WO2015034330A1 - Composition pour le traitement ou la prévention de maladies osseuses, comprenant de l'halofuginone comme principe actif - Google Patents

Composition pour le traitement ou la prévention de maladies osseuses, comprenant de l'halofuginone comme principe actif Download PDF

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WO2015034330A1
WO2015034330A1 PCT/KR2014/008426 KR2014008426W WO2015034330A1 WO 2015034330 A1 WO2015034330 A1 WO 2015034330A1 KR 2014008426 W KR2014008426 W KR 2014008426W WO 2015034330 A1 WO2015034330 A1 WO 2015034330A1
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hellofuginone
bone
differentiation
cells
treating
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PCT/KR2014/008426
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English (en)
Korean (ko)
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박성환
조미라
박미경
곽승기
이주하
박진실
김성민
임미애
백승예
이동건
박은미
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가톨릭대학교 산학협력단
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Priority claimed from KR1020140117469A external-priority patent/KR101654980B1/ko
Application filed by 가톨릭대학교 산학협력단 filed Critical 가톨릭대학교 산학협력단
Priority to US14/917,548 priority Critical patent/US20160220567A1/en
Publication of WO2015034330A1 publication Critical patent/WO2015034330A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis

Definitions

  • the present invention relates to a composition for the treatment or prevention of bone diseases comprising hellofuginone as an active ingredient, and more particularly comprising the hellofuginone having osteoclast differentiation inhibition and osteoblast-related factor activation efficacy as an active ingredient. It relates to a composition for treating or preventing bone diseases.
  • the bones that make up our body go through the process of turning old bones into new bones for life, like normal human tissue. This is called bone remodeling.
  • This process proceeds by balancing osteoblasts, which cause bone formation, and osteoclasts, which cause bone destruction.
  • bone formation is more important than bone destruction. Actively occurs, and adult bone remodeling occurs as a balance between formation and destruction in adulthood, but in older age, bone destruction occurs more actively than bone formation, causing disease. If the balance is not balanced in the bone remodeling process, rheumatoid arthritis, or osteoporosis caused by bone density being depleted by osteoclasts, or osteoporosis, in which osteoblast activity is too active, increasing bone density.
  • bone diseases such as osteopetrosis and Paget's disease called deformative osteoarthritis occur.
  • Osteoclasts is a large multinucleated cell that destroys or absorbs bone tissue that is unnecessary during the growth of bones of vertebrates, and if its activity is too active, bone density is low and causes diseases such as osteoporosis.
  • Receptor activator of nuclear factor-kB ligand (RANKL) is required to differentiate into osteoclasts, and macrophage colony stimulating factor (M-CSF) is required for proliferation of osteoclasts. Differentiation of osteoclasts begins when RANKL binds to its receptor RANK.
  • adapter molecules such as tumor necrosis factor receptor associated factor 6 (TRAF6) are activated.
  • TRAF2 and TRAF6 known as TRAF family members, activate transcription factors such as NF-kB and activator protein-1 (AP-1), which are required for the differentiation of osteoclasts.
  • TRAF6 When TRAF6 is activated by RANKL signaling for osteoclast differentiation, PI3K, transforming growth factor ⁇ -activated kinase (TAK1), Akt / PKB, and MAPKs including JNK, ERK, p38, and also NF-kB, c-Fos , Fra-1, CREB (cyclic-AMP-responsive-element-binding protein), NFATc1 (nuclear factor of activated T cells cytoplasmic 1) are activated.
  • TRAF6 When TRAF6 is activated by RANKL signaling for osteoclast differentiation, PI3K, transforming growth factor ⁇ -activated kinase (TAK1), Akt / PKB, and MAPKs including JNK, ERK, p38, and also
  • This induction is caused by the c-Fos pathway via TRAF6-NF-kB and RANKL-RANK signals. And they are used to express osteoclast-specific genes such as cathepsin K, catapsin-resistant acid phospatase (TRAP), calcitonin receptors, and osteoclast-associated receptors (OSCARs).
  • the process by which osteoclasts attach to bone and breaks it down involves cytoskeleton reoragnization, which includes the formation of sealing zones and filamentous actin rings that are attached to bone surfaces around erosion spaces. Induce.
  • the RANKL / RANK / TRAF6 axis and NFATc1 are essential for differentiation into mature osteoclasts, and these signaling pathways are initiated by RANKL, and the molecules involved can be targets for bone disease drugs.
  • the RANKL / RANK system and the protein kinases and transcription factors underneath are involved in biological processes such as the immune system as well as osteoclast formation.
  • osteoblasts originate from mesenchymal stem cells, and mineralization, including calcium, formed by the differentiation of osteoblasts not only maintains bone strength, but is also important for homeostasis of calcium and hormone metabolism throughout the body. It is functioning. Calcium formation by the differentiation of osteoblasts is regulated by vitamin D and parathyroid hormone, etc.
  • bone morphogenetic protein BMP
  • Wnt Wnt
  • MAP kinase MAP kinase
  • calcineurin-calmodulin kinase Alkaline phosphatase ALP
  • osteopontin osteocalcin, type I collagen, and the like, which are involved in mineralization, are synthesized, and bone formation by osteoblast differentiation is known.
  • the bone remodeling occurs in a bone multicellular unit (BMU) composed of osteoblasts and osteoclasts, and these cells are composed of osteoblasts and osteoblasts, respectively. It is known to play an important role in the bone resorption process. In this process, when the cooperative system between the two cells is damaged, various bone metabolic diseases including osteoporosis occur.
