Application of urolithin A in preparation of composition for preventing or treating periprosthetic osteolysis

Abstract

The invention relates to the field of biological pharmacy, in particular to application of urolithin A in preparation of a composition for preventing or treating periprosthetic osteolysis. The titanium nanoparticles released by the prosthesis can inhibit the bone marrow mesenchymal stem cells from being transformed towards osteoblasts and promote ferroptosis of the osteoblasts, so that osteolysis around the prosthesis is caused. The urolithin A treatment can resist the adverse effect of the titanium nanoparticles on osteogenesis, restore the ability of bone marrow mesenchymal stem cells to transform towards osteoblasts and inhibit ferroptosis of the osteoblasts, so that the urolithin A treatment has prevention and treatment effects on periprosthetic osteolysis generated after artificial joint replacement.

Description

Technical Field

[0001] The present invention relates to the field of biopharmaceuticals, and in particular to application of urolithin A in preparing a composition for preventing or treating periprosthetic bone dissolution. Background Art

[0002] Periprosthetic osteolysis refers to the destruction and absorption of bone tissue around the prosthesis due to various reasons after artificial joint replacement. This complication may lead to prosthesis loosening, pain, dysfunction and even surgical failure. The main causes of periprosthetic osteolysis include the generation of wear particles, inflammatory response, osteoclast activation and osteoblast inhibition. These factors interact with each other to form a vicious cycle, leading to the continuous destruction and absorption of bone tissue.

[0003] Treatments for periprosthetic osteolysis include medication, surgery, and rehabilitation training. Currently, medication is mainly used to relieve symptoms and control inflammatory responses. However, medications usually have certain side effects, such as gastrointestinal discomfort, liver and kidney damage, and immune system suppression, which bring additional health risks to patients. Summary of the invention

[0004] The object of the present invention is to provide a composition for preventing or treating periprosthetic bone dissolution without side effects on the heart, liver and kidney.

[0005] In order to achieve the above object, the present invention provides the following technical solutions:

[0006] Use of urolithin A in preparing a composition for preventing or treating periprosthetic osteolysis.

[0007] Optionally, the active ingredient in the composition is urolithin A, and the urolithin A is used to inhibit titanium nanoparticle-induced osteoblast ferroptosis.

[0008] Optionally, the urolithin A has a strong binding ability with glutathione peroxidase 4, a key regulatory factor of ferroptosis.

[0009] Optionally, the urolithin A promotes the expression of glutathione peroxidase 4 and solute carrier family 7 member 11, key proteins of ferroptosis, and reduces the expression level of cyclooxygenase 2.

[0010] Optionally, the application concentration of urolithin A at the cellular level is any value between 5 μmol / L and 10 μmol / L.

[0011] Optionally, the composition is an oral preparation.

[0012] Optionally, the composition has a dosage form selected from the following: solution, tablet, capsule, powder and granule.

[0013] Optionally, the dosage of urolithin A in the composition is any value between 10 mg / kg / d and 20 mg / kg / d.

[0014] Optionally, the composition is used to promote the differentiation of bone marrow mesenchymal stem cells into osteoblasts.

[0015] The present invention also provides application of the composition in postoperative intervention of artificial joint replacement.

[0016] The beneficial effects of the present invention are as follows: the composition with urolithin A as an effective ingredient prevents or treats periprosthetic bone dissolution, can effectively inhibit the ferroptosis of osteoblasts, has good therapeutic effects, has no toxic side effects on the heart, liver and kidneys, and has high clinical value.

