title: Osteoclastogenesis is negatively regulated by D-serine produced by osteoblasts.
abstract: We have shown the functional expression by chondrocytes of serine racemase (SR) which is responsible for the synthesis of D-serine (Ser) from L-Ser in cartilage. In this study, we evaluated the possible functional expression of SR by bone-forming osteoblasts and bone-resorbing osteoclasts. Expression of SR mRNA was seen in osteoblasts localized at the cancellous bone surface in neonatal rat tibial sections and in cultured rat calvarial osteoblasts endowed to release D-Ser into extracellular medium, but not in cultured osteoclasts differentiated from murine bone marrow progenitor cells. Sustained exposure to D-Ser failed to significantly affect alkaline phosphatase activity and Ca(2+) accumulation in cultured osteoblasts, but significantly inhibited differentiation and maturation in a concentration-dependent manner at a concentration range of 0.1-1 mM without affecting cellular survival in cultured osteoclasts. By contrast, L-Ser promoted osteoclastic differentiation in a manner sensitive to the inhibition by D-Ser. Matured osteoclasts expressed mRNA for the amino acid transporter B(0,+) (ATB(0,+) ) and the system alanine, serine, and cysteine amino acid transporter-2 (ASCT2), which are individually capable of similarly incorporating extracellular L- and D-Ser. Knockdown of these transporters by siRNA prevented both the promotion by L-Ser and the inhibition by D-Ser of osteoclastic differentiation in pre-osteoclastic RAW264.7 cells. These results suggest that D-Ser may play a pivotal role in osteoclastogenesis through a mechanism related to the incorporation mediated by both ATB(0,+) and ASCT2 of serine enantiomers in osteoclasts after the synthesis and subsequent release from adjacent osteoblasts.
authors.affiliation: Laboratory of Molecular Pharmacology, Division of Pharmaceutical Sciences, Kanazawa University Graduate School of Natural Science and Technology, Kanazawa, Ishikawa, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Takarada
authors.forename: Mika
authors.initials: M
authors.lastname: Takarada-Iemata
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Takahata
authors.forename: Daisuke
authors.initials: D
authors.lastname: Yamada
authors.forename: Tomomi
authors.initials: T
authors.lastname: Yamamoto
authors.forename: Yukari
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Eiichi
authors.initials: E
authors.lastname: Hinoi
authors.forename: Yukio
authors.initials: Y
authors.lastname: Yoneda
mesh_terms: D000469:Alkaline Phosphatase / Q000378:metabolism; D026905:Amino Acid Transport Systems / Q000378:metabolism; D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism / Q000502:physiology; D001862:Bone Resorption / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D002118:Calcium / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D019902:Chondrocytes / Q000378:metabolism / Q000502:physiology; D051379:Mice; D010006:Osteoblasts / Q000378:metabolism / Q000502:physiology*; D010010:Osteoclasts / Q000378:metabolism / Q000502:physiology*; D010012:Osteogenesis / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D019998:Racemases and Epimerases / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012694:Serine / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation / Q000235:genetics / Q000502:physiology; D000099300:Serine Racemase
chemical_list: D000469:Alkaline Phosphatase; D026905:Amino Acid Transport Systems; D002118:Calcium; D012333:RNA, Messenger; D019998:Racemases and Epimerases; D012694:Serine; D000099300:Serine Racemase