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WO2023033130A1 - Composition pour le traitement ou la prévention de maladies osseuses - Google Patents

Composition pour le traitement ou la prévention de maladies osseuses Download PDF

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Publication number
WO2023033130A1
WO2023033130A1 PCT/JP2022/033056 JP2022033056W WO2023033130A1 WO 2023033130 A1 WO2023033130 A1 WO 2023033130A1 JP 2022033056 W JP2022033056 W JP 2022033056W WO 2023033130 A1 WO2023033130 A1 WO 2023033130A1
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Prior art keywords
siglec
composition
bone
secretory
secreted
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Japanese (ja)
Inventor
朗仁 山本
登 橋本
史也 加納
伸典 高橋
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University of Tokushima NUC
Tokai National Higher Education and Research System NUC
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University of Tokushima NUC
Tokai National Higher Education and Research System NUC
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Priority to JP2023508573A priority Critical patent/JPWO2023033130A1/ja
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • 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
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • Rheumatoid arthritis is an autoimmune disease of unknown cause characterized by protracted destructive arthritis. Treatment with methotrexate and targeted drugs (biologics and JAK inhibitors) is standard practice. On the one hand, rheumatoid arthritis is a risk factor for osteoporosis. The prevalence of osteoporosis in rheumatoid arthritis patients is about twice that of controls, and fracture risk is also significantly higher. Conventional therapeutic drugs for rheumatoid arthritis, including biologics and JAK inhibitors, do not have the effect of improving bone density, and therapeutic agents for osteoporosis, for example, organisms that inhibit RANKL, an osteoclast-inducing factor, are used as necessary. drug (denosumab) has been used.
  • Siglec-9 is a type I transmembrane receptor protein expressed in monocytes, granulocytes and macrophages, with extracellular, transmembrane and cytoplasmic domains.
  • Secretory Siglec-9 is a form of Siglec-9 lacking the cytoplasmic domain.
  • An object of the present disclosure is to provide new means for treating or preventing bone diseases.
  • secretory Siglec-9 inhibits the differentiation of bone marrow cells and macrophages into osteoclasts and increases bone density. , and suppressed the inflammatory response of fibroblasts.
  • compositions for treating or preventing bone disease comprising secreted Siglec-9.
  • compositions for increasing bone density comprising secreted Siglec-9.
  • compositions for preventing bone fractures comprising secreted Siglec-9.
  • the present disclosure provides a composition for suppressing osteoclast differentiation, comprising secreted Siglec-9.
  • compositions for suppressing fibroblast inflammatory responses comprising secreted Siglec-9.
  • compositions for treating or preventing bone disease compositions for increasing bone density, compositions for preventing fractures, compositions for inhibiting osteoclast differentiation, or fibroblast Compositions are provided for inhibiting cellular inflammatory responses.
  • FIG. 1 shows the experimental schedule of Test 1 using anti-collagen antibody arthritis (CAIA) model mice and the therapeutic effects of sSiglec-9 and JAKi on arthritis.
  • 7 shows the bone area and bone density of the cuboid bone 7 days after the start of treatment intervention in Test 1.
  • FIG. 7 shows the results of hematoxylin and eosin staining of ankle joints on day 7 from the start of therapeutic intervention in Test 1.
  • FIG. 4 is an enlarged view within the frame of FIG. 3;
  • FIG. 7 shows the scores of ankle bone erosion and cartilage destruction on day 7 from the start of treatment intervention in Study 1.
  • FIG. 7 shows the number of cells expressing markers related to inflammation or bone destruction in ankle joints on day 7 from the start of therapeutic intervention in Study 1.
  • FIG. 10 is an image of the lower extremities taken 28 days after ovariectomy in Test 4 using a ⁇ CT imaging device.
  • FIG. Bone parameters of the femur 28 days after ovariectomy in study 4 ratio of cancellous bone volume to intramedullary tissue volume, average trabecular width, average trabecular number per unit length, trabecular gap). .
  • Sialic acid-binding immunoglobulin-like lectin-9 is a transmembrane protein expressed in monocytes, granulocytes and macrophages, and homologues are known in humans and various animals.
  • Siglec-9 can be of any species, typically mammals (e.g., humans, dogs, cats, rabbits, cows, pigs, goats, sheep, horses, monkeys, guinea pigs, rats). and mice), preferably human.
  • Siglec-9 typically contains a signal peptide, an extracellular domain, a transmembrane domain and an intracellular domain, and soluble proteins containing the extracellular domain of Siglec-9 also exist in vivo.
  • "secreted Siglec-9” refers to a protein that contains the extracellular domain of Siglec-9 and does not contain the transmembrane and intracellular domains.
  • the secreted Siglec-9 may further comprise a Siglec-9 signal peptide.
  • Siglec-9 The amino acid sequences of Siglec-9 derived from various species can be easily obtained using publicly known databases.
  • a representative amino acid sequence of human Siglec-9 is shown in SEQ ID NO:1. It consists of 463 amino acids, positions 1-17 are the signal peptide, positions 18-348 are the extracellular domain, positions 349-369 are the transmembrane domain, positions 370-463. The position is the intracellular domain.
  • a secreted Siglec-9 comprises the amino acid sequence from positions 18 to 348 of SEQ ID NO:1 (SEQ ID NO:2).
  • Secreted Siglec-9 may further comprise a signal peptide and the amino acid sequence of positions 1 to 348 of SEQ ID NO: 1 (SEQ ID NO: 3).
  • Secretory Siglec-9 includes a sequence in which one or several amino acids are deleted, substituted or added in the amino acid sequence of SEQ ID NO: 2 or 3, as long as the activity of secretory Siglec-9 is maintained.
  • “several” means preferably 2 to 7, more preferably 2 to 5, and most preferably 2 to 3 amino acids. Amino acid substitutions are preferably conservative substitutions between similar amino acid residues.
  • secretory Siglec-9 has the amino acid sequence of SEQ ID NO: 2 or 3 when calculated using BLAST or the like (for example, the parameters of the initial conditions of BLAST are at least about 70%, preferably at least about 80%, more preferably at least about 90%, particularly preferably at least about 95%, most preferably at least about 97%, about 98% or about 99% It may contain amino acid sequences with identity.
  • amino acid sequence identity means the degree of sequence similarity between proteins, and two proteins aligned in an optimal state (maximum amino acid match) over the region of the sequences to be compared. Determined by comparing sequences. A sequence identity number (%) is determined by determining the number of identical amino acids present in both sequences to determine the number of matching sites, then dividing this number of matching sites by the total number of amino acids in the sequence region being compared. , is calculated by multiplying the resulting value by 100. Algorithms for obtaining optimal alignment and sequence identity include various algorithms commonly available to those of skill in the art (eg, BLAST algorithms, FASTA algorithms, etc.). Sequence identity can be determined, for example, using sequence analysis software such as BLAST, FASTA.
  • the secretory Siglec-9 may be a fusion protein with any protein or polypeptide as long as the activity of the secretory Siglec-9 is maintained.
  • the proteins or polypeptides constituting the fusion protein include, for example, Fc region, histidine tag, GST tag, GFP tag, myc tag, FLAG tag and the like.
  • a protein or polypeptide that constitutes a fusion protein may be attached to the extracellular domain of Siglec-9 via a linker.
  • the secreted Siglec-9 comprises an Fc region.
  • secretory Siglec-9 activity includes at least the activity of suppressing the differentiation of bone marrow cells or macrophages into osteoclasts.
  • This activity can be measured by various methods known in the art. For example, it is known that bone marrow cells or macrophages can be stimulated with macrophage colony-stimulating factor (M-CSF) and NF- ⁇ B-activating receptor ligand (RANKL) to induce osteoclast differentiation.
  • M-CSF macrophage colony-stimulating factor
  • RNKL NF- ⁇ B-activating receptor ligand
  • the number of osteoclasts can be determined based on the expression of osteoclast markers such as TRAP or Cathepsin K. For example, it can be determined by adding a chromogenic substrate for the TRAP enzyme to cultured cells and evaluating the enzymatic activity (TRAP staining). Alternatively, the expression level of each marker can be measured by an immunological method, a quantitative real-time PCR method, or the like.
  • Activity of secretory Siglec-9 may further include activity to suppress inflammation.
  • This activity can be measured by various methods known in the art. For example, it is known that stimulation of fibroblasts such as synovial fibroblasts with TNF ⁇ , an inflammatory cytokine, enhances the expression of inflammatory markers.
  • the anti-inflammatory activity of the protein can be assessed based on the stimulation and expression of inflammatory markers.
  • Known inflammatory markers include, for example, iNos, IL-1 ⁇ , IL-6, and TNF ⁇ .
  • the expression level of each marker can be measured by an immunological method, a quantitative real-time PCR method, or the like.
