Up until now, bone physiology has primarily been studied via bone-tissue sectioning and conventional histomorphometric analyses. A new approach by Junichi Kikuta of Osaka University in Japan and colleagues provides additional information on osteoclast behavior and activity in situ. While previous studies have identified RANKL as a critical factor in the terminal differentiation of osteoclasts, the findings, published in the the Journal of Clinical Investigation, describe the role of RANKL-expressing Th17 cells in inflammatory bone destruction.1
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The authors produced a fluorescent GFP fusion protein from the mouse Tcirg1 locus (a3-GFP mice), thereby labeling mature osteoclasts. They used the fluorescent labeling to calculate a cell deformation index that identified two states for mature osteoclasts: resorbing state (R) and nonresorbing (N) state. They also identified cells that were transitioning between the two states. To further their investigation, the authors developed a chemical fluorescent probe that was capable of detecting bone resorption at specific sites on the bone surface.
In their study, the authors describe how pretreatment of mice with fluorescently labeled RANKL reduced bone-tissue density and stimulated osteoclastogenesis. Moreover, they found that when labeled RANKL was injected intravenously into mice, moving osteoclasts swiftly became static cells, suggesting to the authors an N-to-R transition. This observation was confirmed when the authors applied RANKL to osteoclasts in vitro, and were able to convert N osteoclasts to R osteoclasts. RANKL-expressing Th17 cells had the same effect as RANKL on mature osteoclast function.
“Osteoclasts have been considered to destroy bones continuously once they are formed from monocytoid precursors, and thus to be short lived. By using our intravital bone-imaging technique, we first demonstrated that osteoclasts repeatedly undergo transition between resorbing ‘R’ states, which firmly stick to bones, and nonresorbing ‘N’ states, sliding on the bone surfaces. An inflammatory helper T-cell type, Th17, was shown to contribute to bone destruction by converting N-state osteoclasts into R-type by direct cell-to-cell contact, which is a novel point of action of T cells,” explained Masaru Ishii, MD, PhD, by e-mail. Dr. Ishii is an author on the paper and head of the laboratory where the research was performed.
He elaborated that he was surprised by the dynamic behavior of bone osteoclasts. He was also surprised that Th17 cells seemed to regulate the dynamic movement of osteoclasts by direct cell-to-cell contact. The team hypothesizes that Th17 cells meet mature osteoclasts on erosive surfaces of the inflammatory synovium.
Dr. Pullen is a medical writer based in the Chicago area.