A composition, pharmaceutical preparation and use for treating a vascular-bone coupling imbalance disease

Abstract

The application belongs to the field of treating blood vessel-bone coupling imbalance diseases in traditional Chinese medicine, and particularly relates to a composition for treating blood vessel-bone coupling imbalance diseases, a pharmaceutical preparation and application. Geniposide alone or in combination with crocin I can effectively reduce endothelial cell damage under pathological stimulation conditions, reduce the level of cell apoptosis and the degree of oxidative stress, improve the vascular endothelial function state, and can also significantly inhibit osteoclast differentiation, reduce the number of mature osteoclasts, and reduce bone resorption activity, thereby being conducive to restoring the dynamic balance between bone formation and bone resorption.

Description

Technical Field

[0001] This invention belongs to the field of traditional Chinese medicine treatment of vascular-bone coupling imbalance diseases, specifically relating to a composition, pharmaceutical preparation and application for treating vascular-bone coupling imbalance diseases. Background Technology

[0002] Bone tissue is a highly vascularized and dynamic organ, and its structural homeostasis, metabolic balance, and damage repair processes all depend heavily on a sophisticated blood supply system. Intraosseous blood vessels not only transport oxygen and nutrients but also directly participate in bone formation, bone resorption, and bone microstructural remodeling through signal exchange with bone-related cells such as osteoblasts and osteoclasts. Therefore, the synergistic regulation between vascular function and bone metabolism is considered a key foundation for maintaining bone tissue homeostasis.

[0003] In various bone-related diseases, including degenerative diseases (osteoarthritis), metabolic diseases (osteoporosis), ischemic necrosis (avascular necrosis of the femoral head), and trauma repair disorders (fractures), pathological changes such as vascular endothelial damage, decreased microcirculation perfusion, and local ischemia and hypoxia are commonly observed. These changes can further lead to impaired osteogenic function, increased osteoclast activity, and bone microstructural degeneration, forming a vicious cycle of mutually reinforcing "vascular dysfunction-abnormal bone remodeling." In recent years, an increasing number of studies have proposed that interventions should be made at a holistic level to address the functional coupling between blood vessels and bone, rather than targeting individual tissues in isolation.

[0004] Hypertension, as one of the most common systemic chronic diseases, can lead to vascular stiffness, endothelial dysfunction, and insufficient microcirculation perfusion over a long period. It not only significantly increases the risk of cardiovascular and cerebrovascular events but is also considered an important systemic risk factor for various bone metabolic abnormalities and impaired bone repair. Epidemiological studies suggest that the risk of osteoporosis, osteoarthritis, and poor bone repair is significantly increased in hypertensive individuals, indicating that systemic vascular abnormalities may exacerbate local bone metabolic imbalances by affecting blood supply to bone tissue and cell communication. However, for this complex cross-organ pathological state of "vascular-bone" functional coupling imbalance, there is currently a lack of effective therapeutic drugs that simultaneously improve vascular function and regulate bone metabolism, highlighting the urgent need to develop new therapeutic agents.

[0005] Gardenia is a traditional Chinese medicine with the effects of clearing heat and purging fire, cooling blood and detoxifying, and promoting diuresis and relieving jaundice. Gardenia has potential therapeutic value for hypertension. However, gardenia has problems such as complex composition, difficulty in quality control, and inconvenience in taking traditional decoctions.

[0006] Geniposide (GE) is one of the main active components of Gardenia jasminoides. Previous literature has reported that it has broad-spectrum pharmacological effects, including anti-inflammatory, antioxidant, hepatoprotective, choleretic, neuroprotective, hypoglycemic, and anti-apoptotic effects. In vitro and animal studies have shown that GE can downregulate inflammation-related pathways (such as NF-κB signaling), activate intracellular antioxidant defense systems (such as the Nrf2 / HO-1 axis), and regulate energy metabolism-related pathways (such as AMPK, PI3K / Akt, FoxO1 / PDK4, etc.), thereby exhibiting a protective effect against pathological states such as liver damage, neurodegenerative diseases, metabolic disorders, and cardiovascular and cerebrovascular injuries.

