JP5071759B2 - Fibroblast growth factor agonist - Google Patents

Description

  The present invention relates to a fibroblast growth factor (FGF) agonist, and a pharmaceutical composition, quasi-drug composition, and cosmetic composition containing the same as an active ingredient and useful as a hair growth or skin external preparation. .

  Fibroblast growth factor (FGF) consists of 22 members in human and mouse, and these are FGF receptors (FGFR) consisting of 7 subclasses, namely FGFR1c, FGFR1b, FGFR2c, FGFR2b, FGFR3c, FGFR3b, FGFR4, It has been known that it has a specific binding specificity with any one or more and exhibits various physiological functions in vivo. On the other hand, substances that suppress the action of these FGFs or act like FGFs are known, and these substances are used in pharmaceuticals, quasi drugs, cosmetics, and the like. For example, FGF5 acts on the hair cycle and contributes to alopecia by promoting the transition of the growing hair follicle to the degenerative phase, and administration of the antagonist suppresses hair loss induced by FGF5. (See Non-Patent Document 1). For this reason, peptides having FGF5 antagonist activity are expected to be used as hair restorers (Non-patent Document 2).

  FGF18 has been reported to control the formation and growth of bone and cartilage (Non-patent Documents 3 and 4). Furthermore, it has been reported that FGF18 promotes hair growth by inducing the growth phase of hair follicles (Non-patent Document 5). The FGF18 protein is synthesized as a 207-amino acid polypeptide in the cytoplasm of the production cell in humans and mice, and when it is secreted outside the cell, the N-terminal signal peptide is cleaved, resulting in a physiological function as a secreted body consisting of 181 amino acids. To demonstrate. FGF18 interacts with at least four of the seven types of FGF receptor subclasses (FGFR1c, FGFR1b, FGFR2c, FGFR2b, FGFR3c, FGFR3b, FGFR4), that is, FGFR1c, FGFR2c, FGFR3c, and FGFR4. It is thought that it is involved in life phenomena such as bone and cartilage formation and growth, and lung formation.

  Thus, FGF18 can be applied to pharmaceuticals and the like as a regulator of hair growth and as a regulator of bone, cartilage formation, growth and repair. However, the cost is very high if it is produced by chemical synthesis or genetic recombination of FGF18. Therefore, if an FGF18 agonist can be obtained from a natural product substance such as a plant, it becomes possible to supply a large amount of a substance that acts like FGF18 at a lower price.

  On the other hand, FGF18 is known to interact with FGFR4 in the FGF receptor subclass, as well as other growth factors of the FGF family such as FGF1, FGF2, FGF4, FGF6, FGF8, and FGF9 (non-patented). Reference 6). Therefore, the natural product-derived component that activates FGFR4 can be substituted for the physiological function exhibited by these FGF family growth factors. FGF1 and FGF2 are known to be used as skin ulcer treatments, FGF4 and FGF9 are known to have an effect of increasing platelets, and FGF4 is known to have a radiation damage-protecting action, thus activating FGFR4. It is considered that the natural product-derived FGF18 agonist also has these actions.

Hebert, JM., Rosenquist, T., Gotz, J. and Martin, GR., 1994.FGF-5 as a regulator of the hair growth cycle: Evidencefrom targeted and spontaneous mutations.Cell 78: 1017-1025. Ito, C., Saitoh, Y., Fujita, Y., Yamazaki, Y., Imamura, T., Oka, S. and Suzuki, S. 2003. Decapeptide withfibroblast growth factor (FGF) -5 partial sequence inhibits hair growthsuppressing activity of FGF-5. J. Cell. Physiol. 197: 272-283. Ohbayashi N, Shibayama M, Kurotaki Y, Imanishi M, Fujimori T, ItohN, Takada S. FGF18 is required for normal cell proliferation and differentiation during osteogenesis and chondrogenesis. Genes Dev. 2002, 16 (7): 870-9 Moore EE, Bendele AM, Thompson DL, Littau A, Waggie KS, Reardon B, Ellsworth JL.Fibroblast growth factor-18 stimulates chondrogenesis andcartilage repair in a rat model of injury-induced osteoarthritis.Osteoarthritis Cartilage. 2005, 13 (7): 623-31 Kawano M, Komi-Kuramochi A, Asada M, Suzuki M, Oki J, Jiang J, Imamura T. Comprehensive analysis of FGF and FGFR expression in skin: FGF18 ishighly expressed in hair follicles and capable of inducing anagen from telogenstage hair follicles. Invest Dermatol. 2005, 124 (5): 877-885 Ornitz D.M, Xu J, Colvin J.S, McEwen D.G, MacArthur C.A, Coulier F, Gao G, Goldfarb M, Receptor specificity of the fibroblast growth factor family.J. Biol. Chem. 1996, 271: 15292-15297 MaruyamaS, Mitachi H, Awaya J, Kurono M, Tomizuka N. Angiotensin I-converting enzymeinhibitory activity of the C-terminal hezapeptide of αS1-casein. Agric. Biol. Chem. 1987, 51 (9): 2557-2561 MaruyamaS, Miyoshi S, Kaneko T, Tanaka H. Angiotensin I-converting enzyme inhibitoryactivities of synthetic peptide related to the tandem repeated sequence of amaize endosperm protein. Agric. Biol. Chem. 1989, 53 (4): 1077-1081

