JP2023032210A - Antiinflammatory agent for joint synovial membrane - Google Patents

Abstract

To provide a new antiinflammatory agent for a joint synovial membrane.SOLUTION: The present invention provides an antiinflammatory agent for a joint synovial membrane containing Drynaria Fortunei extract. The present invention also provides an arthralgia inhibitor containing Drynaria Fortunei extract, the agent to inhibit a joint pain through an antiinflammatory effect on a joint synovial membrane. The antiinflammatory agent is preferably an oral agent.SELECTED DRAWING: None

Description

The present invention relates to articular synovial anti-inflammatory agents.

Inflammation is a biological defense reaction induced mainly by external stimuli. Inflammation causes symptoms such as redness, swelling, heat, and pain. Since inflammation also damages living tissues, excessive or chronic inflammatory reactions are rather harmful.

Bone crushing is also known by names such as crushing and crushing, and is a dried rhizome of Drynaria fortunei of the family Polypodiacea, which grows naturally in southern China and Taiwan. Osteoplasty is a crude drug that has long been used in China for the purposes of supplementing kidneys, vitalizing blood, hemostasis, repairing muscles and bones, and the like. The clinical effects of osteoplasty have been reported to promote recovery from bone damage, improve osteoporosis (improve bone density), anti-inflammatory action, and promote tooth growth.

JP 2016-183123 A

An object of the present invention is to provide a new anti-inflammatory agent for joint synovium.

The present invention relates to items exemplified below.
[1] An anti-inflammatory agent for joint synovium containing a bone crushing extract.
[2] An arthralgia suppressant containing a bone crushing extract, which suppresses joint pain by the anti-inflammatory action of the synovial membrane of the joint.
[3] The anti-inflammatory agent according to [1] or [2], wherein the joint is a knee joint.
[4] The agent of any one of [1] to [3], which suppresses joint synovial inflammation by promoting IL-10 expression, suppressing TNF-α expression, or suppressing MMP-13 expression.
[5] An antioxidant containing bone crushing extract.
[6] The agent according to any one of [1] to [5], which is an oral agent.
[7] The agent according to [6], which is a food with health claims, a health supplement, or a supplement.
[8] The agent according to any one of [1] to [7], which is used for people with arthralgia.

INDUSTRIAL APPLICABILITY According to the present invention, new articular synovial anti-inflammatory agents and arthralgia inhibitors are provided.

1 is a graph showing the gene expression level of IL-10 in Experiment 1. FIG. 1 is a graph showing the gene expression level of MMP-13 in Experiment 1. FIG. 2 is a graph showing the gene expression level of TNF-α in Experiment 2. FIG. 2 is a graph showing the gene expression level of SOD1 in Experiment 2. FIG. 2 is a graph showing the antioxidant activity of test substances in Experiment 2. FIG. 10 is a graph showing the gene expression level of IL-10 in Experiment 3. FIG. 10 is a graph showing the gene expression level of MMP-13 in Experiment 3. FIG.

One aspect of the agent according to the present invention is an anti-inflammatory agent for joint synovium containing a bone crushing extract. The synovium attaches around articular cartilage, secretes synovial fluid, and contributes to joint stability. Joint synovial anti-inflammatory agents can inhibit systemic or local joint synovial inflammation. Suppression of inflammation can prevent, suppress, or alleviate joint redness, swelling, heat sensation, pain, and the like. One aspect of the agent according to the present invention is an arthralgia suppressant containing a bone crushing extract, which suppresses joint pain by the anti-inflammatory action of the synovial membrane of the joint.

As used herein, joints include various joints such as knee joints, shoulder joints, neck joints, hip joints, spinal joints, jaw joints, finger joints, elbow joints, wrist joints, and ankle joints. Joint inflammation includes osteoarthritis, rheumatoid arthritis, articular cartilage damage, osteonecrosis of the knee, osteonecrolysis of the femur, shoulder arthritis, bacterial arthritis, viral arthritis, neuropathic arthritis, and the like.