[0007] Crocin I is mainly extracted from the dried stigma of saffron (Crocus sativus L.), a plant in the Iridaceae family, and can also be obtained from gardenia fruit. Currently, gardenia is the primary raw material for industrial production. Modern pharmacological studies have shown that crocin I can improve chronic stress-induced depression and anxiety-like behaviors by regulating the levels of monoamine neurotransmitters (such as 5-HT, DA, and NA) in the hippocampus. It can also inhibit the increase of intracellular calcium ions, thereby reducing myocardial oxygen consumption, preventing arrhythmias, and has certain hypoglycemic and hypolipidemic effects, providing protection against diabetes and its complications (such as diabetic nephropathy).

[0008] Small molecule compounds derived from natural products exhibit unique advantages in intervening in complex chronic diseases due to their favorable safety profile, well-defined structure, and multi-target regulatory properties. Therefore, how to streamline components, precisely formulate drugs to achieve a clear pharmacodynamic basis and definite efficacy, and discover new applications, is a technical problem that those skilled in the art need to solve. Summary of the Invention

[0009] To address the shortcomings of existing technologies and the technical problem of the simultaneous presence of vascular dysfunction and bone metabolism abnormalities in vascular-bone coupling imbalance diseases, and the lack of effective comprehensive intervention methods, this invention systematically studies the use of genipin alone and the combination of genipin and crocin I in the treatment of vascular-bone coupling imbalance diseases from three levels: vascular function, bone metabolism, and their synergistic regulation.

[0010] Terminology Explanation: Unless otherwise defined, all technical terms in this document have the same meanings as commonly understood by one of ordinary skill in the art to which the subject matter of the claims pertains. Unless otherwise stated, all patents, patent inventions, and publications cited in this document are incorporated herein by reference in their entirety. If multiple definitions exist for terms in this document, the definitions in this chapter shall prevail.

[0011] It should be understood that the above brief description and the following detailed description are exemplary and for illustrative purposes only, and do not limit the subject matter of the invention in any way. In this invention, the singular is used in conjunction with the plural unless otherwise specifically stated. It should also be noted that, unless otherwise stated, the use of “or” or “or” means “and / or”. Furthermore, the use of the term “comprising” and other forms such as “including,” “containing,” and “contains” are not limiting.

[0012] The definitions of standard chemical terms can be found in the reference "Pharmacopoeia of the People's Republic of China (2025 Edition)".

[0013] The term "genipin" as used in this article refers to: genipin is an iridoid glycoside organic compound with the chemical formula C17H24O10, a molecular weight of 388.37, and CAS number 24512-63-8. The pure product is a white powder, readily soluble in water and ethanol, but insoluble in petroleum ether. It is commercially available.

[0014] The term "vascular-bone coupling" used in this article refers to "angiogenic-osteogenic coupling," a core mechanism in bone development, remodeling, and repair. Under normal circumstances, the formation of new blood vessels (angiogenesis) provides osteoblasts with oxygen, nutrients, and growth factors, while vascular endothelial cells secrete signaling molecules (such as VEGF and H-type vascular-associated factors) to directly promote osteoogenesis. Conversely, osteoblasts also secrete pro-angiogenic factors to regulate blood vessel growth; the two are mutually reinforcing and closely coordinated. When this coupling relationship is imbalanced, such as inadequate angiogenesis or disrupted signal transduction, bone formation is impaired, leading to or exacerbating various bone diseases.

[0015] To achieve the objectives of this invention, the following technical solution is adopted: On one hand, the present invention provides a composition for treating vascular-bone coupling imbalance, wherein the raw materials of the composition are genipin and crocin I.

[0016] Preferably, the mass ratio of genipin to crocin I is 1:99-99:1.