  An object of the present invention is to provide a natural product-derived substance such as a plant component having FGF18-like activity from the natural world. The second problem of the present invention is that it has growth factor-like activity of the FGF family such as FGF1, FGF2, FGF4, FGF6, FGF8, and FGF9, which are known to exert their physiological functions by activating FGFR4. It is intended to provide a natural product-derived substance.

  As a result of developing a screening system for FGF18 agonists and extensively searching for substances derived from plants and other natural products that exist in nature, the present inventors have found that some natural products that activate the FGF4 receptor among the FGF receptor subclasses. The origin material was found and the present invention was completed.

  The present invention relates to an extract of willow balsilla or blue-crowned shiba, protein hydrolyzate, yeast extract, peptide FFVAP (phenylalanylphenylalanylvalylalanylproline), peptide TTMPLW (threonylthreonylmethionylprolylleucyl) There is provided a fibroblast growth factor agonist selected from the group consisting of tryptophan) and peptide LPP (leucylprolyl proline). Preferably, the fibroblast growth factor agonist is a fibroblast growth factor 18 agonist.

  In another aspect, the present invention relates to a substance selected from the group consisting of an extract of willow balsam or blue-crowned shiba, a protein hydrolyzate, a yeast extract, a peptide FFVAP, a peptide TTMPLW, and a peptide LPP. The composition for hair growth or hair growth regulation characterized by containing as follows. The present invention also contains, as an active ingredient, a substance selected from the group consisting of an extract of willow balsam or blue-crowned shiba, protein hydrolyzate, yeast extract, peptide FFVAP, peptide TTMPLW, and peptide LPP. A composition for regulating osteogenesis or chondrogenesis is provided.

  In yet another aspect, the present invention effectively uses a substance selected from the group consisting of an extract of willow balilla or simula, a protein hydrolyzate, a yeast extract, a peptide FFVAP, a peptide TTMPLW, and a peptide LPP. Provided is a pharmaceutical composition for preventing or treating a disease caused by FGF, characterized by containing it as a component. Preferably, the disease caused by FGF is a disease caused by FGF18.

  In another aspect, the present invention is effective for a substance selected from the group consisting of an extract of willow balilla or Shichikarashiba, a protein hydrolyzate, a yeast extract, a peptide FFVAP, a peptide TTMPLW, and a peptide LPP. Provided is a composition for regulating cell function by interacting with a fibroblast growth factor receptor fourth gene product, characterized in that it is contained as a component.

  Substances derived from natural products found in the present invention include FGF18 and other FGFs such as FGF1, FGF2, FGF4, FGF6, FGF8, FGF9, etc., which are known to activate FGF4 receptors and exert their physiological functions. Since it exhibits a family growth factor-like activity, it can replace physiological functions elicited by these FGFs. Therefore, it can be used as a pharmaceutical, a quasi-drug, or a cosmetic having an action such as hair growth or hair growth regulation, bone formation regulation or chondrogenesis regulation.

Hereinafter, the present invention will be described in detail.
The first aspect of the present invention is an FGF agonist comprising an extract of willow balsam. In this embodiment, the willow balsam used as a raw material for obtaining the extract is a plant belonging to the genus Ruirassau (Ruelllia brittoniana Leonard). A 2nd aspect is an FGF agonist which consists of an extract of Shichikarashiba, and Shishimakara Shiba which becomes a raw material for obtaining an extract is a plant of the genus Chinasashiba (scientific name Pennisetum sordidum).