Anti-inflammatory agents for joint synovium or arthralgia inhibitors have interleukin 10 (IL-10) expression promoting action, tumor necrosis factor α (TNF-α) expression suppressing action or matrix metaprotease 13 (MMP-13) expression suppressing action. It suppresses inflammation of joint synovial membrane by action. IL-10 is an anti-inflammatory cytokine, TNF-α is an inflammatory cytokine, and MMP-13 is a collagenase. One aspect of the present invention can also be said to be an IL-10 expression promoter, TNF-α expression inhibitor, or MMP-13 expression inhibitor containing a bone crushed extract. The bone crushed extract has an antioxidant effect and can suppress the expression of Cu/Zn superoxide dismutase 1 (SOD1). One aspect of the agent according to the present invention is an antioxidant containing bone crushing extract. Antioxidant activity can be determined, for example, by measuring the ORAC value described in Examples below.

Articular synovial anti-inflammatory agents or arthralgia inhibitors can be used to prevent, treat, or suppress aggravation of joint inflammation. Joint synovial anti-inflammatory agents or joint pain inhibitors may be used in people without joint pain or in people with joint pain.

The raw material for bone crushing is a plant belonging to the family Polypodiaceae and Davalliaceae, specifically Drynaria fortunei, Davallia mariesii, Davallia formosana, Atsubashinobu ( Davallia solida), Davallia griffitiana, and Araiostegia perdurans. The bone crushing extract is obtained by concentrating the bone crushing extract liquid extracted from the bone crushing powder and making it into a dry powder or a semi-solid substance. A bone crushed extract can be obtained, for example, by the following method. The bone crushed supplement is placed in an extraction container, distilled water is added, and hot water extraction is performed at 100° C. for 4 hours. After repeating this process three times, the resulting solution is cooled to room temperature and filtered through filter paper. The filtered extract is concentrated under reduced pressure at 40° C. or lower using a vacuum rotary evaporator, and freeze-dried to obtain the bone crushed extract. The bone crushed extract may be derived from either a single species or multiple species of the source plant.

Osteoblastic extracts may contain flavonoids, lignoids and triterpenoids as major components. Flavonoids preferably include naringin.

A commercially available product may be used as the bone crushing extract. Commercially available products include BGG Japan Co., Ltd.'s trade name "Bone Crushing Extract Powder 20%" and AS Material's "Bone Crushing Extract".

The agents according to the present invention may be oral agents or parenteral agents. Parenteral agents can be administered, for example, topically or by injection. Subjects to be administered are not particularly limited, but include humans, mammals such as cows, horses, pigs, sheep, dogs, rabbits, mice and rats, and birds such as chickens. Subjects to be administered may be livestock, poultry, companion animals, laboratory animals, and the like.

Oral agents may be foods, pharmaceuticals, or quasi-drugs. Food includes beverages, feed, and the like. Foods include foods for special dietary uses, foods with health claims (foods for specified health uses, foods with nutrient function claims, foods with function claims), health supplements, and supplements. Pharmaceuticals include therapeutic or veterinary drugs, prophylactic drugs, and the like.

The content of the bone crushing extract in the oral preparation may be 0.01% by mass or more and 50% by mass or less, and may be 0.1% by mass or more, 1% by mass or more, or 3% by mass or more, It may be 30% by mass or less, 20% by mass or 10% by mass or less. The blending amount of the bone crushed extract can be analyzed, for example, by high performance liquid chromatography.

When the agent according to the present invention is an oral agent, it can be widely adjusted according to the sex, age, weight, severity of symptoms, etc. of the person to be ingested. The intake per unit may be 1 mg or more and 2000 mg or less, may be 50 mg or more, 100 mg or more or 150 mg or more, and may be 1000 mg or less or 500 mg or less. Oral preparations may be taken once a day or in several divided doses.