[0017] Preferably, the mass ratio of genipin to crocin I is 1:0.5-1.5.

[0018] Secondly, the present invention provides the use of genipin in the preparation of drugs for treating vascular-bone coupling disorders.

[0019] Thirdly, the present invention provides the application of the combination of genipin and crocin I in the preparation of a drug for treating vascular-bone coupling disorder.

[0020] Preferably, the disease includes osteoporosis.

[0021] Preferably, the treatment of vascular-bone coupling imbalance includes improving the survival rate and proliferation capacity of vascular endothelial cells; and / or increasing the length, number of branch points and network integrity of vascular-like structures, and / or promoting angiogenesis; and / or promoting osteoblast proliferation, and / or increasing alkaline phosphatase activity and mineralized nodule formation levels, and / or upregulating osteogenic function indicators.

[0022] Preferably, the treatment of vascular-bone coupling imbalance includes inhibiting osteoclast differentiation, and / or reducing the number of mature osteoclasts and decreasing bone resorption activity, and / or restoring the dynamic balance between bone formation and bone resorption; and / or simultaneously improving vascular endothelial function and bone metabolism, and / or weakening the synergistic effect between "vascular dysfunction and abnormal bone remodeling", thereby promoting functional synergy and homeostasis reconstruction between blood vessels and bone tissue.

[0023] Preferably, the treatment of vascular-bone coupling imbalance includes significantly reducing ROS levels and LDH release, and / or alleviating AngII-induced endothelial damage, and / or GE promoting cellular eNOS and VEGF secretion, and / or promoting vascular endothelial cell lumen formation.

[0024] Thirdly, the present invention provides a pharmaceutical preparation comprising the aforementioned composition and pharmaceutically acceptable excipients.

[0025] Preferably, the pharmaceutically acceptable excipient is selected from one or more of fillers, binders, disintegrants, lubricants, flavoring agents, preservatives, solubilizers, suspending agents, and emulsifiers.

[0026] Preferably, the dosage form of the pharmaceutical preparation is selected from granules, tablets, capsules, powders, pills, injections, aerosols, sprays, powder sprays, ointments, creams, gels, nasal drops, or oral films.

[0027] Compared with the prior art, the beneficial effects of the present invention are as follows: (1) The results of this study show that genipin and crocin I exhibit a significant and stable comprehensive synergistic effect in the state of vascular-bone coupling imbalance, and can act on two key aspects of vascular function and bone metabolism simultaneously. In terms of vascular function, after treatment with genipin and crocin I, the survival rate and proliferation capacity of vascular endothelial cells were significantly improved, and the cell migration ability was significantly enhanced. The results of the lumen formation experiment showed that the combined use of genipin and crocin I can significantly increase the length, number of branch points and network integrity of vascular-like structures, suggesting that it has the effect of promoting angiogenesis. At the same time, the combined use of genipin and crocin I can effectively reduce endothelial cell damage under pathological stimulation conditions, reduce the level of cell apoptosis and oxidative stress, and improve the functional state of vascular endothelium.

[0028] (2) In terms of bone metabolism, the combined use of genipin and crocin I significantly promoted osteoblast proliferation, increased alkaline phosphatase activity and mineralized nodule formation, and upregulated osteogenic-related functional indicators, suggesting that it has a bone-forming effect. At the same time, the combined use of genipin and crocin I significantly inhibited osteoclast differentiation, reduced the number of mature osteoclasts, and decreased their bone resorption activity, thereby helping to restore the dynamic balance between bone formation and bone resorption.

[0029] (3) In the comprehensive evaluation system of vascular-bone coupling, the combined use of genipin and crocin I effectively weakened the mutually reinforcing effect between "vascular dysfunction and abnormal bone remodeling" by simultaneously improving vascular endothelial function and bone metabolism, thus promoting functional synergy and homeostasis reconstruction between blood vessels and bone tissue. Related results indicate that the combined use of genipin and crocin I does not only act on a single cell type or a single pathological link, but can produce an overall regulatory effect on the imbalance of vascular-bone coupling at multiple levels and in multiple links.