  • BMU bone multicellular unit
  • Osteoporosis is a representative disease among various diseases of bone metabolism. Osteoporosis is a disease in which bone mass decreases due to various causes and the risk of fracture is continuously increased due to degeneration of the microstructure of bone tissue. ), And the formation of osteoclasts is greater than osteoblasts due to a loss of balance in aggregate formation (Iqbal MM., South Med J., 93 (1): 2-18 (2000)). Normal bone inside has a dense structure like a net, but in the case of osteoporosis, the space between the structures is widened and the microstructure becomes thin and weak, so that the bone can be easily broken even in the small impact.
  • Osteoporosis occurs rapidly in the beginning of menopause, with rapid bone loss (2-3% per year), postmenopausal osteoporosis, which increases the risk of vertebral compression and carpal fractures, and occurs slowly in men and women over 70 years old.
  • Senile osteoporosis in old age which leads to progressive bone loss of the hip and vertebrae (0.5 to 1% per year), and age-related diseases (endocrine diseases, gastrointestinal diseases, malignancies) or drugs (Adrenal cortical hormones, chemotherapy, thyroid hormones, anticonvulsants, anticoagulants, methotrexate, cyclosporine, GnRH, etc.), alcohol, smoking, accidental secondary osteoporosis (Secondary osteoporosis) Are classified.
  • bone metastasis almost always occurs in breast cancer, prostate cancer or multiple myeloma patients, and how long these cancer patients can live is affected by bone metastasis.
  • bone metastases observed in prostate cancer are osteoblastic metastasis. Osteoblastic bone metastasis is also known to be closely associated with osteolysis.
  • Cancer cells that have metastasized to bone proliferate in the microenvironment around the bone and stimulate the activity of osteoclasts or osteoblasts to determine whether to progress to osteolytic bone metastasis or osteoblast metastasis.
  • About 80% of breast cancer patients develop bone metastases of cancer cells, and the metastasized breast cancer cells activate osteoclasts.
  • Activated osteoclasts disrupt the balance of the microenvironment around bones, leading to osteolysis, which often causes pathological fractures, as well as leukoerythroblastic anaemia, bone malformations, and hypercalcemia.
  • Bone-related diseases such as pain, nerve compression syndrome, etc.
  • bisphosphonate-based therapeutics such as Fosamax (alendronate) and Actonel (risedronate) are used for bone damage caused by osteoporosis and bone metastasis of cancer cells.
  • Most of these bisphosphonate preparations work to slow or stop bone loss by weakening and inducing the death of osteoclasts that destroy bone.
  • Recently, however, there have been an increasing number of cases of osteonecrosis, severe atrial fibrillation, incapacitation of bones or joints, or musculoskeletal pain in patients taking bisphosphonates (Coleman RE., Br J Cancer, 98: 1736-1740). (2008)). Therefore, much attention has been focused on the development of osteoporosis prevention and treatment that can effectively suppress bone absorption while reducing side effects.
  • the present inventors have completed the present invention by discovering that hellofuginone is very excellent in treating or preventing bone diseases while trying to develop a therapeutic agent that can effectively treat or prevent bone diseases.
  • a pharmaceutical composition for treating or preventing bone diseases comprising a hellofuginone compound or a salt thereof as an active ingredient.
  • Another object of the present invention is to provide a composition for promoting differentiation or activity of osteoblasts, including a hellofuginone compound or a salt thereof as an active ingredient.
  • Still another object of the present invention is to provide a composition for inhibiting osteoclast differentiation, which comprises a hellofuginone compound or a salt thereof as an active ingredient.
  • Still another object of the present invention is to provide a food composition for improving bone function, including a hellofuginone compound or a salt thereof as an active ingredient.
  • the present invention provides a pharmaceutical composition for treating or preventing bone diseases comprising a hellofuginone compound or a salt thereof as an active ingredient.
  • the bone disease is osteoporosis, osteoarthritis, osteoporosis, Paget's disease, osteomalacia, rickets, fibrous osteoarthritis, aplastic bone disease, metabolic bone disease, bone caused by bone metastasis of cancer cells It may be any one selected from the group consisting of rheumatoid arthritis, which is a bone destruction disease through injury and immune inflammatory reaction of.
  • the hellofuginone may exhibit a therapeutic effect by reducing or inhibiting osteoclast differentiation.
  • the hellofuginone may exhibit a therapeutic effect by reducing or inhibiting osteoclast differentiation induced by RANKL.
  • the hellofuginone may reduce or inhibit osteoclast differentiation through inhibition of expression of Th17.
  • the hellofuginone can inhibit the expression of Th17 cells by activating ERK in Th17 cells.
  • the hellofuginone may exhibit a therapeutic effect by inhibiting bone absorption by osteoclasts.
  • the hellofuginone may promote the differentiation or development of osteoblasts.
  • the hellofuginone may be administered to the administered individual in an amount of 0.5 ⁇ g / kg to 2000 ⁇ g / kg.
  • the present invention provides a composition for promoting differentiation or activity of osteoblasts, including a hellofuginone compound or a salt thereof as an active ingredient.
  • the hellofuginone may promote the expression or activity of SOX6 or Rcan3 which is a differentiation factor of osteoblasts.
  • the present invention provides a composition for inhibiting osteoclast differentiation comprising a hellofuginone compound or a salt thereof as an active ingredient.
  • the present invention provides a food composition for improving bone function comprising a hellofuginone compound or a salt thereof as an active ingredient.
  • the present invention also provides a method for treating or preventing bone diseases, comprising administering to a subject an effective amount of a hellofuginone compound or a salt thereof.
  • the present invention is characterized in that it provides a pharmaceutical composition for treating or preventing bone disease, which comprises hellofuginone as an active ingredient.
  • the inventors of the present invention while studying to find a new therapeutic agent for treating bone disease, confirmed that hellofuginone can be used as a new therapeutic agent for bone disease.
