ATP-induced osteoclast function: the formation of sealing-zone like structure and the secretion of lytic granules via microtubule-deacetylation under the control of Syk.
Osteoclasts are bone-resorbing cells which play an exclusive role in bone remodeling, but the molecular mechanisms of osteolysis, how osteoclasts are activated and how the lytic granules are finally released towards the bone matrix are poorly understood. Here we show that an energy molecule ATP induces osteolysis via P2X(7)-nucleotide receptor and that deacetylation of alpha-tubulin is essential for the whole process of osteolysis under the control of a tyrosine kinase Syk. By developing a traceable and reproducible in vitro analyzing system for osteoclast function, we found that ATP-signaling gives rise to two events simultaneously (i) cytoskeletal reorganization for the formation of sealing zones, ring-like adhesion structures which delimit the contact surface, and (ii) the delivery and secretion of lytic granules towards the delimited site on the matrix. We further found that deacetylation of alpha-tubulin is a critical reaction for osteoclast function. Pharmacological inhibition of alpha-tubulin deacetylation resulted in (i) failure of the sealing-zone like structure formation and (ii) ceased secretion of lytic granules. Additionally, kinetics of deacetylation was found to be regulated by Syk. These data suggest a novel P2X(7) microtubular regulation pathway related to Syk for a therapeutic target in osteolytic diseases.
Hazama
Ryoichi
R
Division of Biochemistry, Department of Molecular and Cellular Biology, Kobe University Graduate School of Medicine, Kobe, Japan.
Qu
Xiujuan
X
Yokoyama
Kunio
K
Tanaka
Chisato
C
Kinoshita
Emi
E
He
Jinsong
J
Takahashi
Shusuke
S
Tohyama
Kaoru
K
Yamamura
Hirohei
H
Tohyama
Yumi
Y
D000255:Adenosine Triphosphate / Q000494:pharmacology*; D001862:Bone Resorption; D003599:Cytoskeleton / Q000648:ultrastructure*; D018922:HL-60 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008870:Microtubules / Q000378:metabolism*; D010010:Osteoclasts / Q000166:cytology / Q000201:enzymology* / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D022142:Secretory Vesicles / Q000201:enzymology; D015398:Signal Transduction; D000072377:Syk Kinase
D047908:Intracellular Signaling Peptides and Proteins; D000255:Adenosine Triphosphate; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase