The Roles Of MTOR Activation In Osteoclastogenesisi And Renal Stromal Cells

mTOR signaling pathway is one of the most crucial pathways in human,which can respond to multi-information,including growth factors,energy,nutrients,pressure and so on,regulate cell growth,differentiation,proliferation,autophagy as well as architecture of cytoskeleton via transcription and translation regulation.Gene Tsc1 which is an upstream molecular of mTOR always regulates mTOR negatively,and its mutation or deletion can active mTOR signaling continually.We crossbred LysM-Cre;Tsc1^f/f mice and Ctsk-Cre;Tsc1^f/f mice to activate mTOR signaling pathway in monocytes or osteoclasts respectively by specifically knocking out gene Tsc1,an inhibitor of mTOR signaling.The results showed that there was an increase in bone mass in both of the conditional knockout mouse lines,which could be rescued by rapamycin,an mTORC1 inhibitor.It was found that the formation of this phenotype was not related to the bone formation function of osteoblasts directly.Further studies suggested that the increased bone mass in LysM-Cre;Tsc1^f/f mice was mainly due to the defect of osteoclast fusion,even though mTOR activation promoted the proliferation of monocytes,but the defect of fusion resulted in a decrease in the number of mature osteoclasts.The attenuated ability of bone resorption resulted in increased bone mass.The increase of bone mass in Ctsk-Cre;Tsc1^f/f mice is mainly due to the loss of osteoclast function and bone resorption,even the number of mature osteoclasts was increased.Further study suggested this phenotype might be related to the destruction of actin and cytoskeleton.Tuberous Sclerosis Complex?TSC?is caused by mutations in TSC1 or TSC2.A survey of bone lesions in patients with tuberous sclerosis complex found that the bones of patients bore symptom of“osteosclerosis”and bone degradation was decreased,which were consistent with the results of the mouse model studies.The renal abnormalities associated with TSC include angiomyolipoma,cysts,and so on.We discovered that specific ablation of Tsc1 using the mesenchymal stem cell-osteoblast lineage markers induced cystogenesis in mice.Using Rosa-tdTomato mice,we found that Prx1 and Dermo1 labeled glomerulus and tubules cells.Tsc1 deficiency in Prx1 lineage cells developed mild cysts while Tsc1 deficiency in Osx lineage cells developed many cysts along the renal tubules.On the other hand,Tsc1deficiency in the Dermo1 lineage did not produce detectable phenotyical changes in the kidney.Cyst formation in Prx1-Cre;Tsc1^f/f and Osx-Cre;Tsc1^f/f mice were associated with increase in both proliferative and apoptotic cells in the affected tissue,and was largely suppressed by rapamycin.These results suggest that a portion of renal glomerulus and tubular cells express mesoderm-markers that may contribute to the development of cysts in TSC patients.