Decreased osteogenesis in mesenchymal stem cells derived from the aged mouse is associated with enhanced NF-κB activity.
Aging is associated with significant bone loss and delayed fracture healing. NF-κB activation is highly correlated with inflammatory-associated bone diseases including infection, wear particle exposure, and chronic inflammation during natural aging processes. The critical roles of NF-κB in both the pro-inflammatory response and osteoclast-mediated bone resorption have been well defined. However, the biological effects of NF-κB activation in mesenchymal stem cell (MSC)-mediated bone formation remain largely unknown. In the current study, bone marrow-MSCs were isolated from young (8 weeks old) and aged (72 weeks old) mice. NF-κB activity in MSCs at basal levels and under different biological conditions were determined by our recently established lentiviral vector-based luciferase reporter assay. We found that NF-κB activity was increased in aged MSCs at basal levels or when exposed to low dose (10 or 100 ng/ml) lipopolysaccharide (LPS); this effect was not seen when the cells were exposed to higher dose (1 μg/ml) LPS. During osteogenesis, NF-κB activity was increased in aged MSCs at weeks 1 and 2, but showed no significant difference at week 3. Both Smurf2 and TAZ, the NF-κB target genes that regulate osteogenic differentiation, were increased in aged MSCs. In addition, the expression of RANKL was dramatically increased, and OPG was decreased in aged MSCs. Our findings suggest that targeting NF-κB activity in MSCs has the potential to modulate aging-associated bone loss, or enhance bone-healing in aged patients. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:281-288, 2017.
Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, 300 Pasteur Drive, Palo Alto, California, 94304.
Tzu-Hua
TH
Lin
Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, 300 Pasteur Drive, Palo Alto, California, 94304.|Biomecanics and Bone and Joint Biomaterials Laboratory-UMR CNRS 7052, School of Medicine-Paris7 University, Paris, France.
Emmanuel
E
Gibon
Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, 300 Pasteur Drive, Palo Alto, California, 94304.
Florence
F
Loi
Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, 300 Pasteur Drive, Palo Alto, California, 94304.
Jukka
J
Pajarinen
Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, 300 Pasteur Drive, Palo Alto, California, 94304.|Faculty of Dentistry, Department of Oral and Maxillofacial Surgery, University of Chile-Conicyt, Santiago, Chile.
Luis A
LA
Córdova
Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, 300 Pasteur Drive, Palo Alto, California, 94304.
Akira
A
Nabeshima
Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, 300 Pasteur Drive, Palo Alto, California, 94304.
Laura
L
Lu
Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, 300 Pasteur Drive, Palo Alto, California, 94304.
Zhenyu
Z
Yao
Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, 300 Pasteur Drive, Palo Alto, California, 94304.|Department of Bioengineering, Stanford University, Stanford, California.
Stuart B
SB
Goodman
D000375:Aging / Q000502:physiology*; D000818:Animals; D002454:Cell Differentiation; D005822:Genetic Vectors; D016086:Lentivirus; D008297:Male; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism*; D010012:Osteogenesis; D053244:Osteoprotegerin / Q000378:metabolism; D053245:RANK Ligand / Q000378:metabolism
D016328:NF-kappa B; D053244:Osteoprotegerin; D053245:RANK Ligand; C506031:Tnfrsf11b protein, mouse; C505689:Tnfsf11 protein, mouse
NF-κB; RANKL/OPG; aging; mesenchymal stem cells; osteogenesis