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Serum 1,25-Dihydroxyvitamin D₃ Accumulates into the Fracture Callus during Rat Femoral Fracture Healing

Department of Orthopaedic Surgery (S.J., A.I., J.S., T.I., Y.S., Y.I.), Faculty of Medicine, Kyushu University, Fukuoka 812–82, Japan; Department of Biology (O.H.), Faculty of Science, Kyushu University, Fukuoka 812–82, Japan; Pharmacology Research Department (Y.A., T.O.), Teijin Institute for Bio-Medical Research, Hino, Tokyo 191, Japan; and Department of Orthopaedic Surgery (T.I.), School of Medicine, Kitasato University, Sagamihara 228, Japan

Address all correspondence and requests for reprints to: Seiya Jingushi, M.D., Ph.D., Department of Orthopaedic Surgery, Kyushu University, 3–1-1 Maidashi, Higashi-Ku, Fukuoka 812–82, Japan. E-mail: jingushi{at}ortho.med.kyushu-u.ac.jp

1,25-dihydroxyvitamin D₃ (1,25(OH)₂D₃) is thought to be an important systemic factor in the fracture repair process, but the mechanism of action of 1,25(OH)₂D₃ has not been clearly defined. In this study, the role of 1,25(OH)₂D₃ in the fracture repair process was analyzed in a rat closed femoral fracture model. The plasma concentration of 1,25(OH)₂D₃ rapidly decreased on day 3 and continued to decrease to 10 days after fracture. We assessed whether this decrease was based on the accelerated degradation or retardation of the synthesis rate of 1,25(OH)₂D₃ from 25(OH)D₃. After radiolabeled ³H-1,25(OH)₂D₃ or ³H-25(OH)D₃ was injected iv into fractured or control (unfractured) rats, the concentrations of 25(OH)D₃ and 1,25(OH)₂D₃ metabolites were measured by HPLC. The plasma concentrations of these radiolabeled metabolites in fractured group were similar to those in control rats early after operation. However, radioactivity in the femurs of fractured rats was higher than that of the control group. Furthermore, the radioactivity was concentrated in the callus of the fractured group analyzed by autoradiography. 1,25(OH)₂D₃ receptor gene expression was detected early after fracture and, additionally, both in the soft and hard callus on days 7 and 13 after fracture.

These results showed that the rapid disappearance of 1,25(OH)₂D₃ in the early stages after fracture was not due to either increased degradation or decreased synthesis of 1,25(OH)₂D₃, but rather to increased consumption. Further, these results suggest the possibility that plasma 1,25(OH)₂D₃ becomes localized in the callus and may regulate cellular events in the process of fracture healing.