A novel macrolide–Del-1 axis to regenerate bone in old age
Kridtapat Sirisereephap,
Hikaru Tamura,
Jong-Hyung Lim,
Meircurius Dwi Condro Surboyo,
Toshihito Isono,
Takumi Hiyoshi,
Andrea L. Rosenkranz,
Yurie Sato-Yamada,
Hisanori Domon,
Akari Ikeda,
Tomoyasu Hirose,
Toshiaki Sunazuka,
Nagako Yoshiba,
Hiroyuki Okada,
Yutaka Terao,
Takeyasu Maeda,
Koichi Tabeta,
Triantafyllos Chavakis,
George Hajishengallis,
Tomoki Maekawa
Affiliations
Kridtapat Sirisereephap
Division of Periodontology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8514, Japan; Center for Advanced Oral Science, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8514, Japan; Faculty of Dentistry, Chulalongkorn University, Bangkok 10330, Thailand
Hikaru Tamura
Center for Advanced Oral Science, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8514, Japan
Jong-Hyung Lim
Department of Basic and Translational Sciences, Laboratory of Innate Immunity and Inflammation, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Meircurius Dwi Condro Surboyo
Center for Advanced Oral Science, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8514, Japan; Faculty of Dentistry, Universitas Airlangga, Surabaya 60132, Indonesia
Toshihito Isono
Division of Microbiology and Infectious Diseases, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8514, Japan
Takumi Hiyoshi
Center for Advanced Oral Science, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8514, Japan
Andrea L. Rosenkranz
Center for Advanced Oral Science, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8514, Japan
Yurie Sato-Yamada
Center for Advanced Oral Science, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8514, Japan
Hisanori Domon
Division of Microbiology and Infectious Diseases, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8514, Japan
Akari Ikeda
Ōmura Satoshi Memorial Institute, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan; Graduate School of Infection Control Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan
Tomoyasu Hirose
Ōmura Satoshi Memorial Institute, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan; Graduate School of Infection Control Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan
Toshiaki Sunazuka
Ōmura Satoshi Memorial Institute, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan; Graduate School of Infection Control Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan
Nagako Yoshiba
Division of Cariology, Operative Dentistry and Endodontics, Department of Oral Health Science, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8514, Japan
Hiroyuki Okada
Laboratory of Clinical Biotechnology, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
Yutaka Terao
Division of Microbiology and Infectious Diseases, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8514, Japan
Takeyasu Maeda
Center for Advanced Oral Science, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8514, Japan
Koichi Tabeta
Division of Periodontology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8514, Japan
Triantafyllos Chavakis
Institute for Clinical Chemistry and Laboratory Medicine, University Hospital and Faculty of Medicine, Technische Universität Dresden, Dresden, Germany; Centre for Cardiovascular Science, Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, UK
George Hajishengallis
Department of Basic and Translational Sciences, Laboratory of Innate Immunity and Inflammation, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Tomoki Maekawa
Center for Advanced Oral Science, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8514, Japan; Corresponding author
Summary: Aging is associated with increased susceptibility to chronic inflammatory bone loss disorders, such as periodontitis, in large part due to the impaired regenerative potential of aging tissues. DEL-1 exerts osteogenic activity and promotes bone regeneration. However, DEL-1 expression declines with age. Here we show that systemically administered macrolide antibiotics and a non-antibiotic erythromycin derivative, EM-523, restore DEL-1 expression in 18-month-old (“aged”) mice while promoting regeneration of bone lost due to naturally occurring age-related periodontitis. These compounds failed to induce bone regeneration in age-matched DEL-1-deficient mice. Consequently, these drugs promoted DEL-1-dependent functions, including alkaline phosphatase activity and osteogenic gene expression in the periodontal tissue while inhibiting osteoclastogenesis, leading to net bone growth. Macrolide-treated aged mice exhibited increased skeletal bone mass, suggesting that this treatment may be pertinent to systemic bone loss disorders. In conclusion, we identified a macrolide–DEL-1 axis that can regenerate bone lost due to aging-related disease.
