CN113181344A - Application of STAT3 agonist Colivelin TFA in HIES and osteoporosis treatment - Google Patents
Application of STAT3 agonist Colivelin TFA in HIES and osteoporosis treatment Download PDFInfo
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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
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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
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
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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
Abstract
The invention relates to application of STAT3 agonist ColivelinTFA in HIES (hyper immunoglobulin E syndrome) and osteoporosis treatment. The invention constructs an osteoblast specific Stat3 knockout mouse through a Cre-loxp system, discovers that the mouse shows the HIES-related skeletal deformity such as maxillofacial bone development deformity, spontaneous fracture, osteoporosis and the like, and proves the mechanism of the HIES-related skeletal development deformity and osteoporosis caused by STAT3 inactivation through regulating osteogenesis activity. On the basis, the STAT3 agonist ColivelinTFA is proved to be used for treating osteoporosis caused by STAT3 single-dose insufficiency and stress loss. In contrast to bisphosphonates, collinlifta increases bone mass by promoting, rather than inhibiting, bone metabolism, which may to some extent avoid a series of complications such as bisphosphonates leading to jaw necrosis.
Description
Technical Field
The invention relates to the technical field of medical application, in particular to application of STAT3 agonist Colivelin TFA in HIES and osteoporosis treatment.
Background
Inactivation of the human STAT3 gene mutation results in a complex primary immunodeficiency disease characterized by elevated serum IgE concentrations, known as hyper IgE syndrome (HIES). Spontaneous fracture is a common clinical manifestation of HIES, and a cohort study showed that 57% of patients had at least 3 fractures and were present at all ages; further analysis revealed that bone density of femur and vertebrae of patients with spontaneous fracture was much lower than normal. Clinically, the medicine for treating the osteoporosis is divided into two types, one type is an anti-absorption medicine which can slow down the absorption of osteoclasts to bones; another class is anabolic drugs, which stimulate osteoblasts to form new bone. Bisphosphonates, which are anti-resorptive drugs, are first-line drugs for the treatment of osteoporosis and are also widely used in the treatment of HIES. Although there is evidence that bisphosphonates can increase bone density, the incidence of spontaneous fractures cannot be reduced, and chronic use greatly increases the likelihood of poor bone healing and necrosis of the jaw bone, and bisphosphonates are contraindicated for long term use in growing children. On the other hand, the only osteogenic agents are full-length parathyroid hormone (PTH 1-84) and its N-terminal peptide fragment, teriparatide (PTH 1-34). At present, the research on the HIES-related osteoporosis and spontaneous fracture by the two drugs is rarely reported. In conclusion, the HIES patient has abnormal bone metabolism, limited treatment means, poor treatment effect and prognosis, seriously harms the survival and life quality of the patient and brings heavy mental burden and economic pressure to the patient and family, so the elucidation of the back mechanism is not only beneficial to the treatment of the HIES-related bone diseases, but also has great significance to the treatment of osteoporosis.
Colivelin TFA is a neuroprotective peptide (neuroprotectant peptide) with brain permeability and is a potent agonist of STAT 3. Collivilin inhibits neuronal death in vitro by activating STAT 3. Collilin TFA showed long-term beneficial effects on neurotoxicity, Α β deposition, neuronal apoptosis, in neurodegenerative diseases. Previous studies have demonstrated that collivilin TFA can be used for alzheimer's disease and ischemic brain injury, but its role in the skeletal system has not been elucidated.
Disclosure of Invention
In view of the above-mentioned drawbacks of the prior art, it is an object of the present invention to provide the use of a STAT3 agonist for the preparation of a medicament for the treatment of HIES and osteoporosis, for solving the problems of the prior art.
In order to achieve the above object, the present invention provides, in a first aspect, the use of a STAT3 agonist in the manufacture of a medicament for the treatment of HIES and osteoporosis.
Preferably, the STAT3 agonist is a colicilin.
The present invention also provides a composition for treating HIES and osteoporosis, characterized in that the composition comprises a STAT3 agonist as an active ingredient.
Preferably, the composition is a tablet, powder, injection, capsule, suspension, paste, gel, coating agent, film agent, sustained release agent or microsphere.
Further preferably, the STAT3 agonist is a colicilin.
In the present invention, "pharmaceutically acceptable" means that the molecular entities and compositions do not produce adverse, allergic, or other untoward reactions when they are properly administered to an animal or human.