  In obtaining the extract from willow balsam or Shichikarashiba, all parts of the plant can be used, and each part can be used alone or as an appropriate raw material after mixing. Moreover, the thing of the dry state and the non-dry state can be used for the property of the plant body used as a raw material.

  In order to obtain the extract used in the present invention from willow balsam or Shichikarashiba, these raw materials may be chopped or pulverized if necessary and extracted by a commonly used extraction method using an appropriate solvent. . Although the solvent used for extraction is not specifically limited, For example, water, anhydrous, or a water-containing organic solvent can be illustrated. The anhydrous or hydrous organic solvent may be one or more selected from monohydric alcohols, polyhydric alcohols or derivatives thereof, ketones, esters, ethers, petroleum ethers, aliphatic hydrocarbons, halogen compounds, and aromatic hydrocarbons. Can be illustrated. Specific examples of the solvent include water, methanol, ethanol, butanol, acetone, and ethyl acetate. These can be used alone or in combination of two or more. Among these, it is particularly preferable to use water or a monohydric alcohol such as methanol or ethanol. In the extraction, the amount of the solvent is not particularly limited, but is 0.1 to 1000 times by weight, preferably 1 to 100 times by weight, more preferably 2 to 50 times with respect to the raw material of willow balsilla or shichikarashiba. Weight times.

  The extraction method using the solvent can be performed according to a conventional method. For example, with respect to the extraction temperature, extraction may be performed at a temperature of about room temperature, or may be performed at a temperature near the boiling point of the solvent used. Moreover, also about extraction operation, it extracts by refluxing at the temperature about the boiling point of an extraction solvent, and the method of extracting by immersing the dry pulverized material or crushed material of willow balsilla or Shichikarashiba at room temperature for 1-30 days A method or the like can be used.

  The third aspect of the present invention is an FGF agonist comprising a protein hydrolyzate or a yeast extract. Examples of the protein hydrolyzate include degradation products obtained by treating proteins such as casein, soybean protein, and corn seed protein with protein hydrolyzing enzymes such as pepsin, trypsin, chymotrypsin, thermolysin, papain, and akkari protease. Foods containing a large amount of these protein hydrolases and natural products such as plants may be used. In addition, protein hydrolysates that are commercially available for use in culture media, such as Bactotrypton (Becton Dickinson and Company), Bacto Yeast Extract (Becton Dickinson and Company), Bacto Peptone (DIFCO), Bacto Tripton (DIFCO), Use polypeptone (Nippon Pharmaceutical Co., Ltd.), Proteau Spepton Daigo (Daigo Nutrition Chemical Co., Ltd.), Bactocasiton (DIFCO), Soybean Peptone (DIFCO), Phyton Peptone (BBL), Trypton Peptone (DIFCO), etc. Can do. A commercially available yeast extract (DIFCO) can be used as the yeast extract.

  The fourth aspect of the present invention is a peptide selected from the group consisting of FFVAP, TTMPLW and LPP. These peptides are known to inhibit angiotensin converting enzyme and are effective in preventing and treating hypertension (Non-patent Documents 7 and 8). However, there is no report suggesting whether these peptides have FGF-like activity, whether they have hair growth or hair growth regulating action, or whether they have bone formation regulation or chondrogenesis regulation. The peptide according to the present invention can be produced by chemical synthesis using peptide synthesis techniques well known in the art.

  As shown in the examples below, a substance selected from the group consisting of an extract of willow balsam or lycaensis, protein hydrolyzate, yeast extract, peptide FFVAP, peptide TTMPLW, and peptide LPP of the present invention Has cell growth promoting activity similar to FGF18. In the examples, when a cell in which FGFR4, which is one of the FGF receptors, is forcibly expressed on the cell surface by gene expression manipulation is used, the above-mentioned substance found in the present invention promotes cell growth similar to FGF18. It was shown that there was no cell growth promoting activity against the parental strain that showed activity and none of which expressed FGFR4.

  That is, the substance selected from the group consisting of the extract of the willow balsilla or blue-crowned beetle, protein hydrolyzate, yeast extract, peptide FFVAP, peptide TTMPLW, and peptide LPP of the present invention is FGFR4 as in FGF18. It is an FGF agonist having an activating effect.