[0017] The above description is only an overview of the technical solution of the present invention. In order to more clearly understand the technical means of the present invention and implement it according to the contents of the specification, the following is a detailed description of the preferred embodiments of the present invention in conjunction with the accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 It is the molecular docking diagram of Uro-A and GPX4;

[0019] Figure 2 The mitochondrial morphology diagram of each group of samples in the in vitro cell experiment of Example 1 of the present invention;

[0020] Figure 3 This is a schematic diagram of the expression of key regulatory factors of ferroptosis in each group of samples in the in vitro cell experiment of Example 1 of the present invention;

[0021] Figure 4 This is a schematic diagram of the expression of multiple osteogenic differentiation-related proteins in each group of samples in the in vitro cell experiment of Example 1 of the present invention;

[0022] Figure 5 This is a schematic diagram of the relative expression of the Acsl4 gene, the SLC7A11 gene and the COX2 gene in each group of samples in the in vitro cell experiment of Example 1 of the present invention;

[0023] Figure 6 This is a schematic diagram of the expression of multiple osteogenic differentiation-related genes in each group of samples in the in vitro cell experiment of Example 1 of the present invention;

[0024] Figure 7 This is a schematic diagram of the expression of MDA and GSH in each group of samples in the in vitro cell experiment of Example 1 of the present invention;

[0025] Figure 8 These are observation diagrams and quantitative analysis diagrams of each group of samples after ALP staining in the in vitro cell experiment of Example 1 of the present invention;

[0026] Fig. 9 The observation diagram and quantitative analysis diagram of each group of samples after ARS staining in the in vitro cell experiment of Example 1 of the present invention;

[0027] Fig.10 The micro-CT three-dimensional image reconstruction diagram of the skull samples of each group of mice in the in vivo animal experiment of Example 1 of the present invention;

[0028] Fig.11 This is a micro-CT multi-parameter quantitative analysis diagram of the skull samples of each group of mice in the in vivo animal experiment of Example 1 of the present invention;

[0029] Fig.12 HE staining images of skull slice samples of mice in each group in the in vivo animal experiment of Example 1 of the present invention;

[0030] Fig.13 This is a calcein-labeled tracer image of each group of mouse skull slice samples in the in vivo animal experiment of Example 1 of the present invention;

[0031] Fig.14 This is a schematic diagram of the expression of GPX4 in the skull slice samples of each group of mice in the in vivo animal experiment of Example 1 of the present invention;

[0032] Fig.15 The HE staining images of the visceral slice samples of each group of mice in the in vivo animal experiment of Example 1 of the present invention are shown. DETAILED DESCRIPTION

[0033] The technical solution of the present invention will be described clearly and completely below in conjunction with the accompanying drawings. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0034] In the description of the present invention, it should be noted that the terms "center", "upper", "lower", "left", "right", "vertical", "horizontal", "inner", "outer", etc., indicating the orientation or positional relationship, are based on the orientation or positional relationship shown in the drawings, and are only for the convenience of describing the present invention and simplifying the description, rather than indicating or implying that the device or element referred to must have a specific orientation, be constructed and operated in a specific orientation, and therefore cannot be understood as limiting the present invention. In addition, the terms "first", "second", and "third" are used for descriptive purposes only, and cannot be understood as indicating or implying relative importance.

[0035] In the description of the present invention, it should be noted that, unless otherwise clearly specified and limited, the terms "installed", "connected", and "connected" should be understood in a broad sense, for example, it can be a fixed connection, a detachable connection, or an integral connection; it can be a mechanical connection or an electrical connection; it can be a direct connection, or it can be indirectly connected through an intermediate medium, or it can be the internal communication of two components. For ordinary technicians in this field, the specific meanings of the above terms in the present invention can be understood according to specific circumstances.

[0036] In addition, the technical features involved in the different embodiments of the present invention described below can be combined with each other as long as they do not conflict with each other.

