Osteostat/tumor necrosis factor superfamily 18 inhibits osteoclastogenesis and is selectively expressed by vascular endothelial cells.
Vascular endothelial cells (EC) participate in the process of bone formation through the production of factors regulating osteoclast differentiation and function. In this study, we report the selective expression in primary human microvascular EC of Osteostat/TNF superfamily 18, a ligand of the TNF superfamily. Osteostat protein is detectable in human microvascular EC and is highly up-regulated by IFN-alpha and IFN-beta. Moreover, an anti-Osteostat antibody strongly binds to the vascular endothelium in human tissues, demonstrating that the protein is present in the EC layers surrounding blood vessels. Functional in vitro assays were used to define Osteostat involvement in osteoclastogenesis. Both recombinant and membrane-bound Osteostat inhibit differentiation of osteoclasts from monocytic precursor cells. Osteostat suppresses the early stage of osteoclastogenesis via inhibition of macrophage colony-stimulating factor-induced receptor activator of NF-kappaB (RANK) expression in the osteoclast precursor cells. This effect appears to be specific for the differentiation pathway of the osteoclast lineage, because Osteostat does not inhibit lipopolysaccharide-induced RANK expression in monocytes and dendritic cells, or activation-induced RANK expression in T cells. These findings demonstrate that Osteostat is a novel regulator of osteoclast generation and substantiate the major role played by the endothelium in bone physiology.
Nardelli
Bernardetta
B
Human Genome Sciences, Inc., Rockville, Maryland 20850, USA.
Zaritskaya
Liubov
L
McAuliffe
William
W
Ni
Yansong
Y
Lincoln
Clint
C
Cho
Yun Hee
YH
Birse
Charles E
CE
Halpern
Wendy
W
Ullrich
Stephen
S
Moore
Paul A
PA
D000135:Acid Phosphatase / Q000378:metabolism; D001483:Base Sequence; D002462:Cell Membrane / Q000502:physiology; D017931:DNA Primers; D004730:Endothelium, Vascular / Q000502:physiology*; D006023:Glycoproteins / Q000235:genetics; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D009000:Monocytes / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D016366:Open Reading Frames; D010010:Osteoclasts / Q000502:physiology*; D053244:Osteoprotegerin; D012333:RNA, Messenger / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics; D011994:Recombinant Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000071681:Tartrate-Resistant Acid Phosphatase; D048069:Tumor Necrosis Factors / Q000235:genetics / Q000502:physiology*
D017931:DNA Primers; D006023:Glycoproteins; D007527:Isoenzymes; D053244:Osteoprotegerin; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins; C506030:TNFRSF11B protein, human; C478967:TNFSF18 protein, human; D048069:Tumor Necrosis Factors; D000135:Acid Phosphatase; D000071681:Tartrate-Resistant Acid Phosphatase