  • immunological methods include flow cytometry analysis, radioisotope immunoassay (RIA method), enzyme immunoassay (ELISA method), western blotting, and immunohistochemical staining.
  • the activity of secretory Siglec-9 is maintained means that the activity of secretory Siglec-9 is maintained by about 30% or more, and may exceed 100%. It is preferably maintained at about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, or about 90% or more.
  • Secretory Siglec-9 can be produced by known methods, such as genetic engineering techniques, for example, a method of producing an expression vector containing a polynucleotide encoding the same and expressing it in cells. Specifically, an expression vector is constructed such that a polynucleotide encoding a secretory Siglec-9 is expressed under an expression control region such as an enhancer or promoter, host cells are transformed with this expression vector, and secreted. Type Siglec-9 is expressed and recovered. Alternatively, commercially available secretory Siglec-9 may be used.
  • secretory Siglec-9 improved bone area and bone density and suppressed bone destruction in rheumatoid arthritis models. It also inhibited osteoclast differentiation of myeloid cells and macrophages in vitro. Furthermore, it improved bone parameters and inhibited disease progression in an osteoporosis model. Therefore, secreted Siglec-9 may be used to treat or prevent bone disease.
  • bone disease means a disease characterized by bone abnormalities. Bone abnormalities include, for example, increased or activated osteoclasts or decreased bone density. Bone diseases include osteoporosis, osteoarthritis and femoral head necrosis, especially osteoporosis.
  • treat a disease or “treatment of a disease” means to alleviate, alleviate, ameliorate or eliminate a disease.
  • prevent disease or “prophylaxis of disease” is to prevent disease in a subject, particularly in a subject who may, but has not yet, developed the disease, or , means to reduce the likelihood of developing disease.
  • Subjects who may develop bone disease but have not yet developed it include, for example, subjects with decreased bone density or subjects with risk factors for bone disease.
  • Risk factors for osteoporosis include, for example, aging, menopause, diabetes, chronic kidney disease, rheumatoid arthritis, hyperparathyroidism, hyperthyroidism, steroid drugs, and sex hormone lowering therapy.
  • Risk factors for osteoarthritis include, for example, aging, genetics, occupation, obesity, cartilage fragility, trauma, joint dysplasia, joint lability.
  • Risk factors for femoral head necrosis include, for example, steroid therapy and heavy alcohol consumption.
  • Rheumatoid arthritis is known as a risk factor for osteoporosis.
  • the initial symptoms of rheumatoid arthritis are mainly inflammation of the synovial membrane, and as it progresses, joint destruction occurs due to cartilage destruction and bone erosion. Further progression of rheumatoid arthritis can be complicated by osteoporosis near the joints (paraarticular osteoporosis) and systemic osteoporosis, especially in the elderly, and can increase the risk of fractures. Therefore, in the treatment of advanced rheumatoid arthritis, a therapeutic agent for rheumatoid arthritis and a therapeutic agent for osteoporosis have conventionally been used in combination.
  • Secretory Siglec-9 can treat rheumatoid arthritis as described in Patent Document 1, and can treat and prevent osteoporosis as shown in the Examples of the present application. In such cases, there is no need to concomitantly use other osteoporosis therapeutic agents. Accordingly, in one embodiment, compositions are provided for treating or preventing osteoporosis in patients with rheumatoid arthritis, particularly advanced rheumatoid arthritis, comprising secreted Siglec-9. In another aspect, compositions for treating advanced rheumatoid arthritis, particularly rheumatoid arthritis with osteoporosis, comprising secretory Siglec-9 are provided.
  • stage III highly advanced stage
  • stage IV end stage
  • stage II-IV stage III-IV
  • stage IV stage IV rheumatoid arthritis according to the stain blocker staging system.
  • the above-described treatment or prevention of bone disease or rheumatoid arthritis is characterized by not using agents that inhibit the activity of other osteoclasts.
  • agents that inhibit osteoclast activity include, for example, bisphosphonate drugs (e.g. etidronate, alendronate, risedronate, minodronate, ibandronate), RANKL inhibitors (e.g. denosumab), sclerotin inhibitors (e.g. romosozumab).
  • the above treatment or prevention of bone disease or rheumatoid arthritis is characterized by the absence of secretory Siglec-9 in combination with monocyte chemoattractant-1 (MCP-1).