In the present invention, unless otherwise specified, the pharmaceutical dosage form is not particularly limited, and may be prepared by a conventional method, for example, as tablets, powders, injections, capsules, suspensions, pastes, gels, films, sustained-release agents, or microspheres. The choice of the pharmaceutical dosage form should be matched to the mode of administration.
The invention has the beneficial effects that osteoblast specific Stat3 knockout mice are constructed by a Cre-loxp system, the mice are found to show the bone deformity related to HIES (bone morphogenetic disorder), such as maxillofacial bone development deformity, spontaneous fracture, osteoporosis and the like, and the STAT3 inactivation is proved to cause the mechanism of the bone development deformity related to HIES and the osteoporosis by regulating the bone forming activity. On the basis, the STAT3 agonist Colivelin TFA is proved to be used for treating osteoporosis caused by STAT3 single-dose insufficiency and stress loss. Compared with the existing diphosphate drugs for treating HIES, the Colivelin TFA increases the bone mass by promoting the bone metabolism rather than inhibiting the bone metabolism, which may avoid a series of complications such as jaw necrosis caused by the diphosphate to a certain extent.
Description of the drawings:
FIG. 1A. Stat3 genome, 18 th-20 th exon flanking lox P sequence, selected Osx for specific expression in osteoblast precursor cellscreAs a tool mouse; western detection of STAT3 protein in Day 1OsxcreAnd Osxcre；Stat3fl /flThe expression level of mouse cranial parietal bone cells; osx C.8 week oldcreAnd Osxcre；Stat3fl/flOverall observation of the mouse; day 1Osx D-FcreAnd Osxcre；Stat3fl/flOverall dyeing of the mice; g.4 Weekly old OsxcreAnd Osxcre；Stat3fl/flCarrying out Micro-CT three-dimensional reconstruction on a mouse skull top bone; h.4 mouse femur Micro-CT three-dimensional reconstruction image; osx I-McreAnd Osxcre；Stat3fl/flStatistical analysis of the bone microstructure parameters in mice, wherein Osx is shown on the leftcreMouse data, right Osxcre；Stat3fl/flMouse data including trabecular bone volume to total volume of selected regions (BV/TV), trabecular bone mean thickness (tb.th), number of trabeculae (tb.n), mean width between the medullary cavities of trabeculae (tb.sp) and cortical bone thickness (ct.th).
FIG. 2A. Stat3 genome, 18 th-20 th exons flanked by lox P sequences, Prx specifically expressed in bone marrow stromal stem cells was selectedcreAs a tool mouse; western detection of STAT3 protein at 4 weeks of age Stat3fl/flAnd Prxcre；Stat3fl/flExpression levels of mouse BMSCs; c.8 week old Stat3fl/flAnd Prxcre；Stat3fl/flOverall observation of the mouse; D-E.2 week old Stat3fl/flAnd Prxcre；Stat3fl/flOverall dyeing of the mice; f.1 week old Stat3fl/flAnd Prxcre；Stat3fl/flStaining mice with safranin O; G. stat3 for different age groupsfl/flAnd Prxcre；Stat3fl/flRatio of femur lengths in mice, where Stat3 is on the leftfl/flMouse data, right panel Prxcre；Stat3fl/flMouse data.
FIG. 3A.4 weeks of ageOsxcreAnd Osxcre；Stat3fl/flMouse femur TRAP staining; b.4 weeks old OsxcreAnd Osxcre；Stat3fl/flMarking the experimental result of the mouse femur calcein-alizarin red living body; day 1OsxcreAnd Osxcre；Stat3fl/flResults of immune hybridization of mouse femur Col1a1 and Ocn; d.1 week old OsxcreAnd Osxcre；Stat3fl/flImmunofluorescence staining results of mouse thighbone; e.4 Weekly old OsxcreAnd Osxcre；Stat3fl/flIn vitro osteogenic induction differentiation of mouse BMSCs, ALP staining for 7 days, and alizarin red staining for 14 days; F. the end point of osteogenic induced differentiation, RT-pcr detection of osteogenic related marker gene expression, wherein the left side is OsxcreMouse data, right Osxcre；Stat3fl/flMouse data; g.4 week old Stat3fl/flThe mice are treated in vitro with EGFP and Cre-EGFP adenoviruses in advance and induced to differentiate, and are stained by ALP for 7 days and by alizarin red for 14 days; H. and (3) detecting the expression of an osteogenesis related marker gene by RT-pcr at an osteogenesis induced differentiation terminal.