  FGF18 has physiological functions such as an action of regulating hair production mechanisms, specifically, an action of promoting or suppressing hair growth such as hair, and an action of promoting or suppressing hair growth. FGF18 also has physiological functions such as an action of regulating the formation and growth mechanism of bone and cartilage, specifically, an action of promoting or suppressing the formation of bone and cartilage.

  Therefore, using the FGF agonist of the present invention, a drug having the same activity or specificity as the hair growth or hair growth regulating activity of FGF18, which is a part of the hair production mechanism, and effective in regulating hair growth or hair growth Compositions, quasi-drug compositions, and cosmetic compositions can be provided. Furthermore, it is possible to provide a pharmaceutical composition having an activity similar to or specific to the osteogenesis promoting or chondrogenesis inhibiting activity of FGF18 and effective in regulating osteogenesis or chondrogenesis.

  In addition, the FGF agonist of the present invention can have an effect of regulating other physiological functions of FGF18. Other physiological functions of FGF18 include regulating lung formation, promoting or suppressing the proliferation and differentiation of fibroblasts, vascular endothelial cells, myoblasts, neurons, and glial cells, and Examples include regulating cell function and inhibiting cell death.

  Furthermore, the FGF agonist of the present invention includes at least one of the FGF family growth factor-like physiological functions such as FGF18, FGF1, FGF2, FGF4, FGF6, FGF8, and FGF9 that exert their effects through the activation of the FGFR4 receptor. Has the effect of exerting or adjusting the part. The physiological functions of FGF1, FGF2, FGF4, FGF6, FGF8, and FGF9 are: FGF1 and FGF2 have angiogenesis and skin ulcer treatment effects, FGF4 and FGF9 have platelet-increasing effects, and FGF4 has radiation damage protection effects. It is mentioned to have. Therefore, by using the FGF agonist of the present invention, it is possible to provide a pharmaceutical composition effective for suppressing neuronal cell death, controlling the expression of other FGF factor groups, and the like, and a pharmaceutical composition effective for various regenerative medicine. Further, according to the present invention, a pharmaceutical composition effective as a skin ulcer treatment agent as shown by FGF1 or FGF2, a pharmaceutical composition effective as a platelet increasing action as shown by FGF4 and FGF9, and a radiation disorder as shown by FGF4 A pharmaceutical composition effective as a protective agent can be provided.

  The substance selected from the group consisting of the extract of the willow balsam or blue-crowned beetle, protein hydrolyzate, yeast extract, peptide FFVAP, peptide TTMPLW, and peptide LPP of the present invention is a hair restorer, for example, promoting hair growth, It is envisaged to be used as an active ingredient in pharmaceutical compositions, quasi-drug compositions, and cosmetic compositions used for hair promotion and hair loss prevention. In that case, one or more extracts containing the above organisms are used. It is desirable to produce and administer a pharmaceutical composition containing one or more of the above-mentioned extracts as an active ingredient using one or more kinds of pharmaceutical additives that are used as they are or are pharmaceutically acceptable. The FGF agonist of the present invention uses pharmaceutically acceptable solvents, excipients, carriers, adjuvants, etc., and is in accordance with conventional methods for production of preparations, liquids, lotions, aerosols, injections, powders, granules, tablets Or a suppository, an intestinal solvent, a capsule, or the like, or a quasi-drug composition or a cosmetic composition. For example, it can be used as an external preparation such as a cream, a spray, a coating, or a patch. Furthermore, you may mix | blend said extract with a shampoo or rinse.

  The pharmaceutical composition, quasi-drug composition, and cosmetic composition according to the present invention are a hair growth agent, a hair-restoring agent, an osteogenesis promoter, a cartilage formation inhibitor, a cranial nervous system nutrient / function control agent, and a learning effect regulator. For example, it can be safely administered parenterally or orally to mammals such as humans, mice, rats, rabbits, dogs and cats.

  FGF18 agonists provide drugs that are particularly useful as hair restorers. The dosage of the pharmaceutical composition, quasi-drug composition, and cosmetic composition can be appropriately changed according to the dosage form, administration route, symptoms, etc., but when administered to mammals including humans, for example, 0.0001 to 1000 mg Illustrated is application to the affected area several times a day.

  Hereinafter, examples will be shown to describe the present invention in more detail, but the present invention is not limited to these examples.