  • Hellofuginone an active ingredient contained in the composition of the present invention, is an anti-coccidiostat used in veterinary medicine as a compound having a structural formula represented by the following Chemical Formula 1 and is a natural alkaloid quina found in the Chinese plant Dichroa febrifuga. It is a synthetic halogenated derivative of febrifuginine, a quinazolinone. Collard Biopharmaceuticals is developing Hellofuginone for the treatment of scleroderma and has received a rare drug designation from the US Food and Drug Administration.
  • Hellofuginone is known to inhibit tumor cell growth by inhibiting the expression of collagen type I genes and acts as a high affinity inhibitor of glutamyl-prolyl tRNA synthetase and inhibits amino acid filling of prolyl tRNA It is known to act as a signal to initiate a deficiency reaction.
  • the hellofuginone inhibits bone resorption by inhibiting the differentiation of osteoclasts induced by receptor activator of NF- [kappa] B ligand (RANNKL) It was confirmed that it is possible to reduce or inhibit the differentiation of osteoclasts by inhibiting the expression of Th17, and in particular, to inhibit the expression of Th17 cells by activating ERK in Th17 cells.
  • RANNKL NF- [kappa] B ligand
  • the present invention can provide a pharmaceutical composition for treating or preventing bone diseases, including a hellofuginone compound or a salt thereof as an active ingredient.
  • the hellofuginone used in the present invention may be one synthesized by a chemical synthesis method or may be used as separated and purified from natural products.
  • the hellofuginone usable in the present invention may be used in the form of salts, preferably pharmaceutically acceptable salts.
  • the salt is preferably an acid addition salt formed by a pharmaceutically acceptable free acid, and an organic acid and an inorganic acid may be used as the free acid.
  • the organic acid is not limited thereto, citric acid, acetic acid, lactic acid, tartaric acid, maleic acid, fumaric acid, formic acid, propionic acid, oxalic acid, trifluoroacetic acid, benzoic acid, gluconic acid, metasulfonic acid, glycolic acid, succinic acid, 4-toluenesulfonic acid, Glutamic acid and aspartic acid.
  • the inorganic acid includes, but is not limited to, hydrochloric acid, bromic acid, sulfuric acid and phosphoric acid.
  • the hellofuginone compound or pharmaceutically acceptable salt of the present invention is an amount capable of inhibiting the differentiation of osteoclasts or promoting the differentiation or activity of osteoblasts, the amount of 0.5 ⁇ g / kg to 2000 ⁇ g / kg It may be administered to the subject administered, preferably to the subject administered in an amount of 8 ⁇ g / kg to 40 ⁇ g / kg.
  • the effective amount of the hellofuginone compound to derive the pharmacological effect that is, the osteoclast differentiation or osteoblast differentiation or activity promoting action in mice 100 ⁇ g / It was confirmed that the kg ⁇ 500 ⁇ g / kg, the treatment concentration of the pharmacological substance confirmed through the animal experiments can be expected the treatment concentration of the pharmacological substance applicable to humans through the following formula known in the art.
  • Human application concentration (mg / kg) [animal application concentration (mg / kg) ⁇ animal application Km index] / [human application Km index]
  • the Km index is a predetermined value converted into the body surface of the body of an individual, and is set to 37 for human adult, 25 for human child, 3 for mouse, and 6 for rat. .
  • the treatment concentration of the hellofuginone administered to the mice administered in the animal model performed in the embodiment of the present invention in terms of the human (adult) application concentration 8 ⁇ g / kg ⁇ 40 ⁇ g / It can be seen that it can be processed in humans in the amount of kg.
  • 'pharmaceutically acceptable salts' refers to salts prepared by conventional methods and may be used without limitation by methods known to those skilled in the art.
  • 'Pharmaceutically acceptable salts' include but are not limited to salts derived from the following pharmacologically or physiologically acceptable inorganic and organic acids and bases.
  • suitable acids include hydrochloric acid, bromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, toluene-p-sulfonic acid, tartaric acid, acetic acid, citric acid, methanesulfonic acid, formic acid , Benzoic acid, malonic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid, and the like.
  • Salts derived from suitable bases may include alkali metals such as sodium, alkali cometals such as magnesium, ammonium and the like.
  • the hellofuginone of the present invention or a salt thereof may further include a suitable carrier, excipient or diluent according to a conventional method.
  • carrier refers to a carrier, excipient or diluent that does not significantly stimulate the organism and does not inhibit the biological activity and properties of the administered compound.
  • Carriers, excipients and diluents that may be included in the compositions of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.
  • composition comprising hellofuginone or a salt thereof according to the present invention may be oral formulations, external preparations, suppositories, or sterile injectable solutions, such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, etc., according to conventional methods, respectively.
  • sterile injectable solutions such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, etc., according to conventional methods, respectively.
  • Formulated in the form of can be used.
  • Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, and the solid preparations may include at least one excipient such as starch, calcium carbonate, sucrose in the extract. ), Lactose, gelatin and the like can be mixed.
  • lubricants such as magnesium stearate, talc can also be used.
  • Liquid preparations for oral use include suspensions, solvents, emulsions, and syrups.In addition to the commonly used simple diluents, water and liquid paraffin, various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be included. have.
  • Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations and suppositories.
  • non-aqueous solvent and suspending agent propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate and the like can be used.
  • As the base of the suppository witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerogelatin and the like can be used.
  • osteoblasts is a cell that appears during bone development or regeneration, and bone is formed on one side of bone tissue, while destruction or absorption of bone tissue proceeds on the other side.
  • bone formation is largely involved in two types of cells, that is, osteoblasts producing bones and osteoclasts destroying bones, and bone homeostasis is closely related to each other. Is maintained.
