CN111544374A - Application of deferoxamine mesylate for injection in treating age-increasing bone loss and bone marrow stem cell senescence - Google Patents
Application of deferoxamine mesylate for injection in treating age-increasing bone loss and bone marrow stem cell senescence Download PDFInfo
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Abstract
The invention discloses an application of deferoxamine mesylate for injection in treating age-increasing bone loss and bone marrow stem cell senescence, and discloses that after deferoxamine mesylate is injected into an aged rat, the phenomenon of bone senescence (age-increasing bone loss) is found to be reversed, and bone marrow stromal cell (stem cell) senescence separated from a bone marrow cavity after a medicament is injected is relieved; further proves that the intraperitoneal injection of the deferoxamine mesylate medicine can relieve the age-related bone loss of rats, recover the aging phenotype of rat bone marrow stromal cells, such as promoting cell growth (cell proliferation and colony formation), increasing osteogenesis, reducing lipogenesis, reversing the expression level of cell aging-related markers, resisting oxidative stress and the like.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to application of deferoxamine mesylate for injection in treating age-increasing bone loss and bone marrow stem cell senescence.
Background
Osteoporosis seriously harms the health of the middle-aged and the elderly. China is the country with the most osteoporosis patients. The functional imbalance between osteoclasts and osteoblasts is the main cause of osteoporosis, and the retrospective source is the abnormality of stem cells involved in maintaining bone tissue homeostasis. The aging changes of bone marrow mesenchymal stem cells (BMSCs) are closely related to the occurrence of osteoporosis.
At present, the current research situation analysis and existing problems at home and abroad are as follows:
the bone is constantly in a metabolic state for bone remodeling, thereby maintaining a dynamic balance of bone resorption and bone formation. As the body ages, bone resorption by osteoclasts is greater than the bone formation amount of osteoblasts, and senile osteoporosis occurs. At present, the clinical medicine for treating osteoporosis is mainly used for inhibiting bone resorption of osteoclast in a targeted mode, and can reduce further loss of bone, but the brittleness of bones is increased, and the bone forming function of osteoblast is not improved. BMSCs can differentiate into osteoblasts and osteocytes and play an important role in bone development, aging, and remodeling. The age-related changes in BMSCs are closely related to the development of osteoporosis. The great reason for the degeneration of bone tissue after aging is that the proliferation capacity of BMSCs is reduced, colony formation is reduced, the formation rate is reduced, the number of the BMSCs after aging is reduced, the migration efficiency is low, and the bone formation function is reduced.
(1) Changes in biological properties of BMSCs during bone aging
The molecular mechanism by which BMSCs participate in bone remodeling has greatly advanced in recent years: it was found that transforming growth factor beta 1 (TGF-beta 1) deposited in the bone matrix is released during bone resorption of osteoclasts to recruit BMSCs to the surface of bone resorption lacunae, and Insulin-like growth factor I (IGF-I) in the bone matrix activates mTOR signals to induce differentiation of BMSCs into osteoblasts, which form new bone to realize a complete bone turnover process. BMSCs migration and osteogenic differentiation are reduced during skeletal aging.
With the increase of age, the biological characteristics of BMSCs can be changed remarkably, and national scholars systematically study the expression change of aging-related molecules SA-beta-galactosidase staining method (beta-Gal), p53, p21, p16, Telomerase reverse transcriptase (TERT) and intracellular Reactive Oxygen Species (ROS) in BMSCs in the natural aging process of mice. Beta-gal is a molecule that is specifically expressed in senescent cells and increases in expression as the degree of cellular senescence increases. The p53/p21 pathway and the p16/pRb pathway are two core pathways for regulating the cell cycle in the cell senescence process, and the expression of the pathways is increased in senescence BMSCs. TERT is used as a key enzyme for synthesizing telomerase, plays an important role in maintaining the activity of the telomerase and the length of the telomerase, and the activity is obviously reduced when cells are aged. Oxidative stress ROS are important features of the aging body and play an important role in bone aging, with ROS levels significantly elevated in aging BMSCs compared to younger groups. In addition, studies have shown that BMSCs in aging bones have reduced proliferative and self-renewal capacity and reduced osteogenic function. Aging changes of BMSCs have a crucial influence on bone aging, and the defects of the quantity and biological functions of the BMSCs are closely related to aging osteoporosis.
