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TRAIL inhibits osteoclastic differentiation by counteracting RANKL‐dependent p27 Kip1 accumulation in pre‐osteoclast precursors
Author(s) -
Zauli Giorgio,
Rimondi Erika,
Stea Susanna,
Baruffaldi Fabio,
Stebel Marco,
Zerbinati Carlotta,
Corallini Federica,
Secchiero Paola
Publication year - 2008
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.21165
Subject(s) - rankl , osteoclast , osteoprotegerin , chemistry , endocrinology , medicine , activator (genetics) , osteocalcin , in vivo , in vitro , rank ligand , receptor , tumor necrosis factor alpha , apoptosis , microbiology and biotechnology , alkaline phosphatase , biology , biochemistry , enzyme
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 . J. Cell. Physiol. 214:117–125, 2008. © 2007 Wiley‐Liss, Inc.