CN114732911A - Application of Piezo1 agonist Yoda1 in preparation of medicine for treating postmenopausal osteoporosis - Google Patents
Application of Piezo1 agonist Yoda1 in preparation of medicine for treating postmenopausal osteoporosis Download PDFInfo
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- 239000003814 drug Substances 0.000 title claims abstract description 25
- 101150063303 Piezo1 gene Proteins 0.000 title claims abstract description 22
- 239000000556 agonist Substances 0.000 title claims abstract description 22
- 208000001685 postmenopausal osteoporosis Diseases 0.000 title claims abstract description 16
- 238000002360 preparation method Methods 0.000 title claims abstract description 6
- 208000001132 Osteoporosis Diseases 0.000 claims abstract description 24
- 206010030247 Oestrogen deficiency Diseases 0.000 claims abstract description 7
- 230000007774 longterm Effects 0.000 claims abstract description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 208000002679 Alveolar Bone Loss Diseases 0.000 claims description 4
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- 230000002265 prevention Effects 0.000 claims 1
- 229940079593 drug Drugs 0.000 abstract description 9
- 229940122361 Bisphosphonate Drugs 0.000 abstract description 5
- 102000014128 RANK Ligand Human genes 0.000 abstract description 5
- 108010025832 RANK Ligand Proteins 0.000 abstract description 5
- 150000004663 bisphosphonates Chemical class 0.000 abstract description 5
- 238000002474 experimental method Methods 0.000 abstract description 4
- 241001465754 Metazoa Species 0.000 abstract description 3
- 102000019307 Sclerostin Human genes 0.000 abstract description 3
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- 108010081689 Osteopontin Proteins 0.000 description 5
- 102000007591 Tartrate-Resistant Acid Phosphatase Human genes 0.000 description 5
- 108010032050 Tartrate-Resistant Acid Phosphatase Proteins 0.000 description 5
- 239000002285 corn oil Substances 0.000 description 5
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- RGCKGOZRHPZPFP-UHFFFAOYSA-N alizarin Chemical compound C1=CC=C2C(=O)C3=C(O)C(O)=CC=C3C(=O)C2=C1 RGCKGOZRHPZPFP-UHFFFAOYSA-N 0.000 description 4
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- DEGAKNSWVGKMLS-UHFFFAOYSA-N calcein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC(CN(CC(O)=O)CC(O)=O)=C(O)C=C1OC1=C2C=C(CN(CC(O)=O)CC(=O)O)C(O)=C1 DEGAKNSWVGKMLS-UHFFFAOYSA-N 0.000 description 2
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/12—Drugs for genital or sexual disorders; Contraceptives for climacteric disorders
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- 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
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- Pharmacology & Pharmacy (AREA)
- Physical Education & Sports Medicine (AREA)
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- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
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Abstract
The invention discloses application of a Piezo1 agonist Yoda1 in preparation of a medicine for treating postmenopausal osteoporosis, and belongs to the technical field of biological medicines. The invention firstly uses Piezo1 agonist Yoda1 for treating postmenopausal osteoporosis, and animal experiments prove that the Piezo1 agonist Yoda1 can treat disuse osteoporosis caused by stress loss, prevent alveolar osteoporosis caused by occlusal force loss (such as long-term toothless), and simultaneously can be used for treating postmenopausal osteoporosis caused by estrogen deficiency, thereby effectively avoiding the problem of treating osteoporosis by adopting bisphosphonate, monoclonal RANKL antibody and sclerostin antibody in the prior art.
Description
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to application of a Piezo1 agonist Yoda1 in preparation of a medicine for treating postmenopausal osteoporosis.
Background
Osteoporosis (OP), one of the major age-related diseases, is caused by an imbalance between bone formation and bone resorption. The main types of osteoporosis in humans are: postmenopausal osteoporosis (primary osteoporosis type i), disuse osteoporosis (primary osteoporosis type ii/senile with age) and adverse effects of chronic medication on the disease (secondary OP, glucocorticoid-induced osteoporosis). The drugs currently used for osteoporosis are of a wide variety, with the most common therapies being bisphosphonates, monoclonal RANKL antibodies and sclerostin antibodies. However, since the drawbacks of bisphosphonate treatment include side effects such as the occurrence of atypical femoral fractures, hypocalcemia or mandibular necrosis, monoclonal RANKL antibody can also cause jaw necrosis, and thus the intake is time-limited, there are dosing intervals during which the drug must be replaced, i.e. a new approach today is to combine multiple drugs or treatment techniques to reduce side effects, switching from one drug to another when needed.