Another significant feature of skeletal aging is a decrease in the osteogenic differentiation capacity of BMSCs. Differentiation of bone marrow mesenchymal stem cells into osteoblast precursors is one of the important mechanisms of the bone remodeling process. With age, bone undergoes progressive loss of bone mass, with a progressive increase in the fat in the bone marrow cavity. When bones are aged, the osteogenic and adipogenic differentiation of BMSCs are unbalanced, and aged BMSCs are more prone to differentiate into fat cells, so that the number of the fat cells is greatly increased. Some key signal channels regulate the osteogenic and adipogenic differentiation direction of BMSCs, and VEGF is considered to be an important determinant of the differentiation fate of the BMSCs. In an aging organism, BMSCs have the capacity of differentiating into osteoblast precursors directly due to changes of cell physiology, activity reduction and differentiation capacity reduction caused by aging, so that the occurrence of osteoporosis caused by the formation of new bones is reduced. Therefore, reversing or delaying the aging process of BMSCs may become a new direction for osteoporosis prevention and treatment.
(2) Role of HIF-1 alpha activation in bone aging regeneration
Hypoxia inducible factor 1 alpha (HIF-1 alpha) is a transcriptional regulator produced by cells as a result of adaptation to hypoxic or anoxic environments. Under normoxic conditions, HIF-1 α is extremely unstable and Proline Hydroxylase (PHD) acts on the proline residue of the oxygen-dependent degradation domain, hydroxylates it and binds to the VHL protein for degradation by the proteasome. Under hypoxia or anoxia, HIF-1 alpha accumulates and transports to nucleus to form polymer with HIF-1 beta, and activates HIF-1 sensitive target gene, which causes a series of hypoxia adaptive responses of tissue cells.
HIF-1 α plays a key role in the maintenance of bone tissue homeostasis. Knockdown of VHL in differentiated mature osteoblasts activates HIF-1 α, and a progressive increase in trabecular number and microvascular density in long bone is observed, and an increase in bone formation occurs after increased angiogenesis, the study first reveals a molecular mechanism by which mature osteoblasts couple angiogenesis and osteogenesis through HIF-1 α -VEGF signaling. Further studies have shown that activation of HIF-1 α signaling in osteoblasts can antagonize bone mass loss from ovarian ablation by promoting angiogenesis coupled bone formation. We found earlier that activation of the HIF-1 α signaling pathway in skeletal precursor cells in adult mice significantly increased the number of CD 31-positive vascular endothelial cells in bone marrow, while there were a large number of precursor osteoblasts around the trabecular bone, increased proliferation and differentiation of cells of the osteogenic lineage, significantly increased cancellous bone mass, and antagonism of age-related bone loss. Our findings suggest that HIF-1 α activation increases the number of skeletal osteoblast precursors and promotes differentiation of BMSCS into osteoblasts.
Research shows that HIF-1 alpha activation enhances the osteogenic activity and angiogenesis promoting capacity of BMSCs, and plays a key role in osteogenesis and bone repair. Recently, Nature reports that a novel vascular endothelial subtype (H-ECs) highly expressing CD31 and Endomucin exists in bone marrow, the quantity of the vascular endothelial subtype (H-ECs) is positively correlated with the level of HIF-1 alpha, the quantity of the H-ECs is remarkably reduced along with the increase of age, and when aged mice are treated by Desferrioxamine (DFO) which is a compound inhibiting the degradation of the HIF-1 alpha, the H-ECs, osteoblast precursors and osteoblasts of the mice are greatly expanded, and the bone mass of the mice is also remarkably improved. By utilizing a gene knockout mouse model and a distraction osteogenesis animal model, the expression of HIF-1 alpha and VEGF-A in a skeletal distraction region, angiogenesis and new bone formation of an osteoblast knockout Vhl mouse are increased, and the angiogenesis and bone healing delay appear in the distraction region of the osteoblast knockout HIF-1 alpha mouse, so that the important role of the HIF-1 alpha in bone regeneration is disclosed. In a rat skull defect repair model, HIF1 alpha is overexpressed in BMSCs by using adenovirus, and then the skull defect is repaired by combining scaffold materials, and the HIF-1 alpha activation is found to remarkably accelerate the healing process of the skull defect by promoting the angiogenisis and osteogenesis of the BMSCs. HIF-1 alpha activation also promotes osteogenic differentiation capacity of human BMSCs, inhibiting the potential to differentiate into adipocytes. However, the mechanism of action of HIF-1 alpha activation to improve BMSCs, especially the activity of aging skeletal BMSCs, and the reversion to bone aging have not been reported.