  • osteoblasts regulate bone in the body by regulating the differentiation of osteoclasts responsible for bone resorption through the secretion of substances such as receptor activator of nuclear factor- ⁇ B ligand (RANKL) and osteoprotegerin (OPG).
  • RNKL nuclear factor- ⁇ B ligand
  • OPG osteoprotegerin
  • osteoclast progenitor cells when RANKL binds to RANK, an osteoclast progenitor surface receptor, osteoclast progenitor cells mature into osteoclasts, and bone resorption occurs.
  • OPG binds to RANKL
  • binding between RANKL and RANK blocks osteoclasts. Formation is inhibited (Theill LE. Et al., Annu Rev Immunol., 20: 795-823 (2002); Wagner EF. Et al., Curr Opin Genet Dev., 11: 527-532 (2001)). Therefore, osteoclasts formed from progenitor cells absorb or destroy old bones, and release small amounts of calcium accumulated in bones into the bloodstream to maintain body function.
  • the 'osteoblast' is a cuboidal cell that forms bone, and means a cell that has bone formation and remodeling action.
  • Osteoblasts are lattice-shaped collagen in the parts that are broken down by osteoclasts, and calcium, magnesium, and phosphorus are attached to them to make bone matrix and ultimately form bone.
  • the effect of hellofuginone on the expression of SOX6 and Rcan3 genes was analyzed to confirm whether the osteoblast differentiation or development promotion is involved. It was found that the action to promote expression or activity.
  • the regulators of calcineurin are known to promote bone formation by reducing the expression of NFAT subgenes as calcineurin inhibitors (Mulero MC, Aubareda A, Schluter A, Perez-Riba M 2007 RCAN3, a novel calcineurin inhibitor that down-regulates NFAT-dependent cytokine gene expression.Biochim Biophys Acta 1773: 330-341), Sox6 is known as a factor that can promote chondroblast function (Mulero MC, Aubareda A, Schluter A, Perez-Riba M 2007 RCAN3, a novel calcineurin inhibitor that down-regulates NFAT-dependent cytokine gene expression.Biochim Biophys Acta 1773: 330-341; Smits P, Li P, Mandel J, Zhang Z, Deng JM, Behringer RR, de Crombrugghe B, Lefebvre V 2001
  • the transcription factors L-Sox5 and Sox6 are essential for
  • composition of the present invention was found to play a role in increasing the expression of the genes involved in the differentiation and development of osteoblasts can ultimately contribute to the promotion of bone formation through the development of osteoblasts.
  • the present invention not only provides a pharmaceutical composition for treating or preventing a bone disease comprising the hellofuginone compound or a salt thereof as an active ingredient, but also comprises a hellofuginone compound or a salt thereof as an active ingredient, differentiation of osteoblasts Or it may provide a composition for promoting activity and a composition for inhibiting osteoclast differentiation.
  • 'bone metabolism disease' is a disease caused by a problem in bone formation due to lack of osteoblasts or differentiation of osteoclasts, but is not limited thereto, osteoporosis, osteoarthritis, osteoporosis, Paget's disease, osteomalacia, rickets disease And fibrotic osteoarthritis, aplastic bone disease, metabolic bone disease, bone damage caused by bone metastasis of cancer cells, and rheumatoid arthritis, a bone destruction disease through an immunoinflammatory reaction.
  • the present invention also provides a method for treating or preventing bone diseases, comprising administering to a subject an effective amount of a hellofuginone compound or a salt thereof.
  • the 'treatment' refers to any action that improves or advantageously changes the symptoms of the disease by administration of a composition containing hellofuginone or a pharmaceutically acceptable salt according to the present invention.
  • the 'prevention' refers to any action that inhibits or delays the onset of the disease by administration of a composition containing hellofuginone or a pharmaceutically acceptable salt according to the present invention.
  • the 'administration' means introducing the composition of the present invention to the patient in any suitable way, the route of administration of the composition of the present invention is administered through various routes orally or parenterally as long as the target tissue can be reached In particular, it may be administered in a conventional manner via oral, rectal, topical, intravenous, intraperitoneal, intramuscular, intraarterial, transdermal, nasal, inhalation, intraocular or intradermal routes.
  • the treatment method of the present invention includes administering a composition of the present invention in a pharmaceutically effective amount. It will be apparent to those skilled in the art that a suitable total daily dose may be determined by the practitioner within the correct medical judgment.
  • the specific therapeutically effective amount for a particular patient may be based on the specific composition, including the type and severity of the reaction to be achieved, whether or not other agents are used in some cases, the age, weight, general health, sex and diet of the patient, time of administration, It is desirable to apply differently depending on the route of administration and the rate of release of the composition, the duration of treatment, and the various factors and similar factors well known in the medical arts, including drugs used with or concurrent with the specific composition. Therefore, the effective amount of the composition suitable for the purpose of the present invention is preferably determined in consideration of the above matters.
  • the present invention further provides a method of treating or preventing bone metabolic diseases comprising administering to a subject in need thereof a composition comprising hellofuginone or a pharmaceutically acceptable salt.
  • the method of preventing or treating bone metabolic disease of the present invention is applicable to any individual with bone metabolic disease, and animals include humans and primates, as well as domestic animals such as cattle, pigs, sheep, horses, dogs, and cats.
  • the present invention may provide a food composition for improving bone function, including hellofuginone or a pharmaceutically acceptable salt.
  • composition comprising the hellofuginone of the present invention or a pharmaceutically acceptable salt thereof may be used in various applications, such as drugs, foods and drinks for the prevention of bone metabolism-related diseases.
