] Furthermore, the drug also includes one or more of a diluent, an excipient, and a carrier.

[0008] Furthermore, the dosage form of the drug is: granules, capsules, tablets, pills, or injections.

[0009] Use of a pharmaceutical composition comprising RGFP966 and PT-129 in the preparation of a medicament for treating rheumatoid arthritis.

[0010] Furthermore, the molar ratio of RGFP966 to PT-129 is 2:1.

[0011] Furthermore, the drug is an intra-articular injection.

[0012] Furthermore, the treatment includes inhibiting the proliferation, migration, and invasion of fibroblast-like synovial cells in rheumatoid arthritis.

[0013] Furthermore, it inhibits the proliferation, migration, and invasion of fibroblast-like synovial cells in rheumatoid arthritis, including inhibiting the expression of N-cadherin protein in said synovial cells.

[0014] Furthermore, it inhibits the proliferation, migration, and invasion of fibroblast-like synovial cells in rheumatoid arthritis, including inhibiting the expression of MMP3 in said synovial cells.

[0015] A drug with RGFP966 and PT-129 as active ingredients.

[0016] The beneficial effects of this invention are: This invention uses fibroblast-like synovial cells (RA-FLS) from rheumatoid arthritis as the research object to investigate the inhibitory effect of PT-129 on TNF-α-induced RA-FLS proliferation, migration, and invasion. Furthermore, an adjuvant-induced arthritis (AA) rat model was established using complete Freund's adjuvant (CFA) to evaluate the in vivo efficacy of PT-129. The results showed that intra-articular injection of PT-129 significantly reduced the arthritis index score in AA rats, effectively alleviated pathological symptoms such as joint swelling, reduced synovial tissue hyperplasia and cartilage damage, and simultaneously inhibited the protein expression of N-cadherin and MMP3 in synovial tissue. In summary, this invention, through in vitro and in vivo experiments, demonstrates that PT-129 exhibits good pharmacological activity in the treatment of rheumatoid arthritis, has the potential to intervene in abnormal RA-FLS activation and joint damage, and can be used as a candidate compound for the preparation of drugs for the prevention and treatment of rheumatoid arthritis, showing promising clinical application prospects. Attached Figure Description

[0017] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, for those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0018] Figure 1 This is a graph analyzing the effect of PT-129 on the proliferation of TNF-α-induced RA-FLS. Figure 2 This is a graph analyzing the effects of PT-129 on the migration and invasion ability of TNF-α-induced RA-FLS. Figure 3 This is a graph showing the effect of PT-129 on the arthritis index and symptoms in AA rats; Figure 4 This is a graph showing the effect of PT-129 on the spleen index of AA rats; Figure 5 This is a graph analyzing the effects of PT-129 on joint bone damage in AA rats; Figure 6 This is a graph showing the effect of PT-129 on the pathological characteristics of synovial membrane and cartilage tissue in AA rats. Figure 7 This is a graph showing the effect of PT-129 on abnormal activation of FLS in the synovial tissue of AA rats. Detailed Implementation

[0019] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0020] The technical solution of the present invention will be described and illustrated below through the following embodiments, and the sources of the relevant raw materials used in the embodiments are as follows: The structural formula of PT-129 is as follows: PT-129: Purchased from MedChemExpress, part number HY-170872; N-cadherin antibody: purchased from Abcam, catalog number ab18203; MMP3 antibody: purchased from Abcam, catalog number ab52915; Vimentin antibody: purchased from Proteintech, catalog number 60330-1-Ig; Fluorescently labeled secondary antibodies: Alexa Fluor® 488-conjugated goat anti-rabbit IgG (H+L) and Alexa Fluor® 594-conjugated goat anti-mouse IgG (H+L) were purchased from Beijing Zhongshan Jinqiao Biotechnology Co., Ltd., with catalog numbers ZF-0511 and ZF-0513 respectively; The source of RGFP966 is: purchased from Selleck, catalog number S7229; The source of TNF-α was PeproTech, product number 300-01A-10UG; Male Sprague-Dawley (SD) rats: Six-week-old male SD rats were purchased from Jiangsu Jicui Yaokang Biotechnology Co., Ltd., production license number: SCXK (Su) 2023-0009, experimental unit name: Hefei Comprehensive National Science Center Big Health Research Institute, usage license number: SYXK (Anhui) 2023-004.