Day 1Osx fig. 4acreAnd Osxcre；Stat3fl/flResults of mouse cranial parietal bone tissue RNA seq; osxcre；Stat3fl/flComparison OsxcreThe result of analysis of mouse skull bone expression down-regulated gene GO; osxcre；Stat3fl/flComparison OsxcreThe osteogenic differentiation and ossification related gene which is expressed and down-regulated in the skull bone tissue of the mouse; day 1OsxcreAnd Osxcre；Stat3fl/flMouse skull bone Dlx5 expression level, wherein the left side is OsxcreMouse data, right Osxcre；Stat3fl/flMouse data; e.1 week and 4 weeks OsxcreAnd Osxcre；Stat3fl/flMouse femur DLX5 immunohistochemical staining; f.4 Weekly old OsxcreAnd Osxcre；Stat3fl/flIn vitro EGFP or DLX5 lentivirus treatment and osteogenic induced differentiation of mouse BMSCs, ALP staining in 7 days and alizarin red staining in 14 days; G. the end point of osteogenic induced differentiation, RT-pcr, is the expression of osteogenic related marker gene, wherein Osx is arranged from left to rightcre+EGFP、Osxcre；Stat3fl/fl+EGFP、Osxcre；Stat3fl/fl+ DLX 5.
FIG. 5A is a Micro-CT three-dimensional reconstructed image of femur of a mouse aged 4 weeks; b.4 week old mice femur HE staining; C. statistical analysis of bone microstructural parameters including the ratio of trabecular bone volume to total volume of selected area (BV/TV), average trabecular bone thickness (tb.th), number of trabeculae (tb.n), average width between the medullary cavities of trabeculae (tb.sp) and thickness of cortical bone (ct.th), wherein Osx is in order from left to rightcre、Osxcre；Stat3fl/fl+Vehicle、Osxcre；Stat3fl/fl+ coliverlin data; d.4 week old mice femoral TRAP staining, which is Osx from left to rightcre、Osxcre；Stat3fl /fl+Vehicle、Osxcre；Stat3fl/fl+ coliverlin data.
FIG. 6A is a Micro-CT three-dimensional reconstructed image of femur of a mouse of 5 weeks old; B. statistical analysis results of bone microstructural parameters including the ratio of trabecular bone volume to total volume of the selected region (BV/TV), trabecular bone mean thickness (tb.th), number of trabeculae (tb.n), mean width between the medullary cavities of trabeculae (tb.sp) and cortical bone thickness (ct.th), wherein the data of Vehicle, TS + collivilin are in order from left to right; marking an experimental result of a calcein-alizarin red living body of a femur of a mouse at the age of 5 weeks; TRAP staining of femurs of 5 week old mice, wherein the data of Vehicle, TS + Colivelin are sequentially arranged from left to right.
FIG. 7A is a schematic diagram showing that BMSCs of a 4-week-old wild-type mouse are cultured in vitro, PBS or 1nM collitilin is added to the culture solution and osteogenic induction differentiation is performed, ALP staining is performed on the 7 th day of culture, and alizarin red staining is performed on the 14 th day of culture; B. adding PBS or 1nM Colivelin and carrying out osteogenic induced differentiation for 24h, and carrying out Western detection on the expression quantity of p-STAT3 and STAT3 proteins; C. and at the end point of osteogenic induced differentiation, RT-pcr detects the expression of osteogenic related marker genes of the experimental group and the control group, wherein the left side is data of Vehicle, and the right side is data of Colven.
Detailed Description
The invention will be further understood by reference to the following examples.
Examples
Experimental materials: collivelin TFA was purchased from MCE.
The experimental steps are as follows:
a) stat3 obtained by homologous recombinationflox/floxA mouse. Mouse Osx with toolcreAnd Stat3flox/floxHybridization to obtain Stat3 knockout specifically in osteogenic precursor cells (Osx)Cre；Stat3fl/fl) The process of C57BL6 mouse is shown in FIG. 1A.
b) Take Day 1OsxCreAnd OsxCre；Stat3fl/flMouse skull bone cells, a western detects the expression level of STAT3 protein in skull bone, and verifies whether the mouse with the Stat3 knocked out by the osteoblast precursor cell specificity is successfully constructed, the specific result is shown as B in figure 1, and the result shows that the mouse with the Stat3 knocked out by the osteoblast precursor cell specificity is successfully constructed. Osx age at 8 weekscreAnd Osxcre；Stat3fl/flThe overall appearance of the mice is shown as C in fig. 1.