[0030] (4) This invention systematically reveals for the first time the new efficacy and new uses of genipin and its combination in vascular-bone coupling imbalance diseases, and clarifies that crocin I can significantly enhance the efficacy of genipin and achieve synergistic effect. Genipin and its combination with crocin I can be used as an effective intervention to improve vascular dysfunction and bone metabolism abnormalities at the same time, providing sufficient experimental basis and technical support for its application in vascular osteopathy and related complex comorbidities. Attached Figure Description

[0031] Figure 1 Genipin and crocin I were used in combination to synergistically promote the proliferation of vascular endothelial cells (HUVECs). # P <0.05, ## P <0.01, ### P <0.001 vs. blank group.

[0032] Figure 2 Genipin and crocin I were used in combination to synergistically promote the proliferation of osteoblasts (MG-63). # P <0.05, ## P <0.01, ### P <0.001 vs. blank group.

[0033] Figure 3 This assay measures the level of reactive oxygen species (ROS) within vascular endothelial cells; red fluorescence represents ROS accumulation.

[0034] Figure 4The percentage of reactive oxygen species (ROS) in vascular endothelial cells and the content of lactate dehydrogenase (LDH) in the endothelial cell supernatant were used. * P <0.05, ** P <0.01, *** P <0.001.

[0035] Figure 5 The levels of nitric oxide synthase (eNOS) and vascular endothelial growth factor (VEGF) in the supernatant of vascular endothelial cells were detected by enzyme-linked immunosorbent assay (ELISA). * P <0.05, ** P <0.01, *** P <0.001.

[0036] Figure 6 This is a diagram showing the formation of a lumen.

[0037] Figure 7 The graph shows the cumulative growth length of blood vessels. *P<0.05,**P<0.01,***P<0.001.

[0038] Figure 8 The graph shows the downregulation of Runt-related transcription factor 2 (2RUNX2) positive expression in osteoblasts (MG-63).

[0039] Figure 9 The percentage of area positive for Runt-related transcription factor 2 (2RUNX2) in osteoblasts (MG-63) is *P<0.05,**P<0.01,***P<0.001.

[0040] Figure 10 To detect osteoblast proliferation capacity using the EdU assay.

[0041] Figure 11 Percentage of EdU-positive cells. Data are expressed as Mean ± SD. *P<0.05,**P<0.01,***P<0.001.

[0042] Figure 12 The secretion level of alkaline phosphatase (ALP) in osteoblasts was detected by ELISA. * P <0.05, ** P <0.01, *** P <0.001.

[0043] Figure 13Analyze mature osteoclasts (≥3 nuclei) for tartrate-resistant acid phosphatase (TRAP) staining.

[0044] Figure 14 To detect the expression and localization of RANK membrane receptor / c-Fos transcription factor in osteoclasts using dual immunofluorescence. * P <0.05, ** P <0.01, *** P <0.001.

[0045] Figures 3-11 In this study, CON was the control group, MOD was the model group, GE was the genipin group, and GE+CrocinI was the genipin + crocinI group. Detailed Implementation

[0046] The present invention will be further described below with reference to specific embodiments. All raw materials used are commercially available conventional raw materials. Specifically, the ECM endothelial cell culture medium was purchased from the ScienCell research laboratory; catalog number: 1001; the α-MEM culture medium was purchased from Thermo Fisher Scientific, Inc., under the brand Gbico; catalog number: C12571500BT; and the MG-63 cell culture medium was purchased from Wuhan Pronosai Life Science Technology Co., Ltd.; catalog number: CM-0157.

[0047] Example: Study on the efficacy of genipin and crocin I alone or in combination in treating vascular-bone coupling imbalance.