Examples of foods include dairy products such as cheese, powdered milk, ice cream, and yogurt, frozen desserts, chocolates, tablets, gummies, cookies, biscuits, candies, Japanese sweets, rice crackers, cakes, pies, and puddings. Wheat flour products such as confectionery, bread and noodles, rice products such as porridge and cooked rice, and seasonings such as soy sauce, miso, mayonnaise and dressings. The food may be processed marine products, processed agricultural products, or processed livestock products.

Examples of beverages include tea, coffee, milk, dairy drinks, fruit juice drinks, juices, lactic acid drinks, soft drinks, energy drinks, beauty drinks and the like.

Foods may be food additives such as liquid, paste, powder, flakes and granules. Food additives also include additives for beverages. The food additive can be produced according to a general food additive production method. Oral preparations containing bone crushing extracts may be added to other foods.

Depending on the type of food, the food may contain additional ingredients suitable for oral administration. Additives include sweeteners. Sweeteners include glucose, fructose, sucrose, maltose, sorbitol, stevioside, rubusoside, corn syrup, lactose, maltitol and the like.

Other additives include citric acid, tartaric acid, malic acid, succinic acid, lactic acid, L-ascorbic acid, dl-α-tocopherol, sodium erythorbate, glycerin, propylene glycol, glycerin fatty acid ester, magnesium stearate, calcium stearate. , cellulose derivatives such as hydroxypropyl cellulose, crystalline cellulose, polyglycerin fatty acid ester, sucrose fatty acid ester, sorbitan fatty acid ester, gum arabic, carrageenan, casein, gelatin, pectin, agar, vitamins, nicotinamide, calcium pantothenate, amino acids , calcium salts, pigments, fragrances, preservatives and the like.

The dosage form of oral agents is not particularly limited, and tablets, capsules, granules, powders, fine granules, chewable tablets, pills, lozenges, sublingual tablets, ointments, creams, emulsions, suspensions, and jelly. It may be a drug, syrup, liquid, or the like.

Oral formulations are prepared using non-toxic excipients, binders, lubricants, disintegrants, preservatives, tonicity agents, stabilizers, dispersants, antioxidants, colorants, flavoring agents, and buffers. , a pH adjuster, a thickening agent, a brightening agent and the like, and can be carried out by a known method. Examples of non-toxic additives contained in these preparations include starch, gelatin, glucose, dextrin, hyaluronic acid, lactose, fructose, maltose, magnesium carbonate, silicon dioxide, talc, magnesium stearate, calcium stearate, methylcellulose, carboxymethyl cellulose, crystalline cellulose, gum arabic, polyethylene glycol, propylene glycol, petrolatum, glycerin, ethanol, syrup, sodium chloride, sodium sulfite, sodium phosphate, citric acid, polyvinylpyrrolidone, water, shellac, carnauba wax and the like. Other ingredients such as apple-derived polyphenols, steroidal or non-steroidal anti-inflammatory compounds, etc. may be included in the formulation to enhance the usefulness of the agent of the present invention. One aspect of the present invention is the use of bone crushing extract in the manufacture of the above agents.

Parenteral agents may be pharmaceuticals, quasi-drugs or cosmetics. External preparations can be applied or attached directly to the skin, for example, and may be liquids, creams, emulsions, lotions, ointments, gels, aerosols, packs, microneedle patches, poultices, and the like. Injections can be administered, for example, into joints, veins, subcutaneously or into muscles.

The content of each component in the parenteral preparation may be the same as or different from that in the oral preparation. The content of the bone crushing extract in the parenteral preparation may be, for example, 0.001% by mass or more and 10% by mass or less, or may be 0.01% by mass or more, or 0.05% by mass or more. % or less or 3% or less by mass. Parenteral agents may be administered in one or several divided doses per day.