  • MCP-1 monocyte chemoattractant-1
  • the above treatment or prevention of bone disease or rheumatoid arthritis is characterized by the use of secretory Siglec-9 as the sole active ingredient.
  • composition for suppressing osteoclast differentiation comprising secreted Siglec-9.
  • the composition can be used in vivo to inhibit osteoclast differentiation in vivo. It can also be used in vitro by adding it to the culture medium.
  • compositions are provided for increasing bone density comprising secreted Siglec-9.
  • Increasing bone density includes suppressing a decrease in bone density.
  • compositions are provided for preventing bone fractures comprising secreted Siglec-9. These compositions can be used in accordance with compositions for treating or preventing bone disease.
  • compositions are provided for suppressing fibroblast inflammatory responses comprising secreted Siglec-9.
  • fibroblasts include synovial fibroblasts and periosteal fibroblasts.
  • the composition can be used in vivo to suppress the inflammatory response of fibroblasts in vivo. It can also be used in vitro by adding it to the culture medium.
  • Targets to which secretory Siglec-9 is applied include mammals including humans (pets, livestock, experimental animals, etc.). Examples include humans, dogs, cats, rabbits, cows, pigs, goats, sheep, horses, monkeys, guinea pigs, rats and mice, especially humans.
  • the subject is a patient with rheumatoid arthritis, particularly advanced rheumatoid arthritis. In some embodiments, the subject is a human aged 60 or older, 65 or older, 70 or older, 75 or older, 80 or older, 85 or older, or 90 or older.
  • composition of the present disclosure can contain bioabsorbable materials such as hyaluronic acid, collagen, fibrinogen, platelet plasma, and the like.
  • Compositions of the present disclosure may also include gelling materials such as hyaluronic acid, collagen, fibrin glue, and the like.
  • the compositions of the present disclosure can contain known pharmaceutically acceptable ingredients. For example, carriers, excipients, disintegrants, buffers, emulsifiers, suspending agents, soothing agents, stabilizers, preservatives, preservatives, physiological saline and the like can be included. As these various additives, various known components can be appropriately used.
  • the formulation form of the composition of the present disclosure is not particularly limited. Various known formulation forms can be adopted. Tablets, powders, granules, granules, fine granules, capsules, solid injections that dissolve at the time of use, solids such as suppositories, liquid injections (intravenous/muscular injection), injections, drip infusion Examples include liquid agents such as formulations, eye drops, sprays, lotions, creams, topical agents such as patches, and the like. Moreover, it is possible to adopt a form in which it is carried by an indwelling type medical device or the like. Additionally, the compositions of the present disclosure can contain known pharmaceutically acceptable salts.
  • the dosage form of secretory Siglec-9 is not particularly limited.
  • parenteral administration may be systemic administration or local administration. More specific examples include injection, application or spraying to the diseased site.
  • Intravenous administration, intraarterial administration, intraarticular administration, intraportal vein administration, intradermal administration, subcutaneous administration, intramuscular administration, intraperitoneal administration, intranasal administration, intraoral administration and the like can also be mentioned.
  • the dosage and administration of secretory Siglec-9 is not particularly limited. It can be set in consideration of the age, body weight, disease condition, etc. of the subject. For example, about 0.1 to about 1000 ⁇ g/kg body weight/day, about 1 to about 500 ⁇ g/kg body weight/day, about 10 to about 250 ⁇ g/kg body weight/day, or about 20 to about 100 ⁇ g/kg body weight/day. Secreted Siglec-9 may be administered.
  • the secretory Siglec-9 may be administered once, multiple times, or continuously. In the case of multiple administrations, for example, once to several times a day, for example, once, twice or three times a day, with an administration frequency of every day or every few days, for example, 1 day, 2 days, 3 days. Or it can be administered every 7 days.
  • the administration period is not limited, and a drug holiday period may be provided.
  • a method of treating or preventing a bone disease comprising administering secretory Siglec-9 to a subject in need of treatment or prevention of the bone disease.
  • secreted Siglec-9 for the treatment or prevention of bone disease is provided.
  • use of secreted Siglec-9 for the treatment or prevention of bone disease is provided.
  • use of secreted Siglec-9 in the manufacture of a composition for treating or preventing bone disease is provided.
  • methods are provided for increasing bone density comprising administering secretory Siglec-9 to a subject in need thereof.
  • secreted Siglec-9 is provided for increasing bone density.
  • use of secreted Siglec-9 to increase bone density is provided.
