TRAIL inhibits osteoclastic differentiation by counteracting RANKL-dependent p27Kip1 accumulation in pre-osteoclast precursors.
Experimental evidences indicate that the TNF family member TNF-related apoptosis inducing ligand (TRAIL) might be involved in modulating osteoclastic differentiation. The ability of recombinant soluble TRAIL to affect bone density in vivo was evaluated by using 4-week-old mice subcutaneously (s.c.) injected with TRAIL for 8 days. TRAIL injection induced a significant increase of tibia trabecular thickness and total bone mass in 4-week-old mice, accompanied by a significant decrease of TRAP serum levels, without modulation of osteocalcin and osteoprotegerin (OPG). Parallel experiments performed in vitro showed that inhibition of osteoclastic differentiation, induced by treatment of human peripheral blood osteoclast precursors with TRAIL, was associated to inhibition of receptor activator of nuclear factor kappa B ligand (RANKL)-induced accumulation of p27(Kip1). The potential role of p27(Kip1) pathway in mediating the anti-osteoclastic activity of TRAIL was further suggested by in vitro gene knock-down experiments performed in osteoclast precursor cultures. Taken together, our data strongly suggest that recombinant TRAIL inhibits osteoclastogenesis by inducing the ubiquitin-mediated degradation of p27(Kip1).
Zauli
Giorgio
G
Department of Biomedicine, University of Trieste, Trieste, Italy. zauli@units.it
Rimondi
Erika
E
Stea
Susanna
S
Baruffaldi
Fabio
F
Stebel
Marco
M
Zerbinati
Carlotta
C
Corallini
Federica
F
Secchiero
Paola
P
D000135:Acid Phosphatase / Q000032:analysis / Q000276:immunology; D000818:Animals; D056657:Cathepsin K; D002403:Cathepsins / Q000032:analysis / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D002467:Cell Nucleus / Q000378:metabolism; D002469:Cell Separation / Q000379:methods; D002478:Cells, Cultured; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000096:biosynthesis*; D004334:Drug Administration Schedule; D004797:Enzyme-Linked Immunosorbent Assay; D005456:Fluorescent Dyes; D006801:Humans; D007211:Indoles; D007279:Injections, Subcutaneous; D007527:Isoenzymes / Q000032:analysis / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D015675:Osteocalcin / Q000032:analysis; D010010:Osteoclasts / Q000187:drug effects* / Q000502:physiology; D053245:RANK Ligand / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology; D012995:Solubility; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000008:administration & dosage / Q000235:genetics / Q000494:pharmacology*; D000071681:Tartrate-Resistant Acid Phosphatase
D005456:Fluorescent Dyes; D007211:Indoles; D007527:Isoenzymes; D053245:RANK Ligand; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505654:Tnfsf10 protein, mouse; C505689:Tnfsf11 protein, mouse; D015675:Osteocalcin; D050760:Cyclin-Dependent Kinase Inhibitor p27; C007293:DAPI; D000135:Acid Phosphatase; C000605511:Acp5 protein, mouse; D000071681:Tartrate-Resistant Acid Phosphatase; D002403:Cathepsins; C534130:CTSK protein, human; D056657:Cathepsin K; C534132:Ctsk protein, mouse