The Biological Effect Of RAS In The Process Of Osteoporosis Induced By Ageing Or Renal Injury

With the deepening of global ageing degree, the incidence of osteoporosis is risingyear by year. Osteoporosis is a systemic skeletal disease characterized by deteriorationin bone mass and micro-architecture, with increasing risk to fragility fractures.Osteoporosis fracture is the most serious pathological symptoms. Recent researchesshow that osteoporosis brings much pain and pressure to patients and their families aswell as overwhelming econimc burden to the society. The current prevention andtreatment approaches for osteoporosis are based on the known pathogenesis, however,the long-term clinical study shows that these methods, especially the drug treatment haslimitations, such as side effects, expensive cost and so on. Therefore, we need to explorethe new pathogenesis of osteoporosis and look for the potential therapeutic targets.Above all, the present research is performed on a new perspective-the local bonerenin-angiotensin system (RAS), to illustrate the biological effects of RAS in theprocess of osteoporosis induced by ageing or renal injury, it will provide potentialtherapeutic targets for drug research and development in the future.In part one, the biological effect of local bone RAS in the osteoporosis of ageingmice was investigated. Twelve-month-old and two-month-old ICR male mice wererespectively assigned to the ageing and young groups. Hematoxylin and eosin (H&E)staining was performed on paraffin-embedded bone sections. The proximal metaphysisof the tibia was scanned with Micro-CT. Expressions of genes and proteins wereanalyzed by polymerase chain reaction and Western blotting, respectively. The datashowed that the up-regulation of renin and angiotensinogen expression in the bonetissue of ageing mice contributed to the increased expression of angiotensin II whichthen led to bone loss and deterioration.In part two, the renal pathological changes induced by unilateral ureteralobstruction were investigated. Three-month-old C57BL/6J male mice were used in thestudy. These mice were subjected to unilateral ureteral obstruction or sham operation.All mice were killed on day7after the surgical operation. Kidney sections were stainedwith Masson’s trichrome and gene expression was analyzed by real-time PCR. The dataobtained in this study show that the ureteral obstruction leads to the alteration of renalvitamin D metabolic enzyme expression and calcium transporter abundance, which maysecondarily induce the abnormality of vitamin D endocrine system. Moreover, the study in this part successfully developed the unilateral obstructive nephropathy model, whichprovides the experimental basis for the next study.In part three, the biological effect of local bone RAS in the process of osteoporosisinduced by renal injury was investigated. Two-month-old ICR male mice were used inthe study. These mice were subjected to unilateral ureteral obstruction or shamoperation. All mice were killed on day7after the surgical operation. H&E staining wasperformed on paraffin-embedded bone sections. Expression of bone-specific genes wasanalyzed by real time polymerase chain reaction, and protein expression of RAScomponents was determined by Western blotting. The present study demonstrated thatthe obstructive nephropathy induced the deteriorations of bone mineralization and bonemicrostructure, and the underlying mechanisms are the reduction of bone formation andthe increase of bone resorption, which is mediated, at least partially through localangiotensin II signalling.Conclusion: it is concluded that both obstructive nephropathy and ageing havedefective effects on bone metabolism, which are attributed to the reducedosteoblast-involved bone formation and the increased osteoclast-involved boneresorption. These changes were mediated, at least partially, by angiotensin II signallingin local bone tissue.