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Interleukin-6 Inhibits Receptor Activator of Nuclear Factor B Ligand-Induced Osteoclastogenesis by Diverting Cells into the Macrophage Lineage: Key Role of Serine⁷²⁷ Phosphorylation of Signal Transducer and Activator of Transcription 3

Institut National de la Santé et de la Recherche Médicale (L.D., M.Ba., C.C., M.Be., V.T., F.B., D.H.), ERI 7, and Université de Nantes (L.D., M.Ba., C.C., M.Be., V.T., F.B., D.H.), Nantes atlantique universités, Laboratoire de Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, EA3822, Nantes F-44035, France; and Centre Hospitalier Universitaire (D.H.), Hôtel Dieu, Nantes 86021, France

Address all correspondence and requests for reprints to: Drs. L. Duplomb and D. Heymann, EA3822-Institut National de la Santé et de la Recherche Médicale ERI 7 Laboratoire de Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, 1 rue Gaston Veil 44035 Nantes Cedex 1, France. E-mails: laurence.duplomb{at}univ-nantes.fr and dominique.heymann{at}univ-nantes.fr, respectively.

Osteoclasts are bone-resorptive cells that differentiate from hematopoietic precursors upon receptor activator of nuclear factor B ligand (RANKL) activation. Previous studies demonstrated that IL-6 indirectly stimulates osteoclastogenesis through the production of RANKL by osteoblasts. However, few data described the direct effect of IL-6 on osteoclasts. To investigate this effect, we used several models: murine RAW264.7 cells, mouse bone marrow, and human blood monocytes. In the three models used, the addition of IL-6 inhibited RANKL-induced osteoclastogenesis. Furthermore, IL-6 decreased the expression of osteoclast markers and up-modulated macrophage markers. To elucidate this inhibition, signal transducer and activator of transcription (STAT) 3, the main signaling molecule activated by IL-6, was analyzed. Addition of two STAT3 inhibitors completely abolished RANKL-induced osteoclastogenesis, revealing a key role of STAT3. We demonstrated that a basal level of phosphorylated-STAT3 on Serine⁷²⁷ associated with an absence of phosphorylation on Tyrosine⁷⁰⁵ is essential for osteoclastogenesis. Furthermore, a decrease of Serine⁷²⁷ phosphorylation led to an inhibition of osteoclast differentiation, whereas an increase of Tyrosine⁷⁰⁵ phosphorylation upon IL-6 stimulation led to the formation of macrophages instead of osteoclasts. In conclusion, we showed for the first time that IL-6 inhibits RANKL-induced osteoclastogenesis by diverting cells into the macrophage lineage, and demonstrated the functional role of activated-STAT3 and its form of phosphorylation in the control of osteoclastogenesis.

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