Parenteral preparations can be prepared by mixing the bone crushed extract and bases or carriers that are commonly used in pharmaceuticals, quasi-drugs or cosmetics according to a conventional method. As bases or carriers, fats and oils such as coconut oil, olive oil, rice bran oil, shea butter; hydrocarbons such as petrolatum and liquid paraffin; waxes such as jojoba oil, miura, candelilla wax and lanolin; cetanol and cetostearyl. Higher alcohols such as alcohol, stearyl alcohol, behenyl alcohol, octyldodecanol, isostearyl alcohol, phytosterol, cholesterol; silicones such as dimethicone, cyclic silicone and modified silicone; cellulose derivatives such as ethylcellulose, hydroxypropylcellulose and hydroxypropylmethylcellulose; pyrrolidone; carrageenan; polyvinyl butyrate; polyethylene glycol; dioxane; butylene glycol adipate polyester; Esters such as pentaerythritol; Polysaccharides such as dextrin and maltodextrin; Vinyl polymers such as carboxyvinyl polymer and alkyl-modified carboxyvinyl polymer; Lower alcohols such as ethanol and isopropanol; Propylene glycol, 1,3-butylene glycol , glycerin, polyhydric alcohols such as polyethylene glycol; glycol ethers such as diethylene glycol monoethyl ether; and water. These may be used singly or in combination of two or more, and the amount thereof to be used is appropriately selected from the range known to those skilled in the art. Other ingredients such as apple-derived polyphenols, steroidal or non-steroidal anti-inflammatory compounds, etc. may be included in the formulation to enhance the usefulness of the agent of the present invention.

Parenteral agents may contain known additives such as surfactants, stabilizers, antioxidants, colorants, dispersants, chelating agents, pH adjusters, preservatives, and thickeners, as long as they do not impair the effects of the present invention. Viscous agents, stimulus reducing agents, fragrances, UV absorbers, moisturizing agents, vasodilators, etc. can be added. These additives can be used singly or in combination of two or more.

Examples of surfactants include sorbitan such as sorbitan monoisostearate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, diglycerol sorbitan penta-2-ethylhexylate, and diglycerol sorbitan tetra-2-ethylhexylate. Fatty acid esters; propylene glycol fatty acid esters such as propylene glycol monostearate; polyoxyethylene hydrogenated castor oil 40 (HCO-40), polyoxyethylene hydrogenated castor oil 50 (HCO-50), polyoxyethylene hydrogenated castor oil 60 (HCO-60), hydrogenated castor oil derivatives such as polyoxyethylene hydrogenated castor oil 80; polyoxyethylene (20) sorbitan monolaurate (polysorbate 20), polyoxyethylene (20) sorbitan monostearate (polysorbate 60), Polyoxyethylene sorbitan fatty acid esters such as polyoxyethylene (20) sorbitan monooleate (polysorbate 80) and polyoxyethylene (20) sorbitan isostearate; polyoxyethylene monococonut fatty acid glyceryl; glycerin alkyl ether; alkyl glucoside; polyoxyalkylene alkyl ethers such as polyoxyethylene cetyl ether; and amines such as stearylamine and oleylamine.

Examples of stabilizers include sodium polyacrylate, dibutylhydroxytoluene, butylhydroxyanisole, sodium phosphate, sodium sulfite, sodium hydrogensulfite, sodium pyrosulfite, sodium thiosulfate, cysteine hydrochloride, phosphate, sodium ascorbate, sodium chloride, sodium bicarbonate; glycine, various amino acids and derivatives thereof.

Examples of antioxidants include dibutylhydroxytoluene, sodium pyrosulfite, sodium edetate, butylhydroxyanisole, sorbic acid, sodium sulfite, ascorbic acid, erythorbic acid and L-cysteine hydrochloride.

Examples of coloring agents include inorganic pigments and natural pigments.