[0021] Example 1 In this embodiment, the effect of PT-129 on the proliferation ability of TNF-α-induced RA-FLS was verified; Cell isolation and culture: Synovial tissue was collected from rheumatoid arthritis patients undergoing joint replacement surgery at the Department of Orthopedics, Second Affiliated Hospital of Anhui Medical University. This experiment was approved by the Ethics Committee of the Second Affiliated Hospital of Anhui Medical University and informed consent was obtained from the patients. After washing, the synovial tissue was carefully cleaned to remove fat and fibrous components, and the tissue was cut into pieces with a volume of less than 1 mm. 3Small tissue fragments were evenly adhered to the bottom of the culture flask. After standing at 37℃ for 6 h to allow the tissue fragments to adhere firmly, 4 mL of DMEM / high glucose medium containing 20% ​​fetal bovine serum and 100 IU / mL penicillin / streptomycin was slowly added, and the flask was placed in a cell culture incubator. Cells from passages 3 to 6 were used for subsequent experiments. The effect of PT-129 on RA-FLS cell viability and proliferation was detected using the CCK-8 assay. RA-FLS cells in the logarithmic growth phase were seeded in 96-well plates, and after the cells reached 70%–80% confluence, they were treated with different concentrations of PT-129. Two experimental groups were set up: one was a PT-129 monotherapy group (concentration gradients of 1.25, 2.5, 5, 10, 20, and 40 μM, treated for 48 h) to evaluate the effect of the drug on basal cell viability; the other was a PT-129 and TNF-α co-treatment group (PT-129 concentrations of 5, 10, 20, and 40 μM, combined with 10 ng / mL TNF-α treatment for 48 h) to observe the intervention effect of the drug on cell proliferation under inflammatory stimulation. After incubation, 10 μL of CCK-8 solution was added to each well, and the cells were cultured for another 2–4 h. The absorbance at 450 nm was measured using a microplate reader to calculate the relative cell viability.

[0022] Experimental results are as follows Figure 1 The data is shown below (data is expressed as mean ± standard error, n=6). P <0.01); Figure 1 In this context, A represents the effect of different concentrations of PT-129 on the baseline activity of RA-FLS. Figure 1 In the figure, B represents the effect of different concentrations of PT-129 on TNF-α-induced RA-FLS proliferation. It can be seen that within the concentration range of 1.25-40 μM, PT-129 monotherapy had no significant effect on the basal activity of RA-FLS, suggesting that PT-129 is not cytotoxic within this concentration range. However, under TNF-α stimulation, PT-129 (5-40 μM) significantly inhibited the excessive proliferation of RA-FLS in a concentration-dependent manner. These results indicate that PT-129 can effectively antagonize TNF-α-induced abnormal proliferation of RA-FLS and possesses potential anti-inflammatory and proliferative activity.

[0023] Example 2 In this embodiment, the effect of PT-129 on the migration and invasion ability of TNF-α-induced RA-FLS was verified; Cell seeding and treatment: RA-FLS cells were seeded in 6-well plates. After the cells reached 70%-80% confluence, a control group and a treatment group were set up. The control group was treated with 10 μM PT-129 and / or 10 ng / mL TNF-α for 48 h, respectively, for subsequent detection.