[0037] The inventor accidentally discovered that the titanium particles in the prosthesis can induce periprosthetic bone dissolution, and this phenomenon mainly comes from the iron death of osteoblasts. Glutathione peroxidase 4 (GPX4), a key regulatory factor of iron death, is an antioxidant enzyme that protects cells from damage by oxidative stress by maintaining the redox balance in the cell, and GPX4 is also involved in regulating the inflammatory response and immune response in the cell. Urolithin A (Uro-A) is a natural antioxidant known in the prior art, which can remove free radicals in the cell and reduce the damage of oxidative stress to the cell. In addition, Uro-A can also regulate the inflammatory response and immune response in the cell, thereby reducing the degree of inflammatory response and enhancing the body's immunity. It can be seen from this that the effect of Uro-A in the human body overlaps greatly with GPX4, so the inventor speculates that the effect of Uro-A on cells is related to GPX4, which can affect the expression of GPX4 in the cell, and then affect the process of cell iron death.

[0038] See also Figure 1 , the molecular simulation software AutoDock was used to simulate the binding ability of Uro-A with GPX4, a key regulatory factor of ferroptosis. It can be seen that Uro-A has a strong binding ability with GPX4. It can be inferred that Uro-A can be used as an inhibitor of cell ferroptosis. The effect of Uro-A on osteoblasts was studied by in vitro cell experiments and in vivo animal experiments. It was found that Uro-A can be used as an inhibitor of ferroptosis to inhibit titanium particle-induced periprosthetic bone dissolution without side effects of heart, liver and kidney toxicity. Therefore, the composition with Uro-A as the active ingredient can prevent or treat periprosthetic bone dissolution and can be used in postoperative intervention of artificial joint replacement.

[0039] In some embodiments, the active ingredient in the composition is urolithin A, which is used to inhibit titanium nanoparticle-induced osteoblast ferroptosis.

[0040] In some embodiments, urolithin A has a strong binding ability to glutathione peroxidase 4, a key regulator of ferroptosis.

[0041] In some embodiments, urolithin A promotes the expression of glutathione peroxidase 4 and solute carrier family 7 member 11, key proteins of ferroptosis, and reduces the expression level of cyclooxygenase 2.

[0042] In some embodiments, the application concentration of urolithin A at the cellular level is any value between 5 μmol / L and 10 μmol / L, for example, it can be any value between 5 μmol / L, 6 μmol / L, 7 μmol / L, 8 μmol / L, 9 μmol / L and 10 μmol / L. The application concentration within this range has a better therapeutic effect.

[0043] In some embodiments, the composition is an oral formulation.

[0044] In some embodiments, the composition has a dosage form selected from the group consisting of solution, tablet, capsule, powder, and granules.

[0045] In some embodiments, the dosage of urolithin A in the composition is any value between 10 mg / kg / d and 20 mg / kg / d, for example, it can be any value between 10 mg / kg / d, 12 mg / kg / d, 14 mg / kg / d, 16 mg / kg / d, 18 mg / kg / d and 20 mg / kg / d.

[0046] In some embodiments, the composition is used to promote the differentiation of bone marrow mesenchymal stem cells into osteoblasts.

[0047] Please refer to the following examples for details.

[0048] Embodiment 1:

[0049] In the in vitro cell experiment, bone marrow mesenchymal stem cells (BMSCs) were taken from the femur of mice and cultured in osteogenic medium for 7 days to obtain osteoblasts.

[0050] Four groups of osteoblast samples were taken and cultured for 72 hours after intervention. After stopping the incubation, the samples were resuspended in phosphate buffered saline (PBS) solution and centrifuged to collect the precipitate. Four groups of samples were obtained, which were marked as control group, model group, low-dose intervention group and high-dose intervention group. The control group samples were not intervened, and the model group samples were intervened with only 10 μg / cm 2 Titanium nanoparticles, 10 μg / cm 2 Titanium nanoparticles and urolithin A, and the final concentration of urolithin A in the culture medium was 5 μmol / L. 10 μg / cm 2 Titanium nanoparticles and urolithin A were added, and the final concentration of urolithin A in the culture medium was 10 μmol / L.