Dispersants include, for example, sodium pyrophosphate, sodium hexametaphosphate, polyvinyl alcohol, polyvinylpyrrolidone, methyl vinyl ether/maleic anhydride crosslinked copolymers, organic acids.

Chelating agents include, for example, EDTA.disodium salt and citric acid.

Examples of pH adjusters include inorganic acids such as hydrochloric acid and sulfuric acid; organic acids such as lactic acid, sodium lactate, citric acid, sodium citrate, succinic acid and sodium succinate; inorganic bases such as potassium hydroxide and sodium hydroxide; Organic bases such as triethanolamine, diisopropanolamine and triisopropanolamine are included.

Preservatives include, for example, benzoic acid, sodium benzoate, dehydroacetic acid, sodium dehydroacetate, parabens, and phenoxyethanol.

Examples of thickeners include cellulose-based thickeners such as methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, and carboxyethylcellulose, sucrose, guar gum, pectin, pullulan, gelatin, and locust bean. Gum, carrageenan, agar, xanthan gum, polyvinyl alcohol, polyvinylpyrrolidone, carboxyvinyl polymer, acrylic acid alkyl methacrylate copolymer, polyethylene glycol, bentonite, alginic acid, propylene glycol alginate, macrogol, hyaluronic acid, sodium hyaluronate, (acrylic acid hydroxyethyl/acryloyldimethyltaurate Na) copolymer, (acryloyldimethyltaurate ammonium/vinylpyrrolidone) copolymer.

Irritation reducing agents include, for example, licorice extract, sodium alginate, gum arabic, polyvinylpyrrolidone, licorice extract, and sodium alginate.

UV absorbers include, for example, ethyl para-aminobenzoate, ethylhexyl paradimethylaminobenzoate, amyl salicylate and derivatives thereof, 2-ethylhexyl para-methoxycinnamate, octyl cinnamate, oxybenzone, 2,4-dihydroxybenzophenone, 2-hydroxy-4 -Methoxybenzophenone-5-sulfonate, 4-tert-butyl-4-methoxybenzoylmethane, 2-(2-hydroxy-5-methylphenyl)benzotriazole, urocanic acid, ethyl urocanate, aloe extract. .

Examples of moisturizing agents include glycerin, propylene glycol, dipropylene glycol, 1,3-butylene glycol, polyethylene glycol, sorbitol, xylitol, sodium pyrrolidonecarboxylate, saccharides such as trehalose, mucopolysaccharides (e.g., sodium hyaluronate, heparin ), elastin, collagen, NMF-related substances, lactic acid, urea, higher fatty acid octyldodecyl, seaweed extracts, and serrata root (white and white) extracts.

Vasodilators include, for example, carpronium chloride, benzyl nicotinate, assembly extract, minoxidil, Panax ginseng extract, capsicum tincture.

[Experiment 1: Animal test (gene expression analysis of synovial membrane in rat traumatic arthritis model)]
Ten-week-old male Wister rats (Crij: WI) were used for the experiments. A non-OA model by sham surgery (sham surgery, incision of skin and muscle layer only) and an OA-onset model by medial collateral ligament and medial meniscus resection (MTT surgery) were prepared. Surgery was performed on the right knee only in all animals, and the left knee was left untreated. Two days after the operation, the animals were introduced into the animal breeding room, and after one week of preliminary breeding, the animals were assigned to each test group so that there was no bias in the average body weight. Rat conditions were a 12-hour light-dark cycle and a room temperature of 24±2°C. As feed, solid feed for general breeding (Labo MR Stock, manufactured by Nihon Nosan Kogyo Co., Ltd.) was used, and the animals were bred under constant feeding and watering conditions.

Table 1 shows the test conditions. As the bone crushing extract, "bone crushing extract" (manufactured by BGG JAPAN) was administered. N-acetylcysteine (NAC) was administered as a positive control. Sham group and control group were administered sterilized water. The test substance was orally administered once a day during the test period using a gastric probe.

