Development of antiresorptive therapy targeting immunoglobulin-like receptors

Research Project

Project/Area Number	17H04309
Research Category	Grant-in-Aid for Scientific Research (B)
Allocation Type	Single-year Grants
Section	一般
Research Field	Orthopaedic surgery
Research Institution	Hokkaido University
Principal Investigator	Takahata Masahiko 北海道大学, 医学研究院, 准教授 (40374368)
Co-Investigator(Kenkyū-buntansha)	須田廣美 