c) Take Day 1OsxCreAnd OsxCre；Stat3fl/flThe mice were stained in the whole body to investigate the difference of bones, and the results are shown in D-F in FIG. 1, wherein Osx was found by the whole body stainingCre；Stat3fl/flSkull and clavicle of mice compared to OsxCreThere was a clear abnormality in mouse development.
d) Taking 6 pairs of 4-week-old males OsxCreAnd OsxCre；Stat3fl/flMouse skull bone and femur, Mico-CT three-dimensional reconstruction mouse skull bone and femur image, as shown in figure 1G and H, from the CT reconstruction results can be seen: compared with OsxCreMouse, OsxCre；Stat3 fl/flThe mouse has obvious abnormal skull bone shape and porosity, and the three-dimensional reconstruction and quantitative analysis of the femur show OsxCre；Stat3 fl/flMice showed significant osteoporosis. And quantitative analysis of femur (here, to exclude the influence of estrogen on bone mass, male mice were selected for quantitative analysis of bone microstructure parameters), as shown in FIG. 1, I-M, three-dimensional CT quantitative analysisAnalysis of 4 weeks old OsxCreMouse and OsxCre；Stat3 fl/flMouse, found OsxCre；Stat3 fl/flMice exhibited significant osteoporosis.
Application tool mouse PrxcreAnd Stat3flox/floxHybridization to obtain bone marrow stromal cell specific knockout Stat3 (Prx)Cre；Stat3fl/fl) C57BL6 mice (A in FIG. 2), Western-detected Stat3 at 4 weeks of agefl/flAnd PrxCre；Stat3fl /flSTAT3 expression in mouse BMSCs, results showed PrxCre；Stat3fl/flThe mouse STAT3 expression level is obviously lower than that of Stat3fl/flMice (B in fig. 2) demonstrated the successful construction of mice with a bone marrow stromal cell specific Stat3 knockout. Observe mouse Stat3 at 8 weeks of agefl/flAnd PrxCre；Stat3fl/flMouse, discovery of PrxCre；Stat3fl/flThe mouse body type is obviously smaller than Stat3fl/flMouse (C in fig. 2). Taking Stat3 of 2 weeks oldfl/flAnd PrxCre；Stat3fl/flBulk staining of mice revealed that PrxCre；Stat3fl/flThere were significant abnormalities in both skull and femur in mice, and PrxCre；Stat3fl/flThe mouse limb bones were subject to multiple spontaneous fractures and poor healing (D, E in figure 2). Safranin O showed Prx of 1 week oldCre；Stat3fl/flFracture of mouse femur (F in FIG. 2), further to Stat3 of different age groupsfl/flAnd PrxCre；Stat3fl/flThe length of the femur of the mouse is measured, and Prx is foundCre；Stat3fl/flThe degree of femoral deformity in mice worsens with age (G in fig. 2).
e) 3 pairs of Osx with 4 weeks of age were collectedCreAnd OsxCre；Stat3fl/flFemur of mouse, H&E, observing the difference between cortical bone and trabecular bone after dyeing; TRAP staining was followed by calculation of the number of TRAP positive cells and statistical analysis was performed to analyze the osteoclast activity change, as shown in FIG. 3A, which was found Osx by TRAP stainingCre；Stat3 fl/flThe TRAP positive cell number of the mouse is far less than OsxCreMouse, Explanation OsxCre；Stat3 fl/flThe mouse has weaker osteoclastogenesis ability than OsxCreMouse
f) Collecting 3 week old male OsxCreAnd OsxCre；Stat3fl/flMice were intraperitoneally injected with 20mg/kg calcein (Sigma, C0875-5G, 1mg/ml in 2% NaHCO 3) and 40mg/kg alizarin Red S (Sigma, A5533-25G, 2mg/ml in H2O) at Day 7 and then euthanized, and femurs were fixed, dehydrated and embedded, respectively at Day1 and Day 4. The samples were cut to 5 μm thickness with a hard tissue cutter and images of the fluorescent markers were captured with a microscope by analyzing the distance comparison Osx between two fluorescent lines at the same site on different samplesCreAnd OsxCre；Stat3fl/flThe bone formation rate of the mouse is shown in FIG. 3B, from which Osx can be seenCre；Stat3 fl/flThe rate of new bone formation in mice is much less than in OsxCre mice.
