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

doi:10.1016/j.isci.2024.108798

A novel macrolide-Del-1 axis to regenerate bone in old age

iScience. 2024 Jan 4;27(2):108798. doi: 10.1016/j.isci.2024.108798. eCollection 2024 Feb 16.

Authors

Kridtapat Sirisereephap^{1

2

3}, Hikaru Tamura², Jong-Hyung Lim⁴, Meircurius Dwi Condro Surboyo^{2

5}, Toshihito Isono⁶, Takumi Hiyoshi², Andrea L Rosenkranz², Yurie Sato-Yamada², Hisanori Domon⁶, Akari Ikeda^{7

8}, Tomoyasu Hirose^{7

8}, Toshiaki Sunazuka^{7

8}, Nagako Yoshiba⁹, Hiroyuki Okada¹⁰, Yutaka Terao⁶, Takeyasu Maeda², Koichi Tabeta¹, Triantafyllos Chavakis^{11

12}, George Hajishengallis⁴, Tomoki Maekawa²

Affiliations

¹ Division of Periodontology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8514, Japan.
² Center for Advanced Oral Science, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8514, Japan.
³ Faculty of Dentistry, Chulalongkorn University, Bangkok 10330, Thailand.
⁴ Department of Basic and Translational Sciences, Laboratory of Innate Immunity and Inflammation, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁵ Faculty of Dentistry, Universitas Airlangga, Surabaya 60132, Indonesia.
⁶ Division of Microbiology and Infectious Diseases, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8514, Japan.
⁷ Ōmura Satoshi Memorial Institute, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
⁸ Graduate School of Infection Control Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
⁹ 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.
¹⁰ Laboratory of Clinical Biotechnology, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.
¹¹ Institute for Clinical Chemistry and Laboratory Medicine, University Hospital and Faculty of Medicine, Technische Universität Dresden, Dresden, Germany.
¹² Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.

Abstract

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.

Keywords: Age; Immunology; Small molecule.

Abstract

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