Mechanical load regulates bone growth via periosteal Osteocrin
Haruko Watanabe-Takano,
Hiroki Ochi,
Ayano Chiba,
Ayaka Matsuo,
Yugo Kanai,
Shigetomo Fukuhara,
Naoki Ito,
Keisuke Sako,
Takahiro Miyazaki,
Kazuki Tainaka,
Ichiro Harada,
Shingo Sato,
Yasuhiro Sawada,
Naoto Minamino,
Shu Takeda,
Hiroki R. Ueda,
Akihiro Yasoda,
Naoki Mochizuki
Affiliations
Haruko Watanabe-Takano
Department of Cell Biology, National Cerebral and Cardiovascular Center Research Institute, 6-1 Kishibe-shimmachi, Suita, Osaka 564-8565, Japan; Corresponding author
Hiroki Ochi
Department of Clinical Research, National Rehabilitation Center for Persons with Disabilities, 4-1 Namiki, Tokorozawa, Saitama 359-8555, Japan
Ayano Chiba
Department of Cell Biology, National Cerebral and Cardiovascular Center Research Institute, 6-1 Kishibe-shimmachi, Suita, Osaka 564-8565, Japan
Ayaka Matsuo
Omics Research Center, National Cerebral and Cardiovascular Center Research Institute, 6-1 Kishibe-shinmachi, Suita, Osaka 564-8565, Japan
Yugo Kanai
Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine and Faculty of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan
Shigetomo Fukuhara
Department of Molecular Pathophysiology, Institute of Advanced Medical Sciences, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan
Naoki Ito
Laboratory of Molecular Life Science, Institute of Biomedical Research and Innovation, Foundation for Biomedical Research and Innovation at Kobe, 6-7-6 Minatojima-Minamimachi, Chuo-ku, Kobe 650-0047, Japan
Keisuke Sako
Department of Cell Biology, National Cerebral and Cardiovascular Center Research Institute, 6-1 Kishibe-shimmachi, Suita, Osaka 564-8565, Japan
Takahiro Miyazaki
Department of Cell Biology, National Cerebral and Cardiovascular Center Research Institute, 6-1 Kishibe-shimmachi, Suita, Osaka 564-8565, Japan
Kazuki Tainaka
Department of System Pathology for Neurological Disorders, Center for Bioresources, Brain Research Institute, Niigata University, 1-757 Asahimachidori, Chuo-ku, Niigata 951-8585, Japan
Ichiro Harada
Medical Products Technology, Development Center, R&D headquarters, Canon Inc., 3-30-2, Shimomaruko, Ohta-ku, Tokyo 146-8501, Japan
Shingo Sato
Center for Innovative Cancer Treatment, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan
Yasuhiro Sawada
Department of Cell Biology, National Cerebral and Cardiovascular Center Research Institute, 6-1 Kishibe-shimmachi, Suita, Osaka 564-8565, Japan; Department of Clinical Research, National Rehabilitation Center for Persons with Disabilities, 4-1 Namiki, Tokorozawa, Saitama 359-8555, Japan; Department of Rehabilitation for Motor Functions, National Rehabilitation Center for Persons with Disabilities, 4-1 Namiki, Tokorozawa, Saitama 359-8555, Japan
Naoto Minamino
Omics Research Center, National Cerebral and Cardiovascular Center Research Institute, 6-1 Kishibe-shinmachi, Suita, Osaka 564-8565, Japan
Shu Takeda
Division of Endocrinology, Toranomon Hospital Endocrine Center, 2-2-2 Toranomon, Minato-ku, Tokyo 105-8470, Japan
Hiroki R. Ueda
CREST, Japan Science and Technology Agency, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan; Department of Systems Pharmacology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan; Laboratory for Synthetic Biology, RIKEN Center for Biosystems Dynamics Research, 1-3 Yamadaoka, Suita, Osaka 565-0871, Japan
Akihiro Yasoda
Clinical Research Center, National Hospital Organization Kyoto Medical Center, 1-1 Fukakusa-Mukaihatacho, Fushimi-ku, Kyoto 612-8555, Japan
Naoki Mochizuki
Department of Cell Biology, National Cerebral and Cardiovascular Center Research Institute, 6-1 Kishibe-shimmachi, Suita, Osaka 564-8565, Japan; CREST, Japan Science and Technology Agency, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan; Corresponding author
Summary: Mechanical stimuli including loading after birth promote bone growth. However, little is known about how mechanical force triggers biochemical signals to regulate bone growth. Here, we identified a periosteal-osteoblast-derived secretory peptide, Osteocrin (OSTN), as a mechanotransducer involved in load-induced long bone growth. OSTN produced by periosteal osteoblasts regulates growth plate growth by enhancing C-type natriuretic peptide (CNP)-dependent proliferation and maturation of chondrocytes, leading to elongation of long bones. Additionally, OSTN cooperates with CNP to regulate bone formation. CNP stimulates osteogenic differentiation of periosteal osteoprogenitors to induce bone formation. OSTN binds to natriuretic peptide receptor 3 (NPR3) in periosteal osteoprogenitors, thereby preventing NPR3-mediated clearance of CNP and consequently facilitating CNP-signal-mediated bone growth. Importantly, physiological loading induces Ostn expression in periosteal osteoblasts by suppressing Forkhead box protein O1 (FoxO1) transcription factor. Thus, this study reveals a crucial role of OSTN as a mechanotransducer converting mechanical loading to CNP-dependent bone formation.