[0051] Samples from the control group, model group, low-dose intervention group, and high-dose intervention group were taken and fixed with 2.5% glutaraldehyde solution at 4°C for 16 hours. After fixation, the cells were dehydrated, embedded, sliced, and stained, and the morphological changes of mitochondria in osteoblasts were observed under a transmission electron microscope. Figure 2 It can be seen that under the intervention of titanium nanoparticles, the mitochondrial cristae of osteoblast mitochondria disappeared, which would affect the abnormality of cell function and metabolism and lead to cell death. After low-dose Uro-A treatment, mitochondrial morphology improved, especially mitochondrial fragmentation decreased, indicating that titanium particle-induced cell death was inhibited. The effect of the high-dose Uro-A treatment group was more obvious.

[0052] Samples from the control group, model group, low-dose intervention group, and high-dose intervention group were taken respectively. The cells were lysed with radioimmunoprecipitation assay (RIPA) buffer and centrifuged to obtain the supernatant to obtain the cell lysate, and the protein concentration was determined using a bicinchoninic acid (BCA) kit. The cell lysate was transferred to a nitrocellulose membrane by transfer after electrophoresis, and then blocked for 1 hour with TBST buffer containing 5% skim milk, and the expression of the target protein was detected by immunoblotting. Incubate overnight at 4°C in the primary antibody solution matched to the target protein. After washing with TBST buffer, incubate with a fluorescently labeled secondary antibody matched to the primary antibody at room temperature for 1 hour, and expose the protein membrane with an enhanced chemiluminescence kit (ECL kit). The fluorescence intensity of the target protein was analyzed using the image analysis software Image J for protein quantification. The target proteins in this experiment are glutathione peroxidase 4 (GPX4), solute carrier family 7 member 11 (SLC7A11), cyclooxygenase 2 (COX2) and β-actin. The content of each target protein in the cell lysate extracted from each sample was detected, and β-actin was used as an internal reference for analysis. The result data in this example were analyzed using SPSS11.0 statistical software, and one-way ANOVA test was used for multiple group comparisons. *p<0.05 was considered statistically significant, and **p<0.01 was considered significantly significant. Please refer to Figure 3 From the electrophoresis diagram and the box plot obtained by analysis, it can be seen that despite the intervention of titanium nanoparticles, with the increase of Uro-A treatment concentration, not only the expression levels of ferroptosis key proteins GPX4 and SLC7A11 were promoted, but also the expression level of COX2 was reduced. In other words, Uro-A treatment can effectively counteract the induction of ferroptosis of osteoblasts by titanium nanoparticles.

[0053] Cell samples from the control group, model group, low-dose intervention group, and high-dose intervention group were taken to detect the expression of target proteins in the cells using the same method as the above experiment. In this experiment, the target proteins were osteogenic differentiation-related proteins type I collagen α1 (COL1-a1), runt-related transcription factor 2 (Runx2), Osterix, and β-actin. The content of each target protein in the cell lysate extracted from each sample was detected, and β-actin was used as an internal reference for analysis. Please refer to Figure 4 It can be seen that Uro-A treatment significantly promoted the expression of COL1-a1, Runx2 and Osterix in a dose-dependent manner, suggesting that Uro-A has an effect of promoting osteogenic differentiation in vitro.

[0054] Samples from the control group, model group, low-dose intervention group, and high-dose intervention group were taken for reverse transcription-polymerase chain reaction (RT-PCR) detection. Total RNA was extracted and separated using TRIzol reagent, and the concentration was determined using NanoDrop micro-spectrophotometer. TM After reverse transcription of total RNA in a thermal cycler, qPCR amplification was performed on the target gene and the internal reference gene. After obtaining the Cq value of the number of cycles required for the fluorescence signal to reach the set threshold, the difference ΔCq value between the target gene and the internal reference gene Cq value was calculated. The target genes were acyl-CoA synthetase long-chain family member 4 (Acsl4), SLC7A11, and COX2, and the internal reference gene was β-actin. Any sample in the control group was selected as the calibration sample, and 2 -ΔΔCq The formula quantifies the relative expression of each target gene in each sample. Figure 5 It can be seen that titanium nanoparticles can induce osteoblast ferroptosis and increase the cell metabolic energy demand, but Uro-A treatment can inhibit osteoblast ferroptosis and restore the cell metabolic energy demand.

