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¹ Division of Biochemistry, Department of Molecular and Cellular Biology, Kobe University Graduate School of Medicine, Kobe, Japan
² Division of Gastroenterological Surgery, Department of Surgery, Kobe University Graduate School of Medicine, Kobe, Japan
³ Department of Medical Oncology, The First Affiliated Hospital, China Medical University, Shenyang, China
⁴ Division of Biochemistry, Faculty of Pharmaceutical Sciences, Himeji Dokkyo University, Himeji, Japan
⁵ Department of Pharmaceutical Health Care, Faculty of Pharmaceutical Sciences, Himeji Dokkyo University, Himeji, Japan
⁶ Child Health and Care Section, Department of Health Care Sciences, Himeji Dokkyo University, Himeji, Japan
⁷ Department of Laboratory Medicine, Kawasaki Medical School, Kurashiki, Japan
⁸ Hyogo Prefectural Institute of Public Health and Environmental Sciences, Kobe, Japan

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 P2X₇-nucleotide receptor and that deacetylation of -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 -tubulin is a critical reaction for osteoclast function. Pharmacological inhibition of -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 P2X₇ microtubular regulation pathway related to Syk for a therapeutic target in osteolytic diseases.

^* Correspondence: ytohyama{at}himeji-du.ac.jp