Autologous BMSC transplantation is an important means of stem cell therapy at present, but there is a problem in that the number and activity of cells of autologous BMSCs decrease with aging.
The age-related changes in BMSCs are a significant cause of osteoporosis. Reversing or delaying the aging process of BMSCs may be a new direction for osteoporosis prevention. Platelet Rich Plasma (PRP) has been reported to restore viability of senescent BMSCs, prolonging life and increasing bone mass in a progeria mouse model [9 ]. Our previous and foreign research shows that HIF-1 alpha activation can improve the activity of adult bone precursor cells, mainly manifested by increasing the number of bone precursor cells, promoting differentiation capacity to osteoblasts, and increasing the capacity of osteoblast lineage cells to promote angiogenesis. Therefore, we speculate that targeting HIF-1 α improves the viability of senescent skeletal BMSCs might be a new strategy for osteoporosis treatment. Desferrioxamine DFO is a clinically registered drug currently used for treating patients with multiferroic symptoms, and can increase HIF-1 α levels in cells by inhibiting PHD activity to prevent HIF-1 α degradation, so that the drug has predictability for clinical application to osteoporosis.
The information disclosed in this background section is only for enhancement of understanding of the general background of the invention and should not be taken as an acknowledgement or any form of suggestion that this information forms the prior art already known to a person skilled in the art.
Disclosure of Invention
The invention aims to provide application of deferoxamine mesylate for injection in treating aging bone loss and bone marrow stem cell senescence, which aims to solve the problem that the cell number and activity of autologous BMSCs are reduced along with aging.
In order to achieve the purpose, the invention adopts the following technical scheme:
the invention provides an application of deferoxamine mesylate for injection in treating age-increasing bone loss and bone marrow stem cell senescence.
Preferably, the administration mode of the deferoxamine mesylate includes, but is not limited to, intravenous bolus injection, intramuscular bolus injection, and intraperitoneal injection.
Preferably, the deferoxamine mesylate is administered at a dose of 20-60mg/kg daily.
Preferably, the deferoxamine mesylate is injected 2-5 times per week.
Preferably, the deferoxamine mesylate is injected continuously for 6-10 weeks.
By adopting the technical scheme, the invention has the following beneficial effects:
the invention discloses that after the injection of deferoxamine mesylate, the phenomenon of bone aging (aging bone loss) is reversed in aged rats, and the aging of bone marrow stromal cells (stem cells) separated from a bone marrow cavity after the injection of a medicament is relieved; further proves that the intraperitoneal injection of the deferoxamine mesylate medicine can relieve the age-related bone loss of rats, recover the aging phenotype of rat bone marrow stromal cells, such as promoting cell growth (cell proliferation and colony formation), increasing osteogenesis, reducing lipogenesis, recovering markers related to cell aging, resisting oxidative stress and the like.
In addition, deferoxamine mesylate for injection has a new effect in osteoporosis treatment, is used as a clinically registered medicament for treating patients with multiferroic symptoms at present, has proved to have low toxicity, and ensures the safety of medication.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, and it is obvious that the drawings in the following description are some embodiments of the present invention, and other drawings can be obtained by those skilled in the art without creative efforts.
FIG. 1 is a diagram illustrating histological results of bone mass of vertebrae of senile osteoporotic rats affected by intraperitoneal injection of Desferrioxamine (DFO) according to an embodiment of the present invention;
FIG. 2 is a schematic diagram of a micro CT three-dimensional reconstruction method for influencing femoral bone mass of an elderly osteoporosis rat through intraperitoneal injection of a deferoxamine drug, provided by an embodiment of the invention;
FIG. 3 is a schematic diagram illustrating the quantitative analysis result of the effect of the intraperitoneal injection of the deferoxamine on the femoral bone mass of the senile osteoporosis rat according to the embodiment of the present invention;
FIG. 4 is a schematic diagram of CCK-8 detecting the proliferation of BMSCs of generation P2 at different time points according to an embodiment of the present invention;
FIG. 5 is a schematic diagram of the effect of desferrioxamine drugs in alleviating the osteogenic/adipogenic differentiation imbalance of the BMSCs of an elderly rat according to an embodiment of the present invention;
FIG. 6 is a schematic diagram of the ability of a desferrioxamine drug provided by embodiments of the present invention to alleviate clonogenic behavior of the BMSCs in an elderly rat;
FIG. 7 is a graph showing confocal results of laser ablation of desferrioxamine drugs in an elderly rat;
FIG. 8 is a schematic illustration of the β -gal staining results provided by an embodiment of the invention showing that desferrioxamine drugs can alleviate aging in the BMSCs of elderly rats;
FIG. 9 is a schematic diagram of the real-time PCR results of the molecules related to the sternness and senescence of BMSCs according to the present invention.