g) Take Day 1OsxCreAnd OsxCre；Stat3fl/flThe expression of the osteogenesis related genes Col1a1 and Ocn is detected by immune in situ hybridization experiment on mouse thighbone, and specifically as shown in C in figure 3, Osx can be foundCre；Stat3fl/flMouse osteogenesis related gene Col1a1, Ocn expression is lower than OsxCreA mouse.
h) Osx is collected at 1 week ageCreAnd OsxCre；Stat3fl/flThe mouse femur was subjected to immunohistofluorescence staining for OPN, as shown in FIG. 3D, which shows OsxCre；Stat3fl/flThe OPN expression of the mouse osteogenesis related gene is less than OsxCreA mouse.
i) Osx taken 4 weeks oldCreAnd OsxCre；Stat3fl/flMouse BMSCs, cultured in vitro and induced osteogenic differentiation. ALP and alizarin red staining were performed on days 7 and 14, respectively, of induced differentiation. Inducing differentiation end point, extracting OsxCreAnd OsxCre；Stat3fl/flGroup RNA, RT-pcr detected the bone formation related index, as shown in E and F in FIG. 3, from the results it can be found OsxCre；Stat3 fl/flThe osteogenic differentiation capability of the BMSCs of the mouse is lower than OsxCreA mouse.
j) Taking Stat3 of 4 weeks oldfl/flMouse BMSCs were cultured in vitro with EGFP andafter the pretreatment of BMSCs by Cre-EGFP, osteogenic differentiation is induced. ALP and alizarin red staining were performed on days 7 and 14, respectively, of induced differentiation. And (3) inducing a differentiation end point, extracting EGFP and Cre-EGFP group RNA, detecting osteogenesis related indexes by RT-pcr, and specifically, as shown by G and H in figure 3, finding that after Stat3 is knocked out by BMSCs, osteogenic differentiation capacity is obviously weakened.
k) Collect 3 pairs of Day 1Osx from the same fossaCreAnd OsxCre；Stat3fl/flRNA is extracted from mouse skull bone tissue, RNA sequencing is carried out, the sequencing result is shown as A in figure 4, and the sequencing result is compared with OsxCreMouse, OsxCre；Stat3fl/flThe expression of a large number of genes in mice is down-regulated. To find a new possible Stat 3-regulated signaling pathway, further couple OsxCre；Stat3fl/flDown-regulated expression in the panel (fold chand)>1.5), and the analysis result is shown as B in figure 4, and the down-regulated genes are mostly related to ossification (ossification), osteoblast differentiation (osteoblast differentiation), bone development (skeletal system degradation) and the like, and further, bone-formation related pathways in the GO result are analyzed to find out possible downstream genes of Stat3, and as shown as C in figure 4, Dlx5 shows obvious down-regulation. Detection OsxCreAnd OsxCre；Stat3fl/flExpression of DLX5 in mice, D in FIG. 4, OsxCre；Stat3fl/flDlx5 expression in mouse skull bone tissue is obviously reduced, and DLX5 expression is further detected by mouse femur, as shown in E in figure 4, OsxCre；Stat3fl/flMouse DLX5 expression is significantly lower than OsxCreThe results above show that Stat3 is highly likely to further influence osteogenic differentiation by modulating Dlx5 expression in mice.
Osx taken 4 weeks oldCreAnd OsxCre；Stat3fl/flMouse BMSCs, induced osteogenic differentiation following in vitro culture, EGFP or DLX5 lentiviral treatment, Osx, as shown in FIG. 4 at F, GCre；Stat3fl/flAfter mouse BMSCs overexpress DLX5, osteogenic differentiation capacity is recovered to a certain degree, and further proves that Stat3 may influence osteogenic differentiation by regulating expression of Dlx 5.
l) taking 1 week old Osx of same nestCreAnd OsxCre；Stat3fl/+Mice, classified as OsxCreGroup, OsxCre+ PBS group, OsxCre；Stat3fl/++The Colivelin group, in which the Colivelin/PBS administration mode was intraperitoneal injection at an injection dose of 1.5mg/kg, every other day, mice were sacrificed at 4 weeks of age, the left legs of the mice were subjected to Micro-CT analysis for bone mass change, the right legs were fixed, dehydrated and embedded for further HE staining and Trap staining, and the results are shown in FIG. 5. CT reconstruction (A in FIG. 5) and quantitative analysis (C in FIG. 5) showed OsxCre；Stat3fl/flAfter mice are injected with Colivelin in the abdominal cavity, the phenotype of bone mass reduction is recovered to a certain degree, and further the phenotype of bone mass reduction is recovered through H&E staining (B in fig. 5) and TRAP staining (D in fig. 5) found that collimlin increases bone mass mainly by enhancing osteogenesis rather than weakening osteoclasts.