[Example 1]
Screening for FGF18 agonists using FGFR4-expressing cells According to the teaching in the literature, the Ba / F3 cell line (obtained from RIKEN BRC), a mouse IL-3-dependent proB cell, is one of the FGF receptors by gene expression manipulation. R4 / BaF3 cells in which FGFR4 is forcibly expressed on the cell surface were prepared by introducing FGFR4 (Ornitz, DM., Xu, J., Colvin, JS., McEwen, DG., MacArthur, CA., Coulier , F., Gao, G. and Goldfarb, M., 1996. Receptor specificity of the fibroblast growth factor family. J. Biol. Chem. 271 (25): 15292-15297; Yoneda, A., Asada, M., Oda, Y., Suzuki, M. and Imamura, T., 2000. Engineering of an FGF-proteoglycan fusion protein with heparin-independent, mitogenic activity. Nat. Biotec. 18 (6): 641-644).

  Next, the prepared R4 / Ba / F3 cells were cultured with various plant extracts, protein hydrolysates, peptides and the like as test solutions. A commercially available FGF18 protein was used as a positive control. The number of cells after culturing for a certain period of time was determined by measuring the color development at 450 nm associated with the production amount of WST-8 formazan using WST-8.

  As a result, an extract of willow balsam or striped shiba, protein hydrolyzate, yeast extract, peptide FFVAP, peptide TTMPLW, and peptide LPP can act as FGF18 agonists and promote the growth of R4 / BaF3 cells. I found something.

[Example 2]
Cell Growth Promotion Activity of FGF18 Agonist of the Present Invention 40 ml of 70% ethanol aqueous solution was added to 1.6 g of a dried plant body of Willow balilla soup and extracted by immersion for 7 days at room temperature. 40 ml of distilled water was added to 1.7 g of dried plant of Willow Barra, and boiled for 20 minutes. 40 ml of a 70% aqueous ethanol solution was added to 2.3 g of dried Shichikarashiba plants, and immersed and extracted at room temperature for 7 days. 40 ml of distilled water was added to 2.4 g of dried Shichikarashiba plants and boiled for 20 minutes. The extract obtained as described above was filtered to obtain a filtrate.

  Peptide FFVAP, peptide TTMPLW, and peptide LPP are all produced by chemical synthesis, dissolved in distilled water to a final concentration of 1 mM, and further diluted with distilled water to 0.1 mM and 0.01 mM. A test solution was used.

The protein hydrolyzate was prepared as follows. 500mg soy protein (Sigma, S-9633
) Was dissolved in 50 ml of 0.05 mM Tris · HCl and 20 mM CaCl 2 buffer (pH 7.4), and insoluble protein was removed by centrifugation at 11,000 rpm for 15 minutes to prepare a protein solution. Trypsin (Sigma, T-4799) 10 mg was dissolved in 0.05 mM Tris · HCl, 20 mM CaCl 2 buffer (pH 7.4) to prepare a trypsin solution. 300 μl of a trypsin solution was added to 3 ml of the soy protein solution thus prepared, and the mixture was reacted at 37 ° C. for 24 hours. After completion of the reaction, the mixture was heated in a boiling water bath for 5 minutes, and then insoluble protein was removed by centrifugation at 4 ° C., 11,000 rpm for 15 minutes to prepare a soybean protein hydrolyzate. In addition, the following samples were prepared as commercially available protein degradation products. Bacton trypton (Becton Dickinson and Company), Bact yeast extract (Becton Dickinson and Company), Bacto peptone (DIFCO), Bacto tripton (DIFCO), Polypeptone (Nippon Pharmaceutical Co., Ltd.), Proteose peptone Daigo (Daigo) Nutrition Chemistry Co., Ltd., Bactocasitone (DIFCO), Soybean Peptone (DIFCO), Phyton Peptone (BBL), Tryptone Peptone (DIFCO), Yeast Extract (DIFCO) powder 1g, 5ml of distilled water was added to make a test solution. .

In the same manner as in Example 1, the cell proliferation activity of the FGF18 agonist of the present invention was measured using R4 / Ba / F3 cells. Specifically, the measurement was performed as follows. RPMI1640 medium containing 50 μl of 10% FBS and 1% Antibiotic G-418 Sulfate (Promega Corporation, V7983) was added to each well of a 96-well cell culture plate. Next, after adding 10 μl of various test solutions prepared by diluting each sample with water, 5 × 10 ⁴ R4 / Ba in RPMI1640 medium containing 10% FBS, 1% Antibiotic G-418 Sulfate 50 μl of the cell suspension in which / F3 cells were suspended was added, and gently agitated. Finally, 10 μl of heparin / 10% FBS / 1% Antibiotic G-418 Sulfate / RPMI1640 medium (final concentration of heparin 5 μg / ml) was added and cultured in a carbon dioxide incubator at 37 ° C. for 72 hours in the presence of 5% CO 2. Proliferation of R4 / Ba / F3 cells was performed by adding 10 μl of WST-8 (Wako Pure Chemical Industries, Ltd.) / PBS solution to each well after 72 hours of culture, and further culturing for 3 hours. The color development at 450 nm with the production amount was measured and determined.