Detailed Description
The technical solutions of the present invention will be described clearly and completely with reference to the accompanying drawings, and it should be understood that the described embodiments are some, but not all embodiments of the present invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Firstly, the treatment effect of the methanesulfonic acid Deferoxamine (DFO) for injection on the osteoporosis of the aged rats is defined
The treatment effect of deferoxamine mesylate (trade name: Desfen) for injection at different doses on osteoporosis of aged rats is examined by using a model of the aged rats of 12 months old. Grouping experiments: a 12-month-old high dose group (60mg/kg, n-7), a low dose group (20mg/kg, n-6), a saline group (n-6), and a 2-month-old normal control group (n-6). Intraperitoneal injection is continued for 8 weeks, and 3 times per week (in the present application, deferoxamine mesylate is administered by a route including, but not limited to, intravenous bolus injection, intramuscular bolus injection, and intraperitoneal injection, with intraperitoneal injection being the preferred route of administration).
micct and histological results show: compared with 2-month-old rats, the bone mass of a normal saline group of a 12-month-old rat is remarkably lost, related parameters such as BV/TV, Tb.N and Tb.Th are remarkably reduced, and the trabecular bone separation degree Tb.Sp and the structural model parameter SMI are remarkably increased. When 20mg/kg of deferoxamine mesylate for injection is administered, parameters such as BV/TV and the like have no statistical difference with the group without administration, and when 60mg/kg of deferoxamine mesylate for injection is administered, the osteoporosis phenotype of the aged rats can be obviously improved, and the statistic difference with the group without administration at 12 months of age has BV/TV, Tb.N and Tb.Sp. Our results show that high dose of deferoxamine mesylate (60mg/kg) has significant therapeutic effect on osteoporosis in aged rats. Desferrioxamine DFO is currently used clinically in the treatment of multiferroic patients and can stabilize HIF-1 α levels in cells by inhibiting PHDs activity, and our findings suggest a novel role for desferrioxamine in the treatment of osteoporosis.
Referring to fig. 1, the histological results of the intraperitoneal injection of Desferrioxamine (DFO) affected vertebral bone mass in elderly osteoporotic rats are shown. Compared with 2-month-old rats, the number of trabecular bone of vertebra in the 12-month-old group is obviously reduced, and the number of trabecular bone of vertebra is obviously increased after the administration of DFO abdominal cavity, which shows that the hypoxia mimic agent deferoxamine for stabilizing HIF-1 alpha can obviously improve the bone loss of the osteoporosis rats.
Fig. 2-3 show the results of the micro ct three-dimensional reconstruction and quantitative analysis of the effect of the intraperitoneal injection of the deferoxamine on the femoral bone mass of the senile osteoporosis rats. The results of the analysis of the micro CT scan of the thighbone of the rats show that the cancellous bone mass of the thighbone of the rats at 12 months of age is obviously less than that of the rats at 2 months of age, the cancellous bone mass is obviously increased after the administration of the deferoxamine drug, and the results of the quantitative analysis show that although the low-dose BV/TV is increased, no statistical difference exists, and the BV/TV is obviously increased in the high-dose group (P < 0.05). The 60mg/kg intraperitoneal injection of the deferoxamine medicine can obviously improve the osteoporosis phenotype of the aged rats.
Secondly, the fact that the intraperitoneal injection of a deferoxamine Drug (DFO) can improve the age-increasing change of BMSCs of a 12-month-old rat is proved.
Differences in proliferation, differentiation, aging, etc. of 2-month-old and 12-month-old rat BMSCs were examined. Consistent with the results reported in the literature, BMSCs were decreased in proliferation ability, decreased in osteogenic differentiation and mineralization ability, increased in adipogenic differentiation, decreased in colony formation ability, aging (β -gal) and increased in ROS level in rats of 12 months of age with increasing age, as compared to BMSCs in rats of 2 months of age. The deferoxamine drug (60mg/kg) is injected into the abdominal cavity for 10 days, and then BMSCs are separated, amplified and cultured, and then detected, and the deferoxamine drug is found to improve the biological obstacle of the BMSCs of a 12-month-old rat.