  • Foods to which the extract of the present invention may be added include various foods, for example, beverages, gums, teas, vitamin complexes, dietary supplements, and the like, which are pills, powders, granules, tablets, tablets, capsules or beverages. Available in form.
  • the amount of the hellofuginone in the food or beverage can be generally added to 0.01 to 15% by weight of the total food weight in the case of the health food composition of the present invention, 0.02 to 10g based on 100ml for the health beverage composition Preferably, it can be added in the ratio of 0.3-1 g.
  • the health beverage composition of the present invention is not particularly limited in the liquid component except for containing the hellofuginone as an essential ingredient in the indicated ratio, and may contain various flavors or natural carbohydrates as additional ingredients, such as ordinary drinks.
  • natural carbohydrates include monosaccharides such as glucose, fructose and the like; Disaccharides such as maltose, sucrose and the like; Polysaccharides such as dextrin, cyclodextrin; Conventional sugars such as and the like and sugar alcohols such as xylitol, sorbitol, and erythritol.
  • natural flavoring agents such as, tauumatin, stevia extract (e.g., Rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used.
  • the proportion of said natural carbohydrates is generally about 1-20 g, preferably about 5-12 g per 100 ml of the composition of the present invention.
  • the composition of the present invention includes various nutrients, vitamins, minerals (electrolytes), flavors such as synthetic flavors and natural flavors, coloring and neutralizing agents (such as cheese and chocolate), pectic acid and salts thereof, alginic acid and salts thereof. , Organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated beverages, and the like.
  • the compositions of the present invention may also contain pulp for the production of natural fruit juices and fruit juice beverages and vegetable beverages. These components can be used independently or in combination. The proportion of such additives is not so critical but is generally selected in the range of 0 to about 20 parts by weight per 100 parts by weight of the composition of the present invention.
  • the other ingredients other than the composition having an effect on bone diseases including the hellofuginone or a pharmaceutically acceptable salt thereof as essential ingredients that may be included in the food composition of the present invention, and various kinds of foods such as conventional foods.
  • Herbal extracts, food supplements or natural carbohydrates and the like may be included as additional ingredients.
  • food supplement additives may be further added, and food supplement additives include food supplement additives conventional in the art, such as flavoring agents, flavoring agents, coloring agents, fillers, stabilizers, and the like. .
  • natural carbohydrates examples include monosaccharides such as glucose, fructose, and the like; Disaccharides such as maltose, sucrose and the like; And conventional sugars such as polysaccharides such as dextrin, cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol.
  • natural flavoring agents tauumatin, stevia extract (e.g., rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used. .
  • the food composition of the present invention includes various nutrients, vitamins, minerals (electrolytes), flavors such as synthetic flavors and natural flavors, coloring and neutralizing agents (such as cheese, chocolate), pectic acid and salts thereof, alginic acid and Salts, organic acids, protective colloid thickeners, pH regulators, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated beverages, and the like.
  • Others may contain pulp for the production of natural fruit juices and fruit juice drinks and vegetable drinks. These components can be used independently or in combination.
  • composition for the treatment or prevention of bone diseases comprising Hellofuginone according to the present invention as an active ingredient has the effect of inhibiting osteoclast differentiation by reducing the expression of Th17 cells and increasing the expression of Treg cells, and by osteoclasts Since the bone absorption is also effectively suppressed, it may be usefully used for the treatment or prevention of bone diseases.
  • Figures 1a to 1d shows the arthritis index (Fig. 1a), arthritis staining (Fig. 1b), inflammatory cytokine staining in the joint (Fig. 1c) after administering Hellofuginone to the arthritis animal model, each animal in serum It is analyzed the effect of arthritis treatment through the amount of IgG, IgG1, IgG2a (Fig. 1D).
  • Figures 2a to 2c shows the Treg and Th17 cell expression (Fig. 2a), pSTAT3, pSTAT5 expression (Fig. 2b), splenocytes or lymph nodes of each group after the administration of Hellofuginone to the arthritis animal model IL-17, Foxp3 expression (Fig. 2c) was observed in the cells.
  • FIG. 3A to 3D show the differentiation of Th17 cells (FIG. 3A) in T cells treated with hellofuginone, IL-17, CCR6, SOCS3, Foxp3 expression (FIG. 3B), pERK expression (FIG. 3C), in Th17 cells, In the dendritic cells, we observed the amount of IL-17 production of T cells through increased IDO and HF-mediated IDO expression in dendritic cells (FIG. 4D).
  • FIG. 4A to 4C show that after administering Hellofuginone to an arthritis animal model, TRAP staining in the joint (FIG. 4A), differentiated bone marrow cells into osteoclasts, and TRAP staining (FIG. 4B), differentiation of FIG. 4B In osteoclasts, mRNA expression of osteoclast differentiation-related factors was observed (FIG. 4C).
  • FIG. 5a to 5d shows that Hellofuginone TRAP expression during osteoclast differentiation (FIG. 5a), osteoporosis degree of osteoclasts (Fig. 5b), c-Fos, JunB, Jdp2 expression in osteoclasts (Fig. 5c), cells The effect on the cycle and on the expression of ccdn1 was observed (FIG. 5D).
  • FIG. 6a to 6d shows that Hellofuginone induces Th17 and Treg differentiation in human T cell differentiation (FIG. 6A), TRAP expression in human osteoclast differentiation (FIG. 6B), and NFATc1, CTR and cathepsin in cells of FIG. 6B.
  • Figure 7 shows the expression of SOX6 and Rcan3, factors involved in osteoblast differentiation and development, in groups treated with and without hellofuginone (500 ⁇ g / kg) after immunization with type II collagen in DBA / 1J mice. The results are analyzed by immunohistochemical staining.