m) 4-week-old male C57BL/6J mice were randomly divided into a blank control group, a TS + PBS group and a TS + coiblin group, wherein the blank control group mice were injected intraperitoneally with PBS for 7 days with no tail suspension. TS + PBS group: mice were suspended in individual plastic cages for 7 days with approximately 30 degree head down tilt, with daily intraperitoneal injections of PBS, TS + coitilin groups: the tail of the mouse is suspended while the colicilin is injected into the abdominal cavity every day for 7 days continuously, the injection dose is 1mg/kg, and the change of the bone mass of the mouse is analyzed by Micro-CT after 7 days, and the result is shown in figure 6. CT reconstruction (a in fig. 6) and quantitative analysis (B in fig. 6) showed that tail-suspended mice (TS + PBS group) had significantly reduced bone mass compared to wild-type mice (blank control group); after intraperitoneal injection of collivilin (TS + collivilin group), the phenotype of reduced bone mass was restored to some extent. Further, it was found by calcein-alizarin red double-label staining (C in fig. 6) and TRAP staining (D in fig. 6) that collivilin can increase bone mass by enhancing osteogenesis rather than affecting osteoclasts.
n) taking BMSCs of 4-week-old wild-type mice for in vitro culture, respectively treating samples with PBS/Colivelin and inducing osteogenic differentiation, respectively detecting the expression quantity of P-STAT3 and STAT3 proteins in 24h of induction, and performing ALP and alizarin red staining on the 7 th day and the 14 th day of induction and differentiation. And (3) inducing a differentiation end point, extracting RNA of a PBS group and a Colivelin group, and detecting an osteogenesis related index by using an RT-pcr (reverse transcription-polymerase chain reaction), wherein the result is shown in figure 7. After BMSCs of mice are treated by PBS/Colivelin for 4h, the expression of STAT3 and phosphorylation STAT3(p-STAT3) is detected by western, the result shows that Colivelin can enhance STAT3 phosphorylation (B in figure 7), further ALP and alizarin red staining (A in figure 7) are found, after BMSCs are treated by Colivelin, the bone forming capability is enhanced, and the expression of bone formation related genes is found to be enhanced by RT-pcr detection (C in figure 7).
To sum up, OsxCre；Stat3fl/flMice show HIES-related skeletal deformities such as maxillofacial skeletal development deformity, spontaneous fracture, osteoporosis and the like, and the STAT3 inactivation is proved to cause HIES-related skeletal development deformity and osteoporosis mechanism through regulation and control of osteogenesis activity. On the basis, the STAT3 agonist Colivelin TFA is proved to be used for treating osteoporosis caused by STAT3 single-dose insufficiency and stress loss.
The embodiments of the present invention have been described in detail, but the embodiments are merely examples, and the present invention is not limited to the embodiments described above. Any equivalent modifications and substitutions to those skilled in the art are also within the scope of the present invention. Accordingly, equivalent changes and modifications made without departing from the spirit and scope of the present invention should be covered by the present invention.
Claims (6)
- Application of STAT3 agonist in preparation of medicine for treating HIES and osteoporosis.
- 2. Use of a STAT3 agonist according to claim 1 in the preparation of a medicament for the treatment of HIES and osteoporosis, wherein the STAT3 agonist is a collinlin.
- 3. Use of a STAT3 agonist according to claim 1 in the preparation of a medicament for the treatment of HIES and osteoporosis, wherein the STAT3 agonist is collilin TFA.
- 4. A composition for the treatment of HIES and osteoporosis, comprising as an active ingredient a STAT3 agonist.
- 5. The composition for treating HIES and osteoporosis of claim 4, wherein the composition is in the form of tablets, powders, injections, capsules, suspensions, pastes, gels, coatings, films, sustained release formulations or microspheres.
- 6. The composition for the treatment of HIES and osteoporosis as claimed in claim 4, wherein the STAT3 agonist is a collinlin.
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| CN114732911A (en) * | 2022-04-21 | 2022-07-12 | 上海交通大学医学院附属第九人民医院 | Application of Piezo1 agonist Yoda1 in preparation of medicine for treating postmenopausal osteoporosis |
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