As shown in FIG. 4, CCK-8 measures the proliferation of BMSCs at P2 generations at different time points. The results show that the proliferation rate of the BMSCs of the P3 generation in 12M rats is slower than that of the BMSCs aged 2 months at different time points of day1, day2 and day3, and the proliferation rate is accelerated after the deferoxamine drug is injected, which indicates that the deferoxamine drug can relieve the defect of the proliferation capacity of the BMSCs of the aged rats.
As shown in fig. 5, desferrioxamine drugs were able to alleviate the osteogenic/adipogenic differentiation imbalance of the BMSCs in the aged rats. The results of alkaline phosphatase (ALP) staining and alizarin red staining show that the osteogenic differentiation capacity of 12M rat BMSCs is obviously reduced compared with that of 2M rat BMSCs, but the osteogenic differentiation disorder of the 12M rat BMSCs injected with the deferoxamine drug is obviously improved, and the ALP staining color and the number of mineralized nodules are close to that of the 2M rat BMSCs. The results of oil red O staining showed that the adipogenic differentiation capacity of 12M rat BMSCs was increased as compared to 2M rat BMSCs with increasing age, and decreased after the injection of the desferrioxamine drug. The deferoxamine drug is shown to alleviate osteogenic/adipogenic differentiation disorder of the BMSCS of the elderly rats.
As shown in FIG. 6, the desferrioxamine drug was able to alleviate clonogenic capacity of BMSCs in older rats. Primary rat BMSCs were isolated, mononuclear cells were inoculated into T75 flasks, clone numbers of each group of cells were observed by day9, and the count results were 2M: 122, the number of the channels is 122; 12M: 39 are used; 12M + DFO: 73 pieces of the Chinese herbal medicines. P2 generation cells were seeded at 2 × 103/well in 6-well plates, day9 cells were fixed, stained with hematoxylin, showing that 12M groups had significantly fewer BMSCs clones than 2M groups, and that the clonogenic capacity of BMSCs was significantly increased after the injection of deferoxamine.
As shown in fig. 7, confocal laser results show that desferrioxamine drugs can reduce ROS levels in older rats. Rosu is a positive control result of adding Rosu induced active oxygen level to BMSCs in the 2M group. The active oxygen level of the BMSCs at the age of 12 months is obviously higher than that of the BMSCs at the age of 2 months, and the active oxygen level of the BMSCs is obviously reduced after the deferoxamine is injected.
As shown in FIG. 8, the β -gal staining results show that the desferrioxamine drug can alleviate aging in the BMSCs of the aged rats. The number of the BMSCs beta-Gal positive cells of the P3 generation 12-month-old rat is obviously increased compared with the BMSCs of the 2-month-old rat, and the number of the BMSCs beta-Gal positive cells of the 12-month-old rat after the deferoxamine is injected is obviously reduced compared with the normal saline injection group.
FIG. 9 shows the real-time PCR results of the molecules related to the sternness and senescence of BMSCs. The drying property of the BMSCs of the 12M rat is maintained, the Nanog which is a key molecule is obviously reduced, and the BMSCs are partially increased after the deferoxamine is injected. Oct-4 was not statistically different. The aging-related molecules P16, P21 and P53 in the 12M group are higher than those in the 2M group, and P16, P21 and P53 are partially reduced after deferoxamine is injected.
Finally, it should be noted that: the above embodiments are only used to illustrate the technical solution of the present invention, and not to limit the same; while the invention has been described in detail and with reference to the foregoing embodiments, it will be understood by those skilled in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some or all of the technical features may be equivalently replaced; and the modifications or the substitutions do not make the essence of the corresponding technical solutions depart from the scope of the technical solutions of the embodiments of the present invention.
Claims (5)
1. Application of deferoxamine mesylate for injection in treating aging of bone marrow stem cells and bone-aging.
2. The use of deferoxamine mesylate for injection according to claim 1 for the treatment of aging bone loss and bone marrow stem cells, wherein the deferoxamine mesylate is administered by a route selected from the group consisting of, but not limited to, bolus i.v., bolus i.m. and intraperitoneal.
3. The use of deferoxamine mesylate for injection according to claim 1, wherein the deferoxamine mesylate is administered at a dose of 20-60mg/kg per day for the treatment of age-related bone loss and bone marrow stem cell senescence.
4. The use of deferoxamine mesylate for injection according to claim 1, wherein the deferoxamine mesylate is injected 2-5 times per week for the treatment of age-related bone loss and bone marrow stem cell senescence.
5. The use of deferoxamine mesylate for injection according to claim 1, wherein the deferoxamine mesylate for injection is for 6-10 weeks.
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