Modeled microgravity and hindlimb unloading sensitize osteoclast precursors to RANKL-mediated osteoclastogenesis

被引:68
|
作者
Saxena, Ritu [3 ]
Pan, George [4 ]
Dohm, Erik D. [5 ]
McDonald, Jay M. [1 ,2 ,6 ]
机构
[1] Univ Alabama, Dept Pathol, Birmingham, AL 35294 USA
[2] Univ Alabama, Dept Cell Biol, Birmingham, AL 35294 USA
[3] Univ Illinois, Coll Med Peoria, Dept Canc Biol & Pharmacol, Peoria, IL 61605 USA
[4] Emory Univ, Sch Med, Dept Pediat, Atlanta, GA 30329 USA
[5] Univ Alabama, Anim Resources Program, Birmingham, AL 35294 USA
[6] Vet Adm Med Ctr, Birmingham, AL 35233 USA
关键词
Modeled microgravity; Osteoblasts; Osteoclasts; Hindlimb unloading; Rotary cell culture system; MESENCHYMAL STEM-CELLS; MOUSE LONG BONES; SIMULATED WEIGHTLESSNESS; SPACE-FLIGHT; PARATHYROID-HORMONE; CANCELLOUS BONE; GROWING RATS; OSTEOBLAST DIFFERENTIATION; GENE-EXPRESSION; BED REST;
D O I
10.1007/s00774-010-0201-4
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Mechanical forces are essential to maintain skeletal integrity, and microgravity exposure leads to bone loss. The underlying molecular mechanisms leading to the changes in osteoblasts and osteoclast differentiation and function remain to be fully elucidated. Because of the infrequency of spaceflights and payload constraints, establishing in vitro and in vivo systems that mimic microgravity conditions becomes necessary. We have established a simulated microgravity (modeled microgravity, MMG) system to study the changes induced in osteoclast precursors. We observed that MMG, on its own, was unable to induce osteoclastogenesis of osteoclast precursors; however, 24 h of MMG activates osteoclastogenesis-related signaling molecules ERK, p38, PLC gamma 2, and NFATc1. Receptor activator of NFkB ligand (RANKL) (with or without M-CSF) stimulation for 3-4 days in gravity of cells that had been exposed to MMG for 24 h enhanced the formation of very large tartrate-resistant acid phosphatase (TRAP)-positive multinucleated (> 30 nuclei) osteoclasts accompanied by an upregulation of the osteoclast marker genes TRAP and cathepsin K. To validate the in vitro system, we studied the hindlimb unloading (HLU) system using BALB/c mice and observed a decrease in BMD of femurs and a loss of 3D microstructure of both cortical and trabecular bone as determined by micro-CT. There was a marked stimulation of osteoclastogenesis as determined by the total number of TRAP-positive multinucleated osteoclasts formed and also an increase in RANKL-stimulated osteoclastogenesis from precursors removed from the tibias of mice after 28 days of HLU. In contrast to earlier reported findings, we did not observe any histomorphometric changes in the bone formation parameters. Thus, the foregoing observations indicate that microgravity sensitizes osteoclast precursors for increased differentiation. The in vitro model system described here is potentially a valid system for testing drugs for preventing microgravity-induced bone loss by targeting the molecular events occurring in microgravity-induced enhanced osteoclastogenesis.
引用
收藏
页码:111 / 122
页数:12
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