  • the clinical value of arthritis was observed by observing the mouse (hellofuginone-injected arthritis mouse) produced in Example ⁇ 1-1>. score) was measured.
  • a control group a group treated with a solution of DMSO diluted in saline was used.
  • the clinical values were evaluated by using a clinical scoring system that visually monitors the progression of arthritis disease every day by visually examining arthritis lesions of the mouse and swelling and redness of the foot or tail region.
  • the arthritis level decreased in a concentration-dependent manner in the experimental group treated with hellofuginone.
  • the experimental group treated with 500 ⁇ g / kg of hellofuginone was confirmed that no arthritis lesions at all with the naked eye.
  • the degree of joint destruction is sacrificed by sacrificing the mouse (hellofuginone-injected arthritis mouse) produced in Example ⁇ 1-1>. Analysis was performed by staining.
  • a group treated with a solution of DMSO diluted in saline was used as a control group.
  • Immunohistochemical staining was performed by the following procedure. After collecting the joints of the mouse group used in the above, it was fixed in 10% neutral buffered formalin, demineralized bone with EDTA, embedded in paraffin, and then articular tissue was attached to the slide by making 7 ⁇ m thick sections. After passing through the deparaffinization process using xylene before the basic staining, ethanol was hydrated from high to low concentrations. Hematoxylin / eosin staining was performed, and Safranin O and Toluidine blue methods were used to detect proteoglycans in cartilage. Immunohistochemical staining was performed on mouse joints and analyzed by light microscopy.
  • the inflammation level and the degree of cartilage damage were quantified based on the tissue staining results.
  • inflammatory levels were quantified by H & E staining and cartilage damage by safranin O and toluidine blue staining.
  • the quantification criteria are as follows.
  • mice Four weeks after the injection of hellofuginone into arthritic mice, the serum of the mice was collected, and mouse anti-CII specific IgG, IgG1, and IgG2a concentrations were measured by ELISA (Bethyl Lab Co., Montgomery, TX).
  • ELISA Bethyl Lab Co., Montgomery, TX
  • a control group a group treated with a solution of DMSO diluted in saline was used.
  • Anti-CII specific IgG, IgG1 or IgG2a antibody measurement method is as follows. CII was diluted in 0.05 M sodium carbonate coating buffer (pH 9.6) at a concentration of 4 ⁇ g / ml and applied to a 96 well microtiter plate, and then left at 4 ° C. for 18 hours. After removing the applied solution, 200 ⁇ l of TBS (pH 8.0) containing 1% bovine serum albumin (BSA: Amre-sco, solon, Ohio) was added and reacted at room temperature for 1 hour.
  • TBS pH 8.0
  • BSA bovine serum albumin
  • Samples were diluted 1: 1,000 for anti CII specific IgG, IgG1 or IgG2a determinations, using a diluting solution containing 1% BAS, 0.05% Tween 20 (Amreco), TBS (pH 8.0). Next, 50 ⁇ l of the diluted serum sample was added to each well, and reacted at room temperature for 1 hour. After the reaction, the cells were washed with TBS solution (pH 8.0) containing 0.05% Tween 20 (Amresco) five times, and then diluted with detection antibody / HRP conjugate (anti-mouse IgG HRP) at 1: 75,000. The reaction was carried out for 1 hour at room temperature.
  • the cells were washed with IgG washing buffer five times, and then colored by TMB + H 2 O 2 system (KPL, Gaithersbufg, MD), and the reaction was stopped by adding 1N H 2 SO 4 in the same amount. This was read by absorbance at 450nm using an ELISA reader, and the results of antibody measurements were expressed as absorbance itself.
  • the first antibodies were FITC-labeled anti-Foxp3 Ab, PElabeled anti-IL-17 Ab APC-labeled anti-CD4 Ab, Allophycocyanin-labeled anti-CD25 Ab (Biolegend), biotinylated anti-CD4 Ab (BD Biosciences, San Jose, CA) was diluted 1: 100 in PBS (pH 7.5) and reacted overnight at 4 ° C. After washing with PBS the next day, streptavidin cy-3 was reacted at room temperature for 2 hours. Stained tissues were analyzed by confocal microscopy (LSM 510 Meta.
  • pSTAT3, pSTAT5 was also measured by confocal microscopy after immunostaining in the same manner as above, in this case, PE-conjugated anti-phospho-Stat3 (Y705 and S727; 1:50), Alexa Fluor 488-conjugated anti- phospho-Stat5 (Y694; 1: 100) (all from BD Biosciences) antibody was used.
  • RNA expression of IL-17 and Foxp3 genes was extracted by extracting RNA from spleen cells and draining lymph nodes with Trizol reagent in the animal model. It was confirmed.
  • Real-time PCR was performed using the LightCycler 2.0 System Instrument, and the reaction compound for this was 1 ⁇ l of each cDNA, 10 ⁇ l of premix Ex Taq, an enzyme for start, and 20 ⁇ l of final volume with distilled water. Made with.
  • the reaction conditions were first reacted at 95 ° C. for 10 minutes, followed by 10 times of deformation reaction at 95 ° C., binding reaction at 60 ° C. for 5 seconds, and extension reaction at 50 ° C. for 10 seconds.
  • Cycle threshold (Ct) values were analyzed to express beta-actin mRNA levels and relative quantitative quantities.
  • the primer used at this time is as follows.
  • TRAP of osteoclast marker enzyme with leukocyte acid phosphase kit (387-A, Sigma, St. Louis, MO, USA) according to the manufacturer's method Staining was performed. Cells with five or more nuclei among TRAP positive cells (red color) were considered as osteoclasts.