Autopsy was performed after 8 weeks of administration. Under anesthesia with Sevofurene (registered trademark) inhalation anesthetic (Maruishi Pharmaceutical Co., Ltd.), blood was collected from the inferior vena cava to euthanize the rat, and the synovial tissue under the patellar of the right knee and the knee joint of the right hind leg were collected. A tissue section around the articular cartilage of the right hind leg knee joint was prepared to confirm the development of knee osteoarthritis.

Synovial tissue was collected from the right knee joint for synovial gene expression analysis. The isolated synovial tissue was washed with PBS, immersed in RNAlater (manufactured by Invitrogen) at 4° C. overnight, and then treated with TRIzol (registered trademark) reagent (manufactured by Invitrogen) to purify total RNA. Using this as a template, cDNA was synthesized using PrimeScript RT reagent Kit (Perfect Real Time, manufactured by Takara Bio Inc.). Using this cDNA as a template, quantitative real-time PCR was performed using TB Green Premix Ex Taq II (manufactured by Takara Bio Inc.) and Thermal Cycler Dice Real Time System TP800 (manufactured by Takara Bio Inc.). The base sequences of the primers used are shown in Table 2 and SEQ ID NOS: 1-6.

After completion of the reaction, gene expression levels were analyzed using dedicated software (Thermal Cycler Dice Real Time System TP800 Software Ver. 1.02A). The gene expression level of each sample was standardized with the co-amplified β-Actin, and the results are shown as mean±standard error (SE).

FIG. 1 shows the results of gene expression analysis of IL-10 in synovium. The IL-10 gene expression level was slightly lower in the Control group than in the Sham group. On the other hand, the IL-10 gene expression level was significantly higher in the bone crushed extract-administered group than in the control group. IL-10 is known as one of anti-inflammatory cytokines. It was suggested that the bone crushed extract strongly promoted IL-10 gene expression and reduced synovial inflammation.

FIG. 2 shows the results of gene expression analysis of MMP-13 in synovium. The MMP-13 gene expression level was significantly increased in the Control group compared to the Sham group. On the other hand, in the bone crushed extract-administered group, the gene expression level of MMP-13 was halved compared to the control group. MMP-13 works to degrade collagen, one of the main components of cartilage. It was suggested that the bone crushed extract inhibited the gene expression of MMP-13 and acted to inhibit cartilage degradation.

[Experiment 2: Animal test (gene expression analysis of synovial membrane in rat traumatic arthritis model)]
In Experiment 2, rats were administered the test substance in the same manner as in Experiment 1. Table 3 shows the test conditions. cDNA was obtained from the synovial tissue of the knee joint in the same manner as in Experiment 1, and quantitative real-time PCR was performed. The nucleotide sequences of the primers used are shown in Table 4 and SEQ ID NOS:5-10.

FIG. 3 shows the results of gene expression analysis of TNF-α in synovium. TNF-α gene expression level was significantly higher in the Control group than in the Sham group. On the other hand, in the bone crushed extract-administered group, the TNF-α gene expression level was significantly lower than in the control group, and was equivalent to that in the sham group. TNF-α is one of representative inflammatory cytokines. It was suggested that the bone crushed extract may suppress TNF-α gene expression and reduce synovial inflammation.

FIG. 4 shows the results of gene expression analysis of SOD1 in synovium. The SOD1 gene expression level was significantly higher in the Control group than in the Sham group. On the other hand, in the bone crushed extract-administered group, the SOD1 gene expression level was significantly lower than in the Control group, and was equivalent to that in the Sham group. It is speculated that the antioxidative action of the bone crushed extract alleviated the oxidative stress in the synovial membrane, which was enhanced by inflammation, and reduced the gene expression level of SOD1.

