title: Parathyroid hormone resets the cartilage circadian clock of the organ-cultured murine femur.
abstract: OBJECTIVE
  The circadian clock governs endogenous day-night variations. In bone, the metabolism and growth show diurnal rhythms. The circadian clock is based on a transcription-translation feedback loop composed of clock genes including Period2 (Per2), which encodes the protein period circadian protein homolog 2. Because plasma parathyroid hormone (PTH) levels show diurnal variation, we hypothesized that PTH could carry the time information to bone and cartilage. In this study, we analyzed the effect of PTH on the circadian clock of the femur.
  
  
  METHODS
  Per2::Luciferase (Per2::Luc) knock-in mice were used and their femurs were organ-cultured. The bioluminescence was measured using photomultiplier tube-based real-time bioluminescence monitoring equipment or real-time bioluminescence microscopic imaging devices. PTH or its vehicle was administered and the phase shifts were calculated. Immunohistochemistry was performed to detect PTH type 1 receptor (PTH1R) expression.
  
  
  RESULTS
  Real-time bioluminescence monitoring revealed that PTH reset the circadian rhythm of the Per2::Luc activity in the femurs in an administration time-dependent and dose-dependent manner. Microscopic bioluminescence imaging revealed that Per2::Luc activity in the growth plate and the articular cartilage showed that the circadian rhythms and their phase shifts were induced by PTH. PTH1R was expressed in the growth plate cartilage.
  
  
  CONCLUSIONS
  In clinical practice, teriparatide (PTH (1-34)) treatment is widely used for osteoporosis. We found that PTH administration regulated the femoral circadian clock oscillation, particularly in the cartilage. Regulation of the local circadian clock by PTH may lead to a more effective treatment for not only osteoporosis but also endochondral ossification in bone growth and fracture repair.
authors.affiliation: a 1 Department of Physiology and Systems Bioscience, Kyoto Prefectural University of Medicine.|b 2 Department of Orthopaedics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine.|c 3 Department of Musculoskeletal Chronobiology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine , Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Okubo
authors.affiliation: b 2 Department of Orthopaedics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine.
authors.forename: Hiroyoshi
authors.initials: H
authors.lastname: Fujiwara
authors.affiliation: a 1 Department of Physiology and Systems Bioscience, Kyoto Prefectural University of Medicine.|c 3 Department of Musculoskeletal Chronobiology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine , Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, Japan.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Minami
authors.affiliation: a 1 Department of Physiology and Systems Bioscience, Kyoto Prefectural University of Medicine.|b 2 Department of Orthopaedics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine.|c 3 Department of Musculoskeletal Chronobiology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine , Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Kunimoto
authors.affiliation: a 1 Department of Physiology and Systems Bioscience, Kyoto Prefectural University of Medicine.|b 2 Department of Orthopaedics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine.|c 3 Department of Musculoskeletal Chronobiology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine , Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, Japan.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Hosokawa
authors.affiliation: a 1 Department of Physiology and Systems Bioscience, Kyoto Prefectural University of Medicine.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Umemura
authors.affiliation: a 1 Department of Physiology and Systems Bioscience, Kyoto Prefectural University of Medicine.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Inokawa
authors.affiliation: b 2 Department of Orthopaedics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine.
authors.forename: Maki
authors.initials: M
authors.lastname: Asada
authors.affiliation: b 2 Department of Orthopaedics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine.
authors.forename: Ryo
authors.initials: R
authors.lastname: Oda
authors.affiliation: b 2 Department of Orthopaedics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine.|c 3 Department of Musculoskeletal Chronobiology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine , Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, Japan.
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Kubo
authors.affiliation: a 1 Department of Physiology and Systems Bioscience, Kyoto Prefectural University of Medicine.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Yagita
mesh_terms: D000818:Animals; D002358:Cartilage, Articular / Q000378:metabolism*; D002940:Circadian Rhythm / Q000187:drug effects*; D005260:Female; D005269:Femur / Q000378:metabolism*; D008297:Male; D051379:Mice; D010281:Parathyroid Hormone / Q000494:pharmacology*; D056950:Period Circadian Proteins / Q000187:drug effects*
chemical_list: D010281:Parathyroid Hormone; D056950:Period Circadian Proteins