Piezo1 is a highly expressed mechanical gated cation channel in the skeletal system, and is a key functional site participating in mechanical force sensing and transmission, and domestic and foreign scholars prove that Piezo1 plays an important role in the skeletal system. Yoda1 is a Piezo1 agonist, and previous studies prove that Yoda1 can relieve disuse osteoporosis caused by lack of mechanical stimulation such as weight loss, but the effect on postmenopausal osteoporosis caused by estrogen deficiency is not described.
Disclosure of Invention
Aiming at the problems that bisphosphonates are adopted for treating osteoporosis in the prior art, such as atypical femoral fracture, hypocalcemia or mandibular necrosis, monoclonal RANKL antibody can cause jaw necrosis and other side effects, so that the medicine intake is limited in time, the intermittent period of medication exists and the medicine needs to be replaced, the invention provides the application of a Piezo1 agonist Yoda1 in preparing a medicine for treating postmenopausal osteoporosis, and provides a new available medicine for treating the osteoporosis.
Preferably, the invention also provides application of the Piezo1 agonist Yoda1 in preparing a medicament for treating postmenopausal osteoporosis caused by estrogen deficiency, and provides a novel useful medicament for treating the osteoporosis.
The invention also provides application of the Piezo1 agonist Yoda1 in preparing a medicament for preventing or treating alveolar osteoporosis caused by loss of occlusal force, and provides a novel useful medicament for treating the osteoporosis; preferably, wherein the loss of occlusal force comprises a long-term toothless alveolar bone loss condition.
Preferably, any of the above drugs has the Piezo1 agonist Yoda1 as an active ingredient and is used at a dose of 1-100 ug/kg.
The present invention also provides a pharmaceutical composition for treating postmenopausal osteoporosis, which comprises as an active ingredient the piozo 1 agonist Yoda 1.
Preferably, the dosage form of the pharmaceutical composition is selected from tablets, powders, injections, capsules, suspensions, pastes, gels, coating agents, film agents, sustained-release agents or microspheres.
Compared with the prior art, the invention firstly uses the Piezo1 agonist Yoda1 for treating postmenopausal osteoporosis, and animal experiments prove that the Piezo1 agonist Yoda1 can treat disuse osteoporosis caused by stress loss, prevent alveolar osteoporosis caused by occlusal force loss (such as long-term toothless), and simultaneously can be used for treating postmenopausal osteoporosis caused by estrogen deficiency, thereby effectively avoiding the problems of treating osteoporosis by adopting bisphosphonate, monoclonal RANKL antibody and sclerostin antibody in the prior art.
Drawings
Fig. 1 is the experimental result of the treatment of Yoda1 by gavage after constructing the animal model of the loss of occlusal force in the examples; wherein: (A) after constructing the animal model of the occlusal force loss, performing intragastric lavage and treating for 3 weeks by Yoda 1; (B and C) wild type mice given corn oil (solvent) or Yoda1 were scanned using Micro-CT and reconstructed three-dimensional images showing the sagittal plane perpendicular to occlusal plane (B) and the horizontal plane parallel to occlusal plane (C) for the control group (Ctrl group) and the occlusal force loss group (Unloading group), respectively; (D) quantitative microarchitectural parameters of Micro-CT including the ratio of trabecular bone volume to total volume of selected regions (BV/TV), trabecular bone mean thickness (Tb.Th), boneNumber of trabeculae (tb.n) and average width between the medullary cavities of the trabeculae (tb.sp) and thickness of cortical bone (ct.th); (E) continuously marking the calcein and alizarin by fluorescent dyes to detect the deposition of new bones; (F) bone mineralization rate (MAR) detected by histomorphometric analysis; (G) immunofluorescence analysis of maxillary alveolar bone Osteopontin (OPN), and marking white triangles as OPN + cells; (H) the number of OPN + osteoblasts; (I) the maxillary alveolar bone is stained with tartrate-resistant acid phosphatase (TRAP), and the red triangle marks TRAP + multinucleated osteoclasts; (J) the number of TRAP + multinucleated osteoclasts; (K) ctsk immunofluorescence-TUNEL co-staining is used for detecting osteoclast apoptosis, a white triangle marks Ctsk + multinuclear osteoclasts, and a yellow triangle marks TUNEL + Ctsk + osteoclasts; (L) the number of Ctsk + osteoclasts; (M) the proportion of TUNEL + Ctsk + osteoclasts in Ctsk + osteoclasts; error bars represent mean ± SD, n-6 mice per group,*p<0.05。