  • the present inventors isolated the bone marrow cells from the joints of the arthritis animal model and incubated for 7 days under stimulation with M-CSF and RANKL, according to the manufacturer's method leukocyte acid phosphase Kit (387-A, Sigma, St. Louis, MO , USA).
  • Example ⁇ 1-8> changed in the same manner as in Example ⁇ 1-6>.
  • the primer used at this time is as follows.
  • the test animals were male DBA-1 mice aged 6-7 weeks.
  • the differentiation of osteoclasts in bone marrow cells was observed in a monoculture system.
  • RBCs of the isolated cells were lysed, diluted in 10% Minimum ⁇ -MEM in 24 well plates, and inoculated at 2 ⁇ 10 5 cells / well. Incubated for 12 hours.
  • M-CSF macrophage-colony stimulating factor
  • 10ng / ml M-CSF and 50ng / ml receptor activator of NF- ⁇ B ligand (RANKL).
  • hellofuginone was treated and incubated for 2 days. After 2 days the medium was changed and retreated in the same way and incubated for 2 days.
  • Spleen cells were obtained from the mouse, ie, the spleen extracted from the mouse was chopped splenic tissue using a glass slide and then removed red blood cells in the spleen with erythrocyte hemolysis solution, followed by PBS buffer solution. Splenocytes were obtained by addition and washing by centrifugation. Then, a single cell 1 ⁇ 10 6 isolated from the spleen was dispensed in a 24-well plate coated with anti-CD3 antibody at 1 ⁇ g / ml and stimulated with Th17 cells.
  • treatment of hellofuginone under differentiation conditions of Th17 cells resulted in inhibition of Th17 cells and increase of Treg cells.
  • treatment of hellofuginone under Th1 differentiation conditions did not affect the production of IL-4 when treatment with hellofuginone under IFN-gamma and Th2 differentiation conditions.
  • Example ⁇ 2-2> The expression of IL-17, CCR6, SOCS3, and Foxp3 in the cells under the conditions of Example ⁇ 2-2> was analyzed by real-time PCR by the method described in Example ⁇ 1-6>.
  • the primer sequence used at this time is as follows.
  • hellofuginone was shown to inhibit the expression of IL-17 and CCR6 and to increase the expression of SOCS and Foxp3.
  • Th17 cells were treated with lysis buffer (20 mM Tris-HCl, pH 7.5), 150 mM NaCl, 1% Triton X-100, 1 mM EDTA, 1 mM EGTA, 1 mM phenylmethylsulfonyl fluoride, 10 mM ⁇ - glycerophosphate, 1 mM NaF, 1 mM Na 3 VO 4 , and 19 Protease Inhibitor Cocktail TM (Roche Molecular Biochemicals, Indianapolis, IN, USA). Equal amounts of protein ( ⁇ 20 ⁇ g) in the lysate were separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and transferred onto nitrocellulose membrane.
  • lysis buffer (20 mM Tris-HCl, pH 7.5), 150 mM NaCl, 1% Triton X-100, 1 mM EDTA, 1 mM EGTA, 1 mM phenylmethylsulfony
  • the blots were then subjected to NFATc1 and phospho-Smad2 / 3 (all from Santa Cruz Biotechnology), Stat3, Stat5, ERK, phospho-Stat3, phospho-stat5 and phospho-ERK (all from Cell Signaling Technology) and ⁇ -actin (Sigma) Probes with antibodies. And it confirmed using ECL (Amersham, DE, USA).
  • the culture supernatant of the cells were collected and the amount of IL-17 was investigated using the sandwich ELISA method.
  • the monoclonal anti-IL-17 was treated with 2 g / ml in a 96-well plate and reacted overnight at 4, after which the non-specific binding was blocked with a blocking solution (1% BSA / PBST). Thereafter, IL-17 was serially diluted by 1/2, and used as a standard. The cell culture supernatant was added and reacted at room temperature for 2 hours. Thereafter, the biotinylated anti-IL-17 was reacted at room temperature for 2 hours and washed four times.
  • ExtraAvidin-Alkaline Phosphatase conjugate was diluted and added and reacted at room temperature for 2 hours. Thereafter, PNPP / DEA solution was added, followed by color development, and absorbance at 405 nm was measured.
  • the T cells co-cultured with the dendritic cells stimulated with hellofuginone reduced IL-17 production, but the dendritic cells stimulated with IDO inhibitor 1-MT and hellofuginone together.
  • IDO inhibitor 1-MT and hellofuginone together.
  • Mouse bone marrow cells were stimulated with M-CSF, RANKL and hellofuginone to differentiate for 5 days, followed by TRAP staining in the manner described in Example ⁇ 1-8> to confirm the number of TRAP positive cells. And, the expression of c-Fos, JunB, Jpd2 in the cells was confirmed by real-time PCR in the manner described in Example ⁇ 1-6>.
  • mice bone marrow cells were cultured on dentine slices, stimulated with M-CSF, RANKL and hellofuginone, and further cultured for 21 days. After removal using 5% sodium hypochlorite solution, staining with hematoxylin (Hematoxylin) was taken to photograph the bone absorption site (lacunae) generated by the bone resorption action of osteoclasts.
  • Hematoxylin hematoxylin
  • CD4 T cells isolated from human peripheral blood were treated with Th17 differentiation conditions (0.5 ⁇ g / ml anti-CD3, 0.5 ⁇ g / ml anti-CD28, 10 ⁇ g / ml anti-IFN- ⁇ , 10 ⁇ g / ml anti-IL-4, And incubated with hellofuginone under IL-6 20 ng / ml, IL-1 ⁇ 10 ng / ml). After that, cells were collected and washed with FACs buffer for flow cytometry. After blocking the reaction at 4 ° C for 15 minutes to inhibit nonspecific binding, cell surface markers CD4 and CD25 were treated with anti-CD4-PerCP and anti- CD25-APC was added and reacted at 4 ° C.