  • use of secreted Siglec-9 in the manufacture of a composition for increasing bone density is provided.
  • methods are provided for preventing bone fractures comprising administering secreted Siglec-9 to a subject in need thereof.
  • secreted Siglec-9 is provided for preventing fractures.
  • use of secreted Siglec-9 to prevent fractures is provided.
  • use of secreted Siglec-9 in the manufacture of a composition for preventing bone fracture is provided.
  • methods for inhibiting osteoclast differentiation comprising administering a secreted form of Siglec-9 to a subject in need of inhibiting osteoclast differentiation.
  • methods for inhibiting osteoclast differentiation comprising culturing cells in a culture medium containing secreted Siglec-9.
  • secreted Siglec-9 is provided for inhibiting osteoclast differentiation.
  • the use of secreted Siglec-9 to inhibit osteoclast differentiation is provided.
  • use of secreted Siglec-9 in the manufacture of a composition for inhibiting osteoclast differentiation is provided.
  • methods for suppressing a fibroblast inflammatory response comprising administering a secreted Siglec-9 to a subject in need of suppressing the fibroblast inflammatory response.
  • a method for suppressing a fibroblast inflammatory response comprising culturing cells in a culture medium containing secreted Siglec-9.
  • a secreted form of Siglec-9 is provided for suppressing a fibroblast inflammatory response.
  • the use of secreted Siglec-9 to suppress fibroblast inflammatory responses is provided.
  • use of secreted Siglec-9 in the manufacture of a composition for inhibiting fibroblast inflammatory response is provided.
  • a composition for treating or preventing a bone disease comprising secretory Siglec-9.
  • the composition according to any one of items 1 to 4 for treating or preventing bone disease in patients with rheumatoid arthritis.
  • secreted Siglec-9 comprises an amino acid sequence having at least 90% identity with the amino acid sequence of SEQ ID NO:2 or 3.
  • composition according to any one of items 1 to 15, wherein the secretory Siglec-9 comprises the amino acid sequence of SEQ ID NO:2 or 3.
  • the composition according to any one of items 1 to 16, wherein the secreted Siglec-9 comprises an amino acid sequence having at least 90% identity with the amino acid sequence of SEQ ID NO:2.
  • the composition according to any one of items 1 to 17, wherein the secretory Siglec-9 comprises the amino acid sequence of SEQ ID NO:2.
  • the composition according to any one of items 1 to 18, wherein the secretory Siglec-9 comprises an Fc region.
  • Test 1 sSiglec-9 suppresses bone destruction in rheumatoid arthritis model anti-collagen antibody arthritis (CAIA) model mice (T Kagari, H Doi and T Shimozato. The importance of IL-1 ⁇ and TNF- ⁇ , and the noninvolvement of IL-6, in the development of monoclonal antibody-induced arthritis. J Immunol 169:1459-1466, 2002) was used. Joint destruction progresses when the inflammatory state of CAIA is at its highest level and continues for 7 days.
  • CAIA rheumatoid arthritis model anti-collagen antibody arthritis
  • sSiglec-9 (R & D SYSTEMS, Recombinant Human Siglec-9 Fc Chimera) was administered twice to the tail vein (15th and 17th days).
  • JAKi tofacitinib, 15 mg/kg body weight
  • sSiglec-9 is a fusion protein consisting of the extracellular domain of human Siglec-9 (SEQ ID NO:2), a linker (SEQ ID NO:4) and the Fc region of human IgG1 .
  • FIG. 3 shows the results of hematoxylin-eosin staining.
  • FIG. 4 is an enlarged image within the frame of FIG.
  • the sSiglec-9 group maintained the morphology of bone and cartilage and improved the synovial morphology.
  • the synovial membrane of the sSiglec-9 group exhibited good granulation-like histology and was rich in blood vessels.
  • Test 2 sSiglec-9 suppresses the inflammatory response of synovial fibroblasts Collecting synovial fibroblasts (SF) from the ankle joint of healthy mice It was stimulated with the cytokine TNF ⁇ . Gene expression of cartilage-degrading enzymes and inflammatory markers was assessed using quantitative real-time PCR methods. The results are shown in FIG. TNF ⁇ stimulation increased the gene expression of the cartilage degrading enzyme MMP9 and the inflammatory markers iNos, IL-1 ⁇ , IL-6, and TNF ⁇ , but sSiglec-9 significantly suppressed these gene expressions. .