[0055] Cell samples from the control group, model group, low-dose intervention group, and high-dose intervention group were collected and analyzed by reverse transcription-polymerase chain reaction (RT-PCR) and 2 -ΔΔCq The formula detects and calculates the relative expression of each target gene in each sample. In this experiment, the target genes are COL1-a1 gene, Runx2 gene and Osterix gene, and the internal reference gene is β-actin gene. Figure 6 ,The quantitative analysis by box plots showed that Uro-A has the effect of promoting osteogenic differentiation in vitro.

[0056] Samples from the control group, model group, low-dose intervention group, and high-dose intervention group were taken respectively, and cell lysates were obtained in the same way as the above experiment. The lipid peroxidation of osteoblasts in the samples was evaluated by using a malondialdehyde (MDA) kit and detecting the MDA concentration. The GSH concentration was measured by a reduced glutathione (GSH) detection kit to evaluate the cell death associated with oxidative stress in the samples. Figure 7 It can be seen that titanium nanoparticles increase the MDA content and reduce the GSH content in osteoblasts, thereby inducing the occurrence of osteoblast ferroptosis, which is greatly alleviated after Uro-A treatment.

[0057] Bone marrow mesenchymal stem cells were inoculated in a 24-well plate and cultured in osteogenic medium after intervention in the same manner as the above-mentioned osteoblast samples to form four groups of samples: control induction group, model induction group, low-dose induction group and high-dose induction group.

[0058] The samples of the control induction group, model induction group, low-dose induction group and high-dose induction group were collected after 7 days of culture, washed three times with PBS buffer, and fixed with 4% paraformaldehyde at 4°C for 20 minutes. After washing with PBS buffer three times, the samples were incubated in a staining solution containing 5-bromo-4-chloro-3-indolyl-phosphate / nitro blue tetrazolium (BCIP / NBT) at room temperature and in the absence of light for 30 minutes to complete alkaline phosphatase (ALP) staining. The stained short-term induced samples were observed under an optical microscope and the absorbance was measured at a wavelength of 530nm. Please refer to Figure 8 It can be seen that titanium nanoparticles have an inhibitory effect on the process of bone marrow mesenchymal stem cells transforming into osteoblasts, and Uro-A treatment can alleviate this inhibitory effect and contribute to the generation of osteoblasts.

[0059] The four groups of samples from the control induction group, model induction group, low-dose induction group and high-dose induction group were cultured for 21 days and then fixed in 4% polyoxymethylene solution for 15 minutes after washing with PBS buffer three times. The samples were incubated in Alizarin Red S (ARS) solution for another 30 minutes at room temperature to stain the calcium nodules formed by cell mineralization. After washing with PBS buffer three times, the samples were observed under an electron microscope. After the observation, the calcium nodules were dissolved in a solution containing 10% 1-hexadecylpyridine monohydrate to dissolve the Alizarin Red complex, and the absorbance was measured at a wavelength of. Please refer to Fig. 9 It can be seen that titanium nanoparticles have an inhibitory effect on the process of calcium nodule formation by bone marrow mesenchymal stem cells, and Uro-A treatment can alleviate this inhibitory effect and contribute to the formation of bone tissue.