fig. 2 is the experimental results of the OVX constructed in the examples, intragastric administration after tooth extraction and Yoda1 treatment, wherein: (A) schematic diagram of OVX construction, gastric lavage and treatment with Yoda1 for 4 weeks after tooth extraction model for female C57BL/6J mice of 6 weeks old; (B and C) Sham group (Sham group), ovariectomy group (OVX group), wild type female mice treated with Yoda1 after ovariectomy were scanned with Micro-CT and reconstructed three-dimensional images showing the sagittal plane perpendicular to occlusal plane (B) and the horizontal plane parallel to occlusal plane (C) for the control group (Ctrl group) and the occlusal force loss group (Unloading group), respectively; (D) quantitative Micro-architecture parameters of Micro-CT, including BV/TV, Tb.Th, Tb.N, Tb.Sp and Ct.Th; error bars represent mean ± SD, n-6 mice per group,*p<0.05。
FIG. 3 shows the results of the experiment with Yoda1 after surgery in the example of construction of ovariectomy animal model; wherein: (A) a Sham group (Sham group), an ovariectomy group (OVX group), and a wild type female mouse treated with Yoda1 after ovariectomy were scanned with Micro-CT and reconstructed to show three-dimensional Micro-CT reconstructed images of the femur, the upper panel showing trabecular bone, the lower panel showing cortical bone, and the 1mm wide trabecular bone near the distal growth plate and the 1mm wide cortical bone portion in the middle of the femur were three-dimensionally reconstructed; (B) quantitative Micro-architectural parameters for Micro-CTNumbers including BV/TV, tb.th, tb.n, tb.sp, and ct.th; (C) quantitative microarchitectural parameters of Micro-CT including cortical bone volume (ct.bmd) and cortical bone thickness (ct.th); (D) a representative load displacement plot for a three-point bending test performed on the mouse femur described above; (E) maximum load of femur measured during three-point bending test; error bars represent mean ± SD, n-6 mice per group,*p<0.05。
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions of the embodiments of the present invention are clearly and completely described below with reference to the drawings of the embodiments of the present invention. It is to be understood that the embodiments described are only a few embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the described embodiments of the invention without any inventive step, are within the scope of protection of the invention.
The Piezo1 agonist Yoda1 used in the following examples was purchased from MCE, 6 week old female C57BL/6J mice from Shanghai Jitsie laboratory animals, Inc., and other reagents and starting materials were commercially available without specific instruction.
Example 1
In this example, an animal model of the loss of occlusal force is constructed and tested, and the details are as follows: the right mandibular molars of 6-week-old female wild-type C57BL/6J mice were all pulled out, and the ipsilateral maxillary alveolar bone was defined as the occlusal force loss (Unloading) group; in contrast, left mandibular molars were retained and ipsilateral maxillary alveolar bone was defined as the control (Ctrl) group.
Yoda1 was administered to the animal model for loss of occlusal force for 3 weeks according to the procedure shown in fig. 1A, and three-dimensional micro-CT reconstructed images showed maxillary alveolar bone three weeks after loss of occlusal force of wild-type mice administered with corn oil (solvent) or Yoda1 (fig. 1B and 1C). The results show that the loss of occlusal force reduces alveolar bone BMD, BV/TV and tb.th in mice treated with corn oil, and that there is no statistical significance between the Unloading and Ctrl groups in mice dosed with Yoda1 (fig. 1D), i.e. administration of Yoda1 can prevent alveolar bone loss due to loss of occlusal force.
In addition, this example also investigated the osteoblast and osteoclast metabolism to reveal the cause of the decreased alveolar bone mass, the double labeling of calcein and alizarin showed a severe decrease in MAR in the unoading group (fig. 1E and 1F), a decrease in OPN-positive osteoblast number in the unoading group detected by immunofluorescence analysis as well (fig. 1G and 1H), TRAP staining (fig. 1I and 1J) and Ctsk immunofluorescence staining (fig. 1K and 1L) showing an increase in osteoclast number in the unoading group in the corn oil-treated mice, indicating overactivity of bone resorption, and no statistical significance between the unoding group and the Ctrl group in the Yoda 1-treated mice described above (fig. 1E-J). Meanwhile, after detecting the apoptosis of osteoclasts in alveolar bone, it was also found that the proportion of TUNEL + Ctsk + osteoclasts in the Unloading group was reduced compared to that in Ctrl group of corn oil-treated mice, which was still not statistically significant in Yoda 1-treated mice (fig. 1K and M).
The above experiments show that the Piezo1 agonist Yoda1 can save the loss of occlusal force due to the loss of alveolar bone and can effectively prevent alveolar osteoporosis due to long-term tooth absence.