[0048] 1. Research Methods 1.1 Cell Culture HUVECs (Chinese Academy of Sciences Cell Bank) were cultured in ECM medium (containing 10% FBS and 1% penicillin and streptomycin). Human osteoblast-like cell line MG-63 (ATCC) was cultured in a dedicated medium (containing 10% FBS and 1% penicillin and streptomycin). BMSCs were isolated from the bone marrow of 6-8 week old C57BL / 6 mice and cultured in α-MEM medium (containing 10% FBS and 1% penicillin and streptomycin).

[0049] 1.2 Osteoblast and osteoclast induction Mature osteoblasts were obtained by treating MG-63 cells with 50 μg / mL ascorbic acid and 10 mM sodium β-phosphoglycerate for 5 days.

[0050] BMSCs were first cultured in α-MEM medium containing 20 ng / mL L-CSF for 3 days, and then transferred to α-MEM medium containing 20 ng / mL L-CSF and 50 ng / mL RANKL to induce osteoclast differentiation. Mature osteoclasts appeared in about 6-7 days.

[0051] 1.3 Cell Experiment Grouping The CCK8 experiment consisted of four groups: (1) control group (CON); (2) genipin group (GE, 5μM); (3) crocin I group (CrocinI, 5μM); and (4) genipin + crocin I group (2.5μM + 2.5μM crocinI).

[0052] The remaining experiments consisted of four groups: (1) control group (CON); (2) model group (MOD, AngII, 10μM); (3) genipin group (GE, 5μM); (4) genipin + crocin I group (GE, 2.5μM; CrocinI, 2.5μM).

[0053] 1.4 CCK-8 detection HUVEC and MG-63 cells were seeded in 96-well plates. After cell attachment, the cells were pretreated with the corresponding drugs (37℃, 5% CO2) for 24h, 48h, and 72h, respectively, according to the "Cell Experiment Groups" guidelines. Then, CCK-8 reagent (10μL per well) was added, and the cells were incubated for 2h. The absorbance was measured at 450nm. Cell viability is expressed as a percentage of the control group.

[0054] 1.5 Treatment of vascular endothelial cells HUVECs were seeded in 6-well plates (2.5 × 10⁻⁶). 5 Cells per well were cultured for 24 hours to allow cell adhesion. The cells were then pretreated with the specified drug for 24 hours, followed by treatment with AngII for 24 hours. The supernatant and cell pellet were collected.

[0055] 1.6 Co-culture of vascular endothelial cells and osteoblasts MG-63 cells were seeded in the lower chamber, and HUVECs were seeded in the upper chamber. After 24 hours of pretreatment with the drug in the upper chamber, cells were co-treated with AngII and the drug. Osteogenesis induction was simultaneously initiated in the lower chamber and maintained for 5 days. Cells and supernatant were collected.

[0056] 1.7 Co-culture of vascular endothelial cells and osteoclasts BMSCs were seeded in the lower chamber, and HUVECs were seeded in the upper chamber. After 24 hours of pretreatment with drugs in the upper chamber, AngII treatment was initiated. Osteoclast induction was simultaneously initiated in the lower chamber and maintained for 6 days. Cells and supernatant were collected.

[0057] 1.8 ROS detection After washing with HUVECPBS, DCFH-DA was added and incubated at 37°C in the dark for 30 min. The fluorescence intensity was observed under a fluorescence microscope, and the fluorescence intensity reflected the ROS level.

[0058] 1.9 Lumen Formation Experiment Matrigel was thawed at 4°C and solidified in 96-well plates. HUVECs were incubated for 6 hours after inoculation, and the total length, number of branches, and number of nodes of the network were determined using ImageJ microscopy.

[0059] 1.10 EdU staining Cells were incubated with EdU for 2 hours, followed by fixation, permeabilization, Click reaction, and Hoechst staining. The EdU positivity rate was calculated under a microscope.

[0060] 1.11 TRAP staining Fixed cells were added to TRAP solution and incubated at 37°C for 1 hour. Hematoxylin was used for counterstaining for 2-3 minutes, followed by blue staining with tap water for 10 minutes. Multinucleated purple-red cells were identified as TRAP-positive osteoclasts, and counted in 5 random fields.