  In the measurement, 10 μl (FGF18 final concentration 3 ng / ml) of FGF18 (Peprotech Inc., 100-28) solution was used as a positive control, and water or ethanol solution ( The final concentration of the ethanol solution was adjusted to 1% or less) and measured using 10 μl. Cell proliferation rate (%) is calculated by adding 100% of the absorbance when adding FGF18 (final concentration 3ng / ml) used as a positive control and adding water or ethanol solution as a negative control to the absorbance obtained when adding the test solution. The absorbance at that time was calculated as 0%.

  FIG. 1 shows the results for the willow balsam and the striped extract. When these extracts were used, the amount of color development increased, and it was confirmed that they had FGF18-like cell growth promoting activity. The decrease in activity at a high concentration is considered to be due to cytotoxicity.

  FIG. 2 shows the results for bactopeptone (B9) and bactotripton (B10), and FIG. 3 shows the results for peptide FFVAP, peptide TTMPLW, and peptide LPP, respectively. As is clear from the figure, these protein hydrolysates and peptides were shown to have FGF18-like cell growth promoting activity in a dose-dependent manner.

Example 3
The prescription and manufacturing method of the hair shampoo using the willow balilla soup or Shimachikarashiba extract which is this invention are shown.

A hair shampoo was produced according to the following formulation and production method.
(Prescription)
Component Weight%
1. Diluent obtained in Example 2 0.1
2. Sodium lauryl ether sulfate ethanol 20
3. Sodium lauryl sulfate 10
4.1,3 Butylene glycol 1
5. Perfume appropriate amount 6. Purified water remaining amount (100 in total)
(Manufacturing method)
The prescription ingredients were heated to 80 ° C., stirred and mixed, and then cooled by stirring to produce the hair shampoo of the present invention.

Example 4
The prescription and manufacturing method of the hair liquid using the willow barralassou or Shimachikarashiba extract which are this invention are shown.

A hair liquid was produced according to the following formulation and production method.
(How to)
Component Weight%
1. Diluent obtained in Example 2 0.1
2. Ethanol 40
3. Glycerin 1
4. Perfume appropriate amount 5. Purified water remaining amount (100 in total)
(Manufacturing method)
After adding the formulation components and dissolving with stirring, purified water was added to produce a hair liquid.

Example 5
Example 5 shows the prescription and manufacturing method of the hair cream which uses the willow balsilla or the striped extract of this invention.
A hair cream was produced according to the following formulation and production method.
(Prescription)
Component Weight%
1. Diluent obtained in Example 2 0.1
2. Liquid paraffin 40
3. Vaseline 1
4. Cetostearyl alcohol 1
5. Methylpolysiloxane 1
6. Methyl paraoxybenzoate 0.2
7. Propylene glycol 5
4. Perfume appropriate amount 5. Purified water remaining amount (100 in total)
(Manufacturing method)
The formulation ingredients were mixed with stirring to produce the hair cream of the present invention.

FIG. 1 shows the cell growth promoting activity of the willow balsam and striped extract against R4 / Ba / F3 cells. FIG. 2 shows the cell growth promoting activity of bactopeptone and bactotryptone against R4 / Ba / F3 cells. FIG. 3 shows the cell growth promoting activity of peptide FFVAP, peptide TTMPLW, and peptide LPP against R4 / Ba / F3 cells.

Claims (4)

Ru or extracts of shea Machikarashiba Rana, FGFR4 receptor ligand-like A agonist agents. A composition for regulating hair growth or hair growth, comprising the FGFR4 receptor ligand-like agonist agent according to claim 1 as an active ingredient. A composition for regulating bone formation or chondrogenesis, comprising the FGFR4 receptor ligand-like agonist agent according to claim 1 as an active ingredient. Fibers fibroblast growth factor receptor 4 gene product interacts regulating cell functions, FGFR4 receptor ligand-like agonistic agent according to claim 1.

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