[0024] Transwell migration and invasion assays: For the migration assay, cells from each treatment group were collected, resuspended in DMEM / high glucose medium containing 5% fetal bovine serum, and the cell density was adjusted to 2 × 10⁶ cells / year. 4 Cells / mL. 200 μL of cell suspension was seeded into the upper chamber, and 600 μL of DMEM / high glucose medium containing 20% ​​fetal bovine serum was added to the lower chamber as a chemotactic agent. After incubation at 37°C and 5% CO2 for 48 h, unmigrated cells on the upper membrane of the upper chamber were carefully wiped away with a cotton swab. The cells in the lower membrane were fixed with methanol for 20 min, stained with 1% crystal violet for 20 min, rinsed with PBS, and air-dried. Randomly selected fields of view were photographed under an optical microscope, and the number of migrating cells was counted. For the invasion assay, Matrigel was diluted 1:10 with serum-free medium on ice, and 60 μL was evenly coated onto the bottom of the pre-chilled Transwell upper chamber. The chamber was incubated at 37°C for 24 h to allow gel formation. Before use, 150 μL of serum-free medium was added to each well to hydrate the Matrigel membrane, and the membrane was incubated at 37°C for 30 min before aspiration. Other steps were the same as for the migration assay.

[0025] Experimental results are as follows Figure 2 The data is shown as mean ± standard error, n=3. P <0.01), Figure 2 In this context, A represents the effect of PT-129 on TNF-α-induced RA-FLS migration activity. Figure 2 In the figure, B represents the effect of PT-129 on the TNF-α-induced RA-FLS invasive activity. It can be seen that compared with the control group, TNF-α treatment (10 ng / mL) significantly enhanced the migration and invasion abilities of RA-FLS; while intervention with PT-129 (10 μM) significantly inhibited TNF-α-induced RA-FLS migration and invasion. The results indicate that PT-129 can effectively antagonize TNF-α-mediated RA-FLS migration and invasion activity.

[0026] Example 3 In this embodiment, the effect of PT-129 on the arthritis index and symptoms of AA rats was verified. Animal grouping and model establishment: Male Sprague-Dawley (SD) rats (weighing 180 ± 20 g) were randomly divided into 5 groups (n=6 per group) after one week of acclimatization: normal control group, adjuvant-induced arthritis model group (AA), PT-129 treatment group (AA + PT-129), RGFP966 treatment group (AA + RGFP966), and a combined treatment group of the two (AA + PT-129 + RGFP966). Inactivated BCG and Freund's incomplete adjuvant were thoroughly emulsified to prepare Freund's complete adjuvant (CFA) at a concentration of 10 mg / mL. Except for the normal control group, rats in the other groups received a single subcutaneous injection of 0.1 mL of CFA into the left hind paw to induce the AA model.

[0027] Dosage regimen: Dissolve PT-129 and / or RGFP966 powder in 10% DMSO, then add 40% PEG300 and 5% Tween 80 sequentially, and finally bring the volume to 45% physiological saline. Sonicate thoroughly until clear to obtain a 10 μM clear solution, which should be prepared immediately before use. On days 12, 15, 18, 21, 24, and 27 after modeling, inject the corresponding drugs into the secondary (right) ankle joint cavity of rats in each treatment group: PT-129 (10 μM, 50 μL), RGFP966 (20 μM, 50 μL), or a combination of both (concentration and volume as above). In the AA model group, inject the corresponding solvent into the secondary (right) ankle joint cavity.

[0028] Arthritis Index Score: The arthritis index was scored on rats in each group at days 3, 6, 9, 12, 15, 18, 21, 24, 27, and 30 after modeling to assess the severity of secondary joint inflammation. The scoring criteria were as follows: 0 points, no joint redness or swelling; 1 point, erythema and mild swelling at the ankle joint; 2 points, erythema and mild swelling at the ankle to metatarsophalangeal or metacarpophalangeal joints; 3 points, erythema and moderate swelling at the ankle to metatarsophalangeal or metacarpophalangeal joints; 4 points, erythema and severe swelling at the ankle to toe joints.