[0061] 1.12 ELISA Cell culture supernatant was collected, centrifuged, and the contents of ALP, LDH, eNOS, and VEGF were detected.

[0062] 1.13 Immunofluorescence After cell fixation and membrane permeabilization and blocking, RUNX2, RANK, c-FOS, and antibody were added, and the cells were incubated overnight at 4°C. Secondary fluorescent antibody was then incubated at 37°C for 1 hour. Imaging was performed after DAPI counterstaining, and quantitative analysis was conducted using ImageJ.

[0063] 1.14 Statistical Analysis Experimental results are expressed as mean ± standard error (SEM) and are from three independent experiments, each with three replicates. One-way ANOVA was used, and Dunnett's test was used to compare differences between the model group and different drug administration groups. P < 0.05 was considered statistically significant.

[0064] 2. Research Results 2.1 Genipin combined with crocin I synergistically promotes the proliferation of HUVEC and MG-63 cells. To explore the potential synergistic effect of the combined use of genipin and crocin I, this study used the CCK-8 assay to compare the effects of single and combined administration on the proliferation activity of human umbilical vein endothelial cells (HUVEC) and human osteoblast-like cells (MG-63).

[0065] The results are as follows Figures 1-2The results showed that, at a concentration of 5 μM, both genipin and crocin I, when used alone for 72 h, exhibited proliferative effects on HUVEC and MG-63 cells, with genipin showing significantly stronger proliferative activity than crocin I (P<0.05). Notably, when administered at half the dose (2.5 μM each), the proliferative activity of both cell types was significantly enhanced, and significantly higher than either single-drug 5 μM group (P<0.001). These results indicate that the combined use of genipin and crocin I at half the dose can produce a synergistic proliferative effect, suggesting their potential for combined use in regulating vascular-bone coupling.

[0066] 2.2 Genipin alone and in combination with crocin I can significantly improve abnormal "vascular-bone" functional coupling. This study used a dual co-culture model of "vascular endothelial cells-osteoblasts" and "vascular endothelial cells-osteoclasts" to systematically evaluate the role of genipin (GE) alone and in combination with crocin I (GE+CrocinI) in the "vascular-bone" functional coupling process under the same total dosage.

[0067] 2.2.1 Protective effect against endothelial dysfunction In an AngII-induced endothelial dysfunction model, AngII significantly increased intracellular ROS fluorescence intensity and increased lactate dehydrogenase (LDH) release, suggesting enhanced oxidative stress and impaired cell membrane integrity. Figures 3-4 Compared with the model group, both GE monotherapy (5 μM) and GE combined with crocin (2.5 μM each) significantly reduced ROS levels and LDH release, suggesting that it can alleviate AngII-induced endothelial damage. Figures 3-4 Simultaneously, intervention with GE and its combinations can promote the secretion of eNOS and VEGF in endothelial cells (…). Figure 5 It promotes the formation of vascular endothelial cell lumens, indicating that it has clear vascular protective and angiogenic activities. Figures 6-7 More importantly, the combined effect of half-dose GE was significantly stronger than that of equal dose GE alone, further confirming that crocin I has a synergistic effect on genipin.

[0068] 2.2.2 Indirect regulatory effects on downstream bone metabolism cells In a dual co-culture model, AngII-induced endothelial injury significantly affected the function of downstream bone metabolic cells. Osteoblasts (MG-63) showed downregulated RUNX2 expression. Figures 8-9 The number of EdU-positive cells decreased. Figures 10-11 ) and ALP secretion ( Figure 12The decrease in TRAP-positive multinucleated cells suggests impaired proliferation and differentiation capacity; while osteoclasts show an increase in the number of TRAP-positive multinucleated cells. Figure 13 RANK membrane receptor and c-Fos transcription factor expression are upregulated. Figure 14 The results suggest enhanced osteoclastogenesis and activation. These findings indicate that endothelial dysfunction can simultaneously inhibit osteogenic processes and promote osteoclast activity through the "vascular-bone" coupling axis, leading to an imbalance in bone metabolism.