[0060] In the in vivo animal experiment, 28 8-week-old female SPF-grade healthy C57BL / J6 mice were used for the experiment. The mice in this embodiment were provided by the Animal Experiment Center of Soochow University. The experiment was randomly divided into 4 groups and named as sham operation group, osteolysis model group, Uro-A low intervention group and Uro-A high intervention group. Among them, the mice in the sham operation group were not operated on and were killed after 2 weeks of feeding. After surgical anesthesia, the mice in the osteolysis model group were disinfected with 75% ethanol on the head of the mice and covered with sterile towels. The skin on the top of the mouse skull was cut open with a sterile scalpel to expose the skull and peel off the craniofacial fascia. According to previous studies, 40 mg of titanium nanoparticles (40 μL) were carefully dispersed on the surface of the skull and then finely sutured. After surgery, 200 μl of sterile 0.5% sodium carboxymethyl cellulose (CMC-Na) solution was given by gavage seven times a week and was killed after 2 weeks of continuous gavage. The treatment method of the mice in the Uro-A low intervention group was similar to that of the mice in the sham operation group, except that the CMC-Na solution administered after surgery also contained 10 mg / kg of Uro-A. The treatment method of the mice in the Uro-A high intervention group was similar to that of the mice in the sham operation group, except that the CMC-Na solution administered after surgery also contained 20 mg / kg of Uro-A.

[0061] Five mice were collected from the sham operation group, osteolysis model group, Uro-A low intervention group, and Uro-A high intervention group, and the skulls were fixed with formalin for 24 hours and scanned by micro-CT. The scanning parameters were set to a resolution of 9μm, a voltage of 80kV, and a current of 100μA. A region of interest (ROI) was selected, and the bone density (BMD, mg / mm2), bone volume (BV), bone volume to tissue volume (BV / TV%), and number of pores in the ROI were recorded, and three-dimensional image reconstruction and quantitative analysis were performed. Please refer to Fig.10 , it can be seen that the skull bone tissue of the sham-operated mice is denser. Compared with the sham-operated group, the number of pores on the skull surface of the osteolysis model group increased, and the bone tissue was sparse. After low-dose Uro-A administration, the number of pores decreased compared with the model group, and the bone tissue became denser. The effect was more obvious after high-dose Uro-A treatment. Please refer to Fig.11 , it can be seen that compared with the osteolysis model group, the bone density, bone volume, and bone volume to tissue volume ratio of the skull increased significantly after Uro-A intervention, and the number of pores decreased.

[0062] The skulls of the remaining mice in the sham operation group, osteolysis model group, Uro-A low intervention group and Uro-A high intervention group were collected, fixed with 4% paraformaldehyde for 24 h, decalcified with 10% ethylenediaminetetraacetic acid (EDTA) solution for 3 weeks, dehydrated and fixed, and embedded in a paraffin embedding machine, and sliced ​​to obtain section samples.

[0063] Slice samples from the sham operation group, osteolysis model group, Uro-A low intervention group and Uro-A high intervention group were taken for hematoxylin-eosin (HE) staining. After dewaxing with xylene, they were dehydrated with 100%, 95%, 80%, and 70% ethanol, respectively, for 5 minutes each. After dehydration, they were rinsed with distilled water for 3 minutes and stained with hematoxylin solution for 2.5 minutes. After staining, they were rinsed with tap water 3 times, each time for 5 minutes. After differentiation with 2% acetic acid solution for 1 minute, they were rinsed with tap water for 1 minute. After anti-blueing in 10% ammonia solution for 1 minute, they were rinsed with tap water for 2 minutes. Then they were counterstained with 1% eosin solution for 3 minutes and rinsed with tap water for 1 minute. After routine dehydration, they were transparent and sealed. The bone structure of the mouse skull was observed under an optical microscope. Please refer to Fig.12 It can be seen that the bone structure of the skull of mice in the osteolysis model group was distorted and incomplete, while after Uro-A treatment, the degree of bone separation of the damaged bone structure was reduced and the volume of trabeculae increased, that is, the bone structure was repaired to varying degrees.