The antioxidant effect (ORAC value) of the bone crushing extract is shown based on the method described in Cao G et al., Free Radical Biology and Medicine, vol 14, Issue 3, 303-311, March 1993. . It was found that the antioxidative activity of the bone crushed extract was higher than that of vitamin C (L-ascorbic acid) used as a standard substance (Fig. 5).

[Experiment 3: Animal test (gene expression analysis of synovial membrane in spontaneous knee osteoarthritis model)]
The STR/Ort mouse, which is a model animal of spontaneous knee arthritis (OA), is a species separated from the STR/1N species, and develops knee OA with aging, abrasion degeneration of articular cartilage, and cartilage calcification. It is known to exhibit pathological conditions similar to those of knee OA in humans, such as hyperplasia and joint space narrowing. It has been reported that STR/Ort mice begin to develop OA in the medial tibial cartilage of the male hind limbs at around 20 weeks of age, and frequently after 35 weeks of age, but not in female knee joints. In addition, STR/Ort mice are also known to develop obesity and dyslipidemia, which are risk factors for developing OA in humans. In this experiment, the bone crushed extract was orally administered to STR/Ort mice, and the effect on knee OA was examined.

The mice were reared under a 12-hour light-dark cycle and a room temperature of 24±2°C. As feed, solid feed for general breeding (Labo MR Stock, manufactured by Nihon Nosan Kogyo Co., Ltd.) was used, and the animals were bred under constant feeding and watering conditions. At the age of 27 weeks, 10 male STR/Ort mice were divided into groups so that there was no weight bias. In addition, 5 female STR/Ort mice were used as a female non-symptomatic group. Table 5 shows the test conditions. The test substance was orally administered once a day during the test period using a gastric probe. Only sterilized water was administered to the female non-onset group and the male onset control group.

Autopsy was performed after 8 weeks of administration. Mice were euthanized by collecting blood from the inferior vena cava under anesthesia with Sevofurene (registered trademark) inhalation anesthetic (Maruishi Pharmaceutical Co., Ltd.), and the synovial tissue under the patellar of both knees and the knee joints of both hind legs were collected. Histological sections were prepared around the articular cartilage of both hind knee joints to confirm the development of knee osteoarthritis. cDNA was obtained from the synovial tissue of the knee joint in the same manner as in Experiment 1, and quantitative real-time PCR was performed.

FIG. 6 shows the results of gene expression analysis of IL-10 in synovium. The gene expression level of IL-10 was slightly increased in the male onset control group compared to the female non-onset group. A marked increase in IL-10 gene expression was observed in the bone crushed extract-administered group compared to the androgenetic control group. IL-10 is known as one of anti-inflammatory cytokines. It was suggested that the bone crushed extract strongly promoted IL-10 gene expression and reduced synovial inflammation.

FIG. 7 shows the results of gene expression analysis of MMP-13 in synovium. The gene expression level of MMP-13 was remarkably increased in the male onset control group compared to the female non-onset group. On the other hand, in the bone crushed extract administration group, the gene expression level of MMP-13 was greatly reduced compared to the androgenetic control group. MMP-13 works to degrade collagen, one of the main components of cartilage. It was suggested that the bone crushed extract may suppress the gene expression of MMP-13 and suppress cartilage degradation.

Claims (8)

An articular synovial anti-inflammatory agent comprising an osteoclast extract. An arthralgia suppressant containing a bone crushing extract, which suppresses joint pain by the anti-inflammatory action of joint synovial membrane. 3. The anti-inflammatory agent according to claim 1 or 2, wherein said joint is a knee joint. 4. The agent according to any one of claims 1 to 3, which suppresses joint synovial inflammation by promoting IL-10 expression, suppressing TNF-α expression, or suppressing MMP-13 expression. Antioxidant with bone crushing extract. The agent according to any one of claims 1 to 5, which is an oral agent. 7. The agent according to claim 6, which is a food with health claims, a health supplement, or a supplement. The agent according to any one of claims 1 to 7, which is used for people with arthralgia.

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