[0029] Joint morphology observation: On day 30 after the last administration, gross photographs were taken of the hind limb joints on the secondary side (right side) of rats in each group to record the degree of joint swelling and morphological changes. The specific experimental procedure is as follows: Figure 3 As shown in A in the diagram.

[0030] Experimental results are as follows Figure 3 As shown in B and C (data are expressed as mean ± standard error, n=6), P <0.01); from Figure 3As shown in B, PT-129 and / or RGFP966 treatment reduced the arthritis index in AA rats. Typical images of the secondary arthritis lesions in AA rats are shown below. Figure 3 As shown in Figure C, compared with the normal group, the AA model group rats had significantly swollen joints, while compared with the AA model group rats, the PT-129 and RGFP966 treatment groups showed significantly improved joint swelling symptoms. These results indicate that PT-129 alone or in combination with RGFP966 can significantly improve the arthritis index in AA rats and effectively alleviate the symptoms of secondary joint lesions in AA rats.

[0031] Example 4 In this embodiment, the effect of PT-129 on the spleen index of AA rats was verified. The experimental procedure included: rats in each group were anesthetized and sacrificed, their spleens were quickly separated, rinsed in pre-cooled physiological saline, and their surface moisture was blotted dry with filter paper before being weighed (mg). The spleen index was calculated using the following formula: Spleen index = Spleen mass (mg) / Rat body weight (g).

[0032] Experimental results are as follows Figure 4 The data is shown below (data is expressed as mean ± standard error, n=6). P <0.01), Figure 4 In the image, A represents a representative photograph of the spleen of each group of rats. Figure 4 B in the figure represents the spleen index of each group of rats. It can be seen that the spleen index of the AA model group rats was significantly increased compared with the normal control group, indicating that the AA rats have obvious abnormal proliferation of immune organs and systemic immune inflammatory response. Intra-articular injection of PT-129 or / and RGFP966 can reduce the spleen index of AA rats, suggesting that PT-129 alone or in combination with RGFP966 can alleviate the systemic inflammatory state of AA rats.

[0033] Example 5 In this embodiment, the effect of PT-129 on joint bone injury in AA rats was verified. Micro-CT Analysis: The rat ankle joints were fixed to a sample holder after fixation, and scanned using a micro-computed tomography (Micro-CT) system. The scanning parameters were set as follows: X-ray tube voltage 85 kV, current 200 μA, scan resolution 10.13 μm, exposure time 384 ms, and scan rotation angle 180°. During the scan, a standard phantom was scanned under the same conditions for grayscale calibration. After scanning, the original projected images were acquired. The original scan data were imported into the 3D reconstruction software NRecon (version V1.7.4.2, Bruker, Germany) for image reconstruction. A preview was performed before reconstruction to optimize parameter settings. To reduce image artifacts and improve reconstruction quality, the main correction parameters were set as follows: Smoothing = 3, Beam-hardening correction = 5%, and Ring artifacts correction = 30. After parameter optimization, the reconstruction area was selected, and batch reconstruction was performed to obtain 3D tomographic images for subsequent analysis.

[0034] Experimental results are as follows Figure 5 The data is shown as mean ± standard error, n=3. P <0.05, P <0.01), Figure 5 In the image, A represents a representative Micro-CT image of the ankle joint of each group of rats. Figure 5 In the figure, B represents the bone parameters of the ankle joint bone tissue in each group of rats. It can be seen that PT-129 or / and RGFP966 treatment effectively eliminated ankle joint swelling in AA rats and inhibited bone erosion and destruction. Further analysis revealed that PT-129 or / and RGFP966 treatment significantly increased bone mineral density, bone percentage, and trabecular thickness, and significantly reduced the bone surface area / volume ratio and trabecular pattern factor. PT-129 combined with RGFP966 treatment significantly reduced trabecular separation. These results indicate that PT-129, alone or in combination with RGFP966, has a osteoprotective effect.