[0064] One mouse was taken from each of the sham operation group, osteolysis model group, Uro-A low intervention group, and Uro-A high intervention group. Calcein solution was intraperitoneally injected at a dose of 10 mg / kg on the 1st and 8th day before sacrifice. Calcein-labeled images were captured using a fluorescence microscope. Fig.13 , it can be seen that the skull bone formation ability of the model group mice was reduced, while Uro-A treatment greatly alleviated this situation.

[0065] The slice samples of the sham operation group, osteolysis model group, Uro-A low intervention group and Uro-A high intervention group were respectively subjected to routine dewaxing and dehydration steps, and then incubated with protease for tissue antigen repair. The expression of the target protein was detected by immunoblotting and analyzed. Fig.14 , using GPX4 as the target protein for detection, it can be seen that Uro-A promoted the expression of GPX4, a key protein in ferroptosis, in vivo, suggesting that Uro-A has an inhibitory effect on osteoblast ferroptosis in vivo.

[0066] The heart, liver and kidney tissues of the mice in the sham operation group, osteolysis model group, Uro-A low intervention group and Uro-A high intervention group were collected, sliced ​​and stained with HE, and observed under an optical microscope. Fig.15 It can be seen that long-term oral administration of Uro-A did not cause damage to the heart, liver, and kidney tissues of mice, proving that the in vivo application of Uro-A is safe and has no toxic side effects on the heart, liver, and kidneys.

[0067] The beneficial effects of the present invention are: providing a compound urolithin A for preventing or treating periprosthetic bone dissolution without toxic side effects on the heart, liver and kidneys, and a composition containing urolithin A, and revealing its mechanism of action. Titanium nanoparticles released by the prosthesis inhibit the transformation of human bone marrow mesenchymal stem cells toward osteoblasts, and promote the iron death of osteoblasts, thereby leading to periprosthetic bone dissolution, and urolithin A treatment can counteract the adverse effects of titanium nanoparticles in the body, restore the ability of bone marrow mesenchymal stem cells to transform toward osteoblasts, and inhibit the iron death of osteoblasts, thereby preventing and treating periprosthetic bone dissolution caused by artificial joint replacement.

[0068] The technical features of the above-described embodiments may be arbitrarily combined. To make the description concise, not all possible combinations of the technical features in the above-described embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0069] The above-mentioned embodiments only express several implementation methods of the present invention, and the descriptions thereof are relatively specific and detailed, but they cannot be understood as limiting the scope of the invention patent. It should be pointed out that, for ordinary technicians in this field, several variations and improvements can be made without departing from the concept of the present invention, and these all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be subject to the attached claims.

Claims

1. Use of urolithin A in the preparation of a composition for preventing or treating periprosthetic bone dissolution.

2. The use according to claim 1, characterized in that The effective ingredient in the composition is urolithin A, and the urolithin A is used to inhibit the iron death of osteoblasts induced by titanium nanoparticles.

3. The use according to claim 2, characterized in that The urolithin A has a strong binding ability with glutathione peroxidase 4, a key regulatory factor of ferroptosis.

4. The use according to claim 2, characterized in that The urolithin A promotes the expression of glutathione peroxidase 4 and solute carrier family 7 member 11, which are key proteins in ferroptosis, and reduces the expression level of cyclooxygenase 2.

5. The use according to claim 2, characterized in that The application concentration of urolithin A at the cellular level is any value between 5 μmol / L and 10 μmol / L.

6. The use according to claim 1, characterized in that The composition is an oral preparation.

7. The use according to claim 6, characterized in that The composition has a dosage form selected from the following: tablets, capsules, powders and granules.

8. The use according to claim 7, characterized in that The dosage of urolithin A in the composition is any value between 10 mg / kg / d and 20 mg / kg / d.

9. The use according to claim 1, characterized in that The composition is used for promoting the differentiation of bone marrow mesenchymal stem cells into osteoblasts.

10. Use of the composition according to any one of claims 1 to 9 in postoperative intervention for artificial joint replacement.

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