  • Th17 differentiation conditions 0.5 ⁇ g / ml anti-CD3, 0.5 ⁇ g / ml anti-CD28, 10 ⁇ g / ml anti-IFN- ⁇ , 10 ⁇ g / ml anti-IL-4, And in
  • TRAP Human peripheral blood mononuclear cells were stimulated with M-CSF, RANKL and hellofuginone and incubated for 9 days. Thereafter, these cells were TRAP stained according to the manufacturer's method, and mRNA levels of TRAP, NFATc1, calcitonin receptor (CTR), cathepsin K, MMP9, and RANK were confirmed by real-time PCR.
  • CTR calcitonin receptor
  • Example ⁇ 2-7> using human peripheral blood mononuclear cells, the effect of hellofuginone on the bone resorption capacity of osteoclasts was observed.
  • the present inventors confirmed whether the hellofuginone compound of the present invention may influence the expression and activity of Rcan3 and Sox6, which are related factors for osteoblast differentiation, to confirm whether the hellofuginone compound may promote osteoblast differentiation and activity.
  • the following experiment was performed. Specifically, 100 ⁇ l of bovine type II collagen (hereinafter referred to as “CII”) was first immunized with intradermal injection in DBA / 1J mice for 1 week. Hellofuginone was then injected intraperitoneally at 500 ⁇ g / kg. After 50 days after the mouse was killed, the expression level of Rcan3 and Sox6 in the joint tissue of the mouse was confirmed by immunohistochemistry. As a control, a group of mice not treated with hellofuginone was used.
  • CII bovine type II collagen
  • Immunohistochemical staining was performed by the following procedure. After collecting the joints of the mouse group used in the above, fixed in 10% neutral buffered formalin, demineralized bone with a Calci-Clear Rapid bone decalcifier, embedded in paraffin and attached to the slide by making 7 ⁇ m thick sections of the joint tissue. It was. After passing through the deparaffinization process using xylene before the basic staining, ethanol was hydrated from high to low concentrations. In this case, immunostaining was performed using antibodies against Sox-6 (Santa Cruz Biotechnology, sc-20092) and Calcipressin 3 (abcam, ab38312) to detect the expression levels of Rcan3 and Sox6, and then analyzed by light microscopy. The degree of expression of these proteins was observed through.
  • the present inventors were able to confirm that hellofuginone is active to inhibit osteoclast differentiation and at the same time to promote osteoblast differentiation and development. It can be seen that it can be used as a therapeutic agent.
  • the present invention was carried out with the support of the following national R & D program.
  • composition for the treatment or prevention of bone diseases comprising Hellofuginone according to the present invention as an active ingredient has the effect of inhibiting osteoclast differentiation by reducing the expression of Th17 cells and increasing the expression of Treg cells, and by osteoclasts Since the bone absorption is also effectively suppressed, the composition containing hellofuginone as an active ingredient can be usefully used for the treatment or prevention of bone diseases.

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Abstract

La présente invention concerne une composition pour le traitement ou la prévention de maladies osseuses, comprenant de l'halofuginone comme principe actif et, plus spécifiquement, une composition pour le traitement ou la prévention de maladies osseuses comprenant, comme principe actif, de l'halofuginone ayant un effet inhibiteur sur la différentiation des ostéoclastes et une activité stimulatrice sur la différenciation des ostéoblastes. La composition pour le traitement ou la prévention de maladies osseuses, comprenant l'halofuginone comme principe actif, de la présente invention, réduit l'expression des cellules Th17 et augmente l'expression des cellules Treg, ce qui donne un effet inhibiteur de la différenciation des ostéoclastes et permet également une inhibition efficace de la résorption osseuse par les ostéoclastes. En outre, la composition de la présente invention pourra être utilisée de façon utile comme traitement ou prophylaxie de maladies osseuses par sa capacité à favoriser la différentiation et l'activité des ostéoblastes.
PCT/KR2014/008426 2013-09-09 2014-09-05 Composition pour le traitement ou la prévention de maladies osseuses, comprenant de l'halofuginone comme principe actif WO2015034330A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6028075A (en) * 1997-02-11 2000-02-22 Pines; Mark Quinazolinone containing pharmaceutical compositions for prevention of neovascularization and for treating malignancies
US20070010538A1 (en) * 1998-08-13 2007-01-11 Mark Pines Inhibition of pathogenic processes related to tissue trauma
WO2010019210A2 (fr) * 2008-08-11 2010-02-18 President And Fellows Of Harvard College Analogues d'halofuginone pour l'inhibition d'arnt synthétases et leurs utilisations
US20110311519A1 (en) * 2010-06-20 2011-12-22 Washington University Methods of treatment of bone degenerative diseases
US20130164284A1 (en) * 2007-02-02 2013-06-27 Novartis Ag Compositions and methods to treat bone related disorders

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6028075A (en) * 1997-02-11 2000-02-22 Pines; Mark Quinazolinone containing pharmaceutical compositions for prevention of neovascularization and for treating malignancies
US20070010538A1 (en) * 1998-08-13 2007-01-11 Mark Pines Inhibition of pathogenic processes related to tissue trauma
US20130164284A1 (en) * 2007-02-02 2013-06-27 Novartis Ag Compositions and methods to treat bone related disorders
WO2010019210A2 (fr) * 2008-08-11 2010-02-18 President And Fellows Of Harvard College Analogues d'halofuginone pour l'inhibition d'arnt synthétases et leurs utilisations
US20110311519A1 (en) * 2010-06-20 2011-12-22 Washington University Methods of treatment of bone degenerative diseases

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