Example 2
This example performed Ovariectomy (OVX) and tooth extraction simultaneously on 6-week old female wild-type C57BL/6J mice followed by Yoda 14 weeks (fig. 2A and 2E); three-dimensional micro-CT reconstructed images show post-treatment maxillary alveolar bone (fig. 2B and 2C), and quantitative analysis found that loss of occlusal force reduced alveolar bone mass, even more severe in OVX-operated mice. After treatment with the Piezo1 agonist Yoda1, estrogen deficient mice were rescued from partial alveolar bone loss due to loss of occlusal force (fig. 2D), and more importantly, Yoda1 treatment significantly restored estrogen deficiency induced osteoporosis in both Ctrl and Unloading groups, even to healthy alveolar bone levels without OVX (fig. 2D).
In addition, testing the femoral bone mass of the above mice, the same quantitative microstructural parameters showed that Yoda1 treatment significantly restored estrogen-deficiency induced osteoporosis, nearly to a healthy level (fig. 3B). Furthermore, the three-point bending test showed increased femoral bone stiffness in Yoda1 treated mice compared to untreated OVX mice (fig. 3D and 3E).
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and should not be taken as limiting the scope of the present invention, which is intended to cover any modifications, equivalents, improvements, etc. within the spirit and scope of the present invention.
Claims (7)
- Use of the Piezo1 agonist Yoda1 in the manufacture of a medicament for the treatment of postmenopausal osteoporosis.
- Use of the Piezo1 agonist Yoda1 for the preparation of a medicament for the treatment of postmenopausal osteoporosis due to estrogen deficiency.
- Use of the Piezo1 agonist Yoda1 for the preparation of a medicament for the prevention or treatment of alveolar osteoporosis caused by loss of occlusal force.
- 4. Use according to claim 3, wherein said loss of occlusal force comprises alveolar bone loss caused by long-term toothless.
- 5. The use according to any one of claims 1 to 4, wherein the medicament comprises as active ingredient the Piezo1 agonist Yoda1, and is administered at a dose of 1-100 ug/kg.
- 6. A pharmaceutical composition for the treatment of postmenopausal osteoporosis, which comprises as an active ingredient the piozo 1 agonist Yoda 1.
- 7. The pharmaceutical composition of claim 6, wherein the pharmaceutical composition is in a dosage form selected from the group consisting of tablets, powders, injections, capsules, suspensions, pastes, gels, coatings, films, sustained release formulations, and microspheres.
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| Application Number | Priority Date | Filing Date | Title |
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| CN202210420315.6A CN114732911A (en) | 2022-04-21 | 2022-04-21 | Application of Piezo1 agonist Yoda1 in preparation of medicine for treating postmenopausal osteoporosis |
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| CN202210420315.6A CN114732911A (en) | 2022-04-21 | 2022-04-21 | Application of Piezo1 agonist Yoda1 in preparation of medicine for treating postmenopausal osteoporosis |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108627638A (en) * | 2018-05-04 | 2018-10-09 | 南京医科大学附属口腔医院 | Sirtuin 1 mediates the research method of senile Alveolar Bone Loss mechanism of action through Bmi1 |
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| CN113181344A (en) * | 2021-06-09 | 2021-07-30 | 上海交通大学医学院附属第九人民医院 | Application of STAT3 agonist Colivelin TFA in HIES and osteoporosis treatment |
| CN114126617A (en) * | 2019-07-08 | 2022-03-01 | 东芬兰大学 | Piezoelectric agonists for preventing or reversing abnormal amyloid deposition |
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- 2022-04-21 CN CN202210420315.6A patent/CN114732911A/en active Pending
Patent Citations (4)
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| CN108627638A (en) * | 2018-05-04 | 2018-10-09 | 南京医科大学附属口腔医院 | Sirtuin 1 mediates the research method of senile Alveolar Bone Loss mechanism of action through Bmi1 |
| CN114126617A (en) * | 2019-07-08 | 2022-03-01 | 东芬兰大学 | Piezoelectric agonists for preventing or reversing abnormal amyloid deposition |
| CN112816697A (en) * | 2019-11-18 | 2021-05-18 | 中国科学院分子细胞科学卓越创新中心 | Reagent for inhibiting osteoclast activity and treating osteoporosis and application thereof |
| CN113181344A (en) * | 2021-06-09 | 2021-07-30 | 上海交通大学医学院附属第九人民医院 | Application of STAT3 agonist Colivelin TFA in HIES and osteoporosis treatment |
Non-Patent Citations (3)
| Title |
|---|
| XUEHUA LI等: "Stimulation of Piezo1 by mechanical signals promotes bone anabolism" * |
| YANYAN XING等: "Effects of mechanosensitive ion channel Piezo1 on proliferation and osteogenic differentiation of human dental follicle cells" * |
| 王旭霞等: "咬合力丧失对老年骨质疏松大鼠牙槽骨吸收的影响" * |
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