疾病动物模型,骨质疏松症 z-bio 2021-10-22 803

　　Osteoporosis is a systemic bone disease characterized by low bone mass, destruction of bone microstructure, increased bone fragility, and increased sensitivity to gastric fractures. It is characterized by calcium salt and bone tissue. The matrix is usually calcified, but the amount of bone tissue per unit volume is reduced. Pathological anatomy showed that the cortical bone was thin, with many holes, and the trabecula was sparse and even ruptured. Clinically, bone mineral density (BMD) can be used as an indicator of osteoporosis diagnosis and fracture risk assessment. Osteoporosis is a group of systemic metabolic bone diseases caused by many reasons. According to the classification of the cause, it can be divided into primary osteoporosis and secondary osteoporosis. Among them, primary osteoporosis accounts for more than 90%, including senile osteoporosis, postmenopausal osteoporosis and juvenile idiopathic osteoporosis. Secondary osteoporosis is mainly caused by diseases or drugs. Factors and glucocorticoids cause osteoporosis. Hormonal-induced osteoporosis is the most common. In addition, special physiological conditions such as pregnancy and breastfeeding can easily induce osteoporosis. The animal models currently used in osteoporosis research mainly include spontaneous osteoporosis models, induced osteoporosis models and transgenic animals. Among them, the induced osteoporosis model is the most widely used method, and the most commonly used methods are ovarian castration, drug therapy, abolition and nutrition. Model animals are mainly rats, rabbits, ovaries, dogs, pigs, etc. Each animal has its own advantages and disadvantages in research applications.

　　Rats are the earliest and most widely used model animals in osteoporosis research. The first bilateral ovariectomized female rat model established by Saville et al. in 1969 is a classic model for studying postmenopausal osteoporosis. However, there are still some limitations in using rats as model animals. (1) The rat bone cortex lacks the Haval system, which is unlikely to cause fragility fractures. It is not suitable for studying the changes of bone cortex in the process of osteoporosis. (2) The bone epi of a long mouse will not close for life. , The bone reconstruction cycle is short, and the continuous renewal of bone tissue interferes with the analysis of experimental results. ③ Rats are small in size and low in blood volume, but they are not. Repeated blood draws and bone biopsy are easy. Therefore, in recent years, large animals, such as dogs, sheep, and pigs, which have abundant reconstructions of the Haval system and are convenient for long-term experimental observation, are becoming model animals for osteoporosis research. However, dogs do not experience significant bone loss after ovarian and hysterectomy, so they should not be used in postmenopausal osteoporosis research. Ovarian bone biochemical indicators, histomorphology, bone density and other indicators have seasonal and daily rhythmic fluctuations that affect the experiment. .. Therefore, sheep and dogs are not ideal animals for studying osteoporosis. Since the 1950s, the successful breeding of miniature pigs has solved many of the above-mentioned problems and has gradually become a new type of osteoporosis model animal. The use of miniature pigs in osteoporosis research has the following unique advantages: (1) Hormonal regulation rules, continuous rash cycle, the cycle is 21 days ± 2.5 days. ②When the body weight reaches about 80 kg, the bones are mature and the vertebral bodies are similar. Humans are similar. ③Bone reconstruction and bone deformation are very similar to human bones, and the reconstructed parts of trabecular bone and cortical bone are the same as human bones. ④ Mini-pigs are ubiquitous animals, and their gastrointestinal tract structure is similar to that of the human body, which is convenient for oral administration. ⑤The volume is large and the blood volume is abundant, so it is possible to perform tissue biopsy and blood sampling many times. Commonly used piglet osteoporosis models mainly include low-calcium diet, glucocorticoid induction model, ovarian castration model and paralytic osteoporosis model.

　　(1) Glucocorticoid-induced osteoporosis model

　　For the model of osteoporosis induced by glucocorticoids in miniature pigs, there are two methods for oral prednisolone, 1.0 mg/kg orally for the first 8 weeks, and then 0.5 mg/kg orally. Accept it. A short-term effect of up to 34 weeks can be observed, and a long-term effect of up to 64 weeks should be observed. The second common method is to inject prednisolone 0.5mag/(kg?D) subcutaneously once a week. Five injections lasted 24-26 weeks. .. Either way, you can get the ideal model. Studies have shown that glucocorticoids can lead to impaired metabolism of calcium, phosphorus, vitamin D and parathyroid hormone in miniature pigs, promote bone resorption, and directly inhibit osteoblast activity, reduce bone formation rate and frequency, and significantly reduce. The amount of bone that causes osteoporosis, reduces bone formation and causes bone resorption is greater than the amount of bone formation. In the early stage, it is mainly manifested as serum bone alkaline phosphatase, blood calcium and other biochemical indicators, serum vitamin D, osteocalcin, parathyroid hormone, urine type I collagen amino terminal peptide (N-terminal peptide) Decline. )) and other indicators are significantly reduced. In tissue morphology, changes in serum length and cross-sectional area, thinning of porous trabeculae, and significant reduction in BMD. At the same time, the elastic limit and the biomechanical properties of the bone's maximum load are also severely damaged. Long-term use of glucocorticoids continues to accumulate this effect. The etiology and pathological changes of the osteoporosis model are very similar to that of human osteoporosis. It can maintain the state of osteoporosis for a long time. It is easy to operate, easy to operate, economical and effective, reproducible, and has good properties. Researchers used this model to study the biological role of vascular endothelial growth factor and other cytokines in osteoporosis, and to test the effectiveness of bisphosphonates and other drugs in the treatment of osteoporosis. In the future, due to the continuous in-depth study of osteoporosis and the continuous updating of treatment methods, the glucocorticoid-induced small osteoporosis model will have a broader application prospect. (2) Low-calcium diet combined with ovariectomy model

　　Mosekilde et al. reported that Sinclair mini-pigs were given 0.75% hypocalcemia when they were 4 months old and underwent bilateral oophorectomy when they were 10 months old. Reproduction postmenopausal osteoporosis. After modeling, the bone resorption of Sinclair miniature pigs accelerated. After 6 months of continuous 0.75% low-calcium diet, the vertebral body BMD decreased by 10%, and the central BMD of the bone and femur also decreased. The trabecular bone is reduced and the gap is reduced. Expansion characterized by increased bone resorption and decreased spongy bone mass. This animal model is a good model for studying the microstructure changes and strength remodeling of cancellous bone, and can well reflect the process of female perimenopausal bone loss. However, some studies have reported that the uterine blood vessels of miniature pigs are prone to rupture, so care should be taken when modeling.

　　(3) Discarded osteoporosis model

　　Abandoned osteoporosis animal model is also a commonly used model for the study of osteoporosis in miniature pigs. The modeling methods are mainly mechanical fixation, suspension method, tendonectomy and other fixation methods. , Generally, the limb suspension method is used to obtain the desired effect. The model can self-control the unbraked limbs to reduce the interference caused by various factors, eliminate the braking factors, and then gradually restore the bone quality.

　　(4) Other models

　　Spencer et al. found that lactating pigs on a high-phosphorus and low-calcium diet had severe bone loss, spontaneous osteoporosis, and vertebrae, femurs and phalanges. We found that it can cause multiple sclerosis. fracture. This model can simulate the pathological changes of osteoporosis in lactating women and study the effects of calcium and phosphorus on bone metabolism. In addition, the vertebral bodies of pigs are larger and resemble humans in structure. Some scholars use in vitro decalcification of ethylenediaminetetraacetic acid disodium dihydrate (EDTA-Na2) to create a biomechanical model of osteoporosis. These methods for modeling gastric osteoporosis in livestock can also be applied to miniature pigs.