[0069] In terms of intervention, both GE monotherapy (5 μM) and GE combined with crocin I (2.5 μM each) significantly restored endothelial function and correspondingly improved downstream bone metabolism balance. Specifically, this was manifested in the recovery and enhancement of osteoblast proliferation (EdU+ cell number), RUNX2 expression, and ALP secretion. Figures 8-12 Simultaneously, the number of TRAP-positive osteoclasts decreased, and RANK and c-Fos expression was downregulated, suggesting that it can effectively inhibit osteoclast differentiation and overactivation. Figures 13-14 Consistent with the observations in 2.2.1, the combined drug group with half the dose showed significantly better efficacy than the GE monotherapy group with the same dose in all the above indicators (P<0.05).

[0070] In summary, GE alone and in combination with crocin I can indirectly promote osteoblast proliferation and differentiation while inhibiting osteoclast differentiation and activation by protecting endothelial function, thereby maintaining the homeostasis of the blood vessel-bone axis. The combined application of genipin and crocin I exhibits a significant synergistic effect.

[0071] The above detailed description is a specific description of one of the feasible embodiments of the present invention. This embodiment is not intended to limit the patent scope of the present invention. All equivalent implementations or modifications that do not depart from the present invention should be included within the scope of the technical solution of the present invention.

Claims

1. A composition for treating vascular-bone coupling imbalance, characterized in that, The raw materials for the composition are genipin and crocin I.

2. The composition according to claim 1, characterized in that, The mass ratio of genipin to saffron glycoside I is 1:0.5-2.

3. Application of genipin in the preparation of drugs for treating vascular-bone coupling disorders.

4. Application of the combination of genipin and crocin I in the preparation of drugs for treating vascular-bone coupling disorders.

5. The application according to claim 4, characterized in that, The diseases mentioned include osteoporosis.

6. The application according to claim 4, characterized in that, The treatment of vascular-bone coupling imbalance includes improving the survival and proliferation of vascular endothelial cells, and / or increasing the length, number of branch points and network integrity of vascular-like structures, and / or promoting angiogenesis, and / or promoting osteoblast proliferation, and / or increasing alkaline phosphatase activity and mineralized nodule formation levels, and / or upregulating osteogenic function indicators.

7. The application according to claim 4, characterized in that, The treatment of vascular-bone coupling imbalance includes inhibiting osteoclast differentiation and / or reducing the number of mature osteoclasts and decreasing bone resorption activity, and / or restoring the dynamic balance between bone formation and bone resorption, and / or simultaneously improving vascular endothelial function and bone metabolism, and / or weakening the synergistic effect between "vascular dysfunction and abnormal bone remodeling", thereby promoting functional synergy and homeostasis reconstruction between blood vessels and bone tissue.

8. The application according to claim 4, characterized in that, The treatment of vascular-bone coupling imbalance includes significantly reducing ROS levels and LDH release, and / or alleviating AngII-induced endothelial damage, and / or promoting cellular eNOS and VEGF secretion, and / or promoting vascular endothelial cell lumen formation.

9. A pharmaceutical preparation, characterized in that, The pharmaceutical preparation comprises the composition according to any one of claims 1-2, and pharmaceutically acceptable excipients.

10. The pharmaceutical preparation according to claim 9, characterized in that, The pharmaceutically acceptable excipients are selected from one or more of fillers, binders, disintegrants, lubricants, flavoring agents, preservatives, solubilizers, suspending agents, and emulsifiers; and / or, the dosage form of the pharmaceutical preparation is selected from granules, tablets, capsules, powders, pills, injections, aerosols, sprays, powders, ointments, creams, gels, nasal drops, or oral films.

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