  • Test 3 sSiglec-9 suppresses differentiation induction into osteoclasts
  • Mouse bone marrow cells were seeded in a 24-well culture dish, stimulated with MCSF and RANKL in the presence or absence of sSiglec-9, and TRAP. + differentiated into osteoclasts.
  • the number of TRAP + cells was assessed by immunostaining and the number of viable cells by WST-8 assay.
  • the results are shown in FIG.
  • Treatment with sSiglec-9 during induction dose-dependently decreased the number of TRAP + cells (FIG. 8, left).
  • WST cell proliferation activity
  • mBM Mouse bone marrow cells
  • RANKL fibroblast growth factor
  • sSiglec-9 Gene expression of the osteoclast markers TRAP and cathepsin K (ctsk) was assessed using quantitative real-time PCR methods. The results are shown in FIG. sSiglec-9 treatment during induction decreased gene expression of TRAP and cstk. This result suggests that sSiglec-9 suppresses osteoclast differentiation.
  • Test 4 sSiglec-9 prevents osteoporosis and suppresses progression of osteoporosis model mice (OVX mice) were prepared as follows. C57BL/6J (female, 8 weeks old) was anesthetized by intraperitoneal administration of a mixed anesthesia of three types (medetomidine hydrochloride, mitasozolam, butorphanol tartrate). The body hair on the back was shaved with clippers and depilatory cream, and then fixed in a prone position. A #11 scalpel was used to make an incision of about 1 cm in the midline of the back. Using forceps, the incision was moved to the right side of the lumbar spine to confirm the subperitoneal ovary.
  • OVX mice osteoporosis model mice
  • a blunt dissection was made into the peritoneum over the perovarian fat using the tips of sharp curved forceps.
  • the tip of sharp curved tweezers was opened by about 1 to 2 mm to grasp the fat and pulled it out from the incision.
  • the ovary, fallopian tube, and part of the uterus were pulled, and the fallopian tube side and adipose tissue side of the ovary were ligated with 4-0 polyglycolic acid absorbable sutures to remove the ovaries.
  • Other tissues were put back into the abdominal cavity and the peritoneum was simply sutured with 4-0 polyglycolic acid absorbable thread.
  • the skin was closed with suture clips. They were placed in a heater at 37°C and observed until they awoke from anesthesia.
  • sSiglec-9FC was administered to the tail vein every 3 days (FIG. 10).
  • a control group received PBS.
  • Twenty-eight days after ovariectomy the lower extremities were removed and photographed with a ⁇ CT imaging device (FIG. 11).
  • a bone component region was extracted for the femur, and the following bone parameters were measured. The measurement area was set between 1 and 2.5 mm from the lower end of the growth plate of the distal femur, which is a site where remarkable changes in cancellous bone were observed by macroscopic observation. Bone extraction was performed with a cutoff value of 315 mg/cm 3 .
  • the present disclosure relates to treatment or prevention of bone disease, and can be used in the medical field.

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Abstract

Les présents inventeurs ont découvert que la Siglec-9 sécrétoire inhibe la différenciation des cellules de la moelle osseuse et des macrophages en ostéoclastes et augmente la densité minérale osseuse, et que la Siglec-9 sécrétoire inhibe la réaction inflammatoire des fibroblastes. Par conséquent, la présente divulgation concerne une composition qui est destinée au traitement ou à la prévention de maladies osseuses, et qui contient de la Siglec-9 sécrétoire. Dans un autre mode de réalisation, la présente divulgation concerne une composition qui est destinée à l'augmentation de la densité minérale osseuse, et qui contient de la Siglec-9 sécrétoire. Dans encore un autre mode de réalisation, la présente divulgation concerne une composition qui est destinée à la prévention de fracture, et qui contient de la Siglec-9 sécrétoire. Dans encore un autre mode de réalisation, la présente divulgation concerne une composition qui est destinée à l'inhibition de la différenciation en ostéoclastes, et qui contient de la Siglec-9 sécrétoire. Dans encore un autre mode de réalisation, la présente divulgation concerne une composition qui est destinée à l'inhibition de la réaction inflammatoire de fibroblastes, et qui contient de la Siglec-9 sécrétoire.
PCT/JP2022/033056 2021-09-03 2022-09-02 Composition pour le traitement ou la prévention de maladies osseuses Ceased WO2023033130A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
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JP2015166694A (ja) * 2014-03-03 2015-09-24 国立大学法人名古屋大学 幹細胞の培養産物の評価指標及びその利用
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