[0035] Example 6 In this embodiment, the effects of PT-129 on the pathological characteristics of synovial membrane and cartilage tissue in AA rats were verified. The experimental procedure included: collecting rat ankle joints on day 30, fixing them with 4% paraformaldehyde for 48 h, decalcifying them with EDTA, and finally embedding them in paraffin and sectioning them. The paraffin sections of the ankle joints were stained with hematoxylin-eosin (H&E), safranin O-fast green, and toluidine blue.

[0036] H&E staining of tissue sections: Paraffin sections were baked in a 60℃ oven for 2 hours, then dewaxed by immersing in xylene I and II solutions for 10 minutes each, followed by stepwise hydration with a gradient of ethanol (100%, 95%, 90%, 80%, and 70% by volume), and finally rinsed with distilled water. The staining process strictly followed the standard H&E staining procedure: hematoxylin staining for 10 minutes, differentiation with 1% hydrochloric acid ethanol for 10 seconds, rinsing with running water for 15 minutes to return to blue, followed by eosin staining for 2 minutes, and rinsing with running water 3 times to terminate the staining. The dehydration and clearing steps were reverse dehydration with a gradient of ethanol (90%, 95%, and 100% ethanol, 2 times each, 1 minute each), clearing with xylene 3 times (3 minutes each time), and finally mounting with neutral resin. After drying at room temperature in the dark, the sections were observed under an optical microscope.

[0037] Safranin O-Fix Green staining of tissue sections: The dewaxing and hydration steps of the sections were the same as those for H&E staining. The sections were then stained with Fast Green solution for 5 minutes, rinsed with running water until the cartilage area was colorless; differentiated with 0.1% acetic acid for 10–15 seconds, and then counterstained with safranin solution for 5 minutes; dehydrated sequentially with 95% ethanol and anhydrous ethanol, cleared with xylene for 5 minutes, mounted with neutral resin, dried at room temperature in the dark, and then observed under a microscope for the degradation of the cartilage matrix.

[0038] Toluidine blue staining of tissue sections: Sections were baked in a 60℃ oven for 2 hours, then dewaxed by sequentially immersing in xylene I and II solutions for 10 minutes each, followed by graded hydration with ethanol (100%, 95%, 90%, 80%, and 70% v / v), and rinsed with distilled water. Sections were then immersed in toluidine blue staining solution for 15-30 minutes (adjusting the time according to the staining results), and rinsed briefly with distilled water to remove excess stain. Differentiation was then performed in glacial acetic acid differentiation solution (0.1%-0.5% v / v) for several seconds to several minutes, with microscopic control of the differentiation degree until the nuclei and cartilage matrix showed a clear blue-purple color while the background was nearly colorless or pale blue. Rapid dehydration was performed with graded ethanol (70%, 80%, 90%, 95%, and anhydrous ethanol, several seconds to 1 minute each), followed by clearing with xylene three times (2-3 minutes each time), mounting with neutral resin, and drying at room temperature in the dark before observation under an optical microscope.

[0039] Histopathological examination results as follows Figure 6 As shown, Figure 6 In the image, A represents a representative image of H&E stained ankle joint sections from each group of rats. Figure 6 In the image, B represents a representative image of safranin O-fast green stained ankle joint sections from each group of rats. Figure 6In the figures, C represents representative images of toluidine blue-stained ankle joint sections from each group of rats. It can be seen that the ankle joint tissue structure of the normal control group rats was intact, with no synovial hyperplasia, clear joint cavity, and no inflammatory infiltration or cartilage damage. The AA model group, however, exhibited typical pathological features of arthritis, including significant synovial tissue hyperplasia, joint cavity narrowing, marked cartilage matrix degradation, and bone erosion. Compared with the model group, rats treated with PT-129 and / or RGFP966 showed significantly reduced synovial hyperplasia, cartilage destruction, and bone erosion, suggesting that PT-129 alone or in combination with RGFP966 has a significant ameliorative effect on joint damage in AA rats.

[0040] Example 7 In this embodiment, the effect of PT-129 on abnormal activation of FLS in the synovial tissue of AA rats was verified. Immunofluorescence staining of tissue sections: After baking, dewaxing, and hydration, paraffin sections of the ankle joint were permeabilized with 0.5% Triton X-100 at room temperature for 10 min, followed by washing three times with PBS. Then, they were blocked with 1% BSA at room temperature for 30 min, followed by washing three times with PBS. Diluted N-cadherin, MMP3 (matrix metalloproteinase 3), and Vimentin primary antibodies were added to the sections, and incubated overnight at 4°C. After washing three times with PBS, fluorescently labeled secondary antibody diluted 1:100 was added, and the sections were incubated at room temperature in the dark for 2 h. Subsequently, cell nuclei were stained with DAPI at room temperature in the dark for 10 min, followed by washing three times with PBS. Finally, the sections were mounted with anti-fluorescence quenching mounting medium, and images were acquired under a fluorescence microscope.

[0041] Experimental results are as follows Figure 7 The data is shown as mean ± standard error, n=3. P <0.05, P <0.01), Figure 7 In the figure, A represents a representative image of N-cadherin and Vimentin immunofluorescence double staining of ankle joint sections from each group of rats, as well as the relative fluorescence intensity of N-cadherin. Figure 7In the figure, B represents representative images of MMP3 and Vimentin immunofluorescence double staining of ankle joint sections from each group of rats, along with the relative fluorescence intensity of MMP3. It can be seen that in the synovial tissue of the ankle joint of rats in the AA model group, the fluorescence intensity of N-cadherin and MMP3 in the Vimentin-positive area, a marker of fibroblast-like synovial cells (FLS), was significantly enhanced, indicating abnormal FLS activation. Compared with the model group, the expression levels of N-cadherin and MMP3 were significantly reduced in the PT-129 or / and RGFP966 intervention groups. These results indicate that PT-129 alone or in combination with RGFP966 can effectively inhibit abnormal FLS activation in the synovial tissue of AA rats.

[0042] In the description of this specification, references to terms such as "an embodiment," "example," "specific example," etc., indicate that a specific feature, structure, material, or characteristic described in connection with that embodiment or example is included in at least one embodiment or example of the invention. In this specification, illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples.

[0043] The foregoing has shown and described the basic principles, main features, and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited to the above embodiments. The embodiments and descriptions in the specification are merely illustrative of the principles of the invention. Various changes and modifications can be made to the invention without departing from its spirit and scope, and all such changes and modifications fall within the scope of the claimed invention.

Claims

1. Application of PT-129 in the preparation of drugs for treating rheumatoid arthritis.

2. The application according to claim 1, characterized in that, The drug also includes one or more of the following: diluent, excipient, and carrier.

3. The application according to claim 1, characterized in that, The dosage form of the drug is: granules, capsules, tablets, pills, or injections.

4. Use of a pharmaceutical composition comprising RGFP966 and PT-129 in the preparation of a medicament for treating rheumatoid arthritis.

5. The application according to claim 4, characterized in that, The molar ratio of RGFP966 to PT-129 is 2:

1.

6. The application according to claim 4, characterized in that, The drug is an intra-articular injection.

7. The application according to claim 4, characterized in that, The treatment includes inhibiting the proliferation, migration, and invasion of fibroblast-like synovial cells in rheumatoid arthritis.

8. The application according to claim 7, characterized in that, Inhibiting the proliferation, migration, and invasion of fibroblast-like synovial cells in rheumatoid arthritis, including inhibiting the expression of N-cadherin protein in these synovial cells.

9. The application according to claim 7, characterized in that, Inhibit the proliferation, migration, and invasion of fibroblast-like synovial cells in rheumatoid arthritis, including inhibiting the expression of MMP3 in these synovial cells.

10. A drug, characterized in that, The active ingredients are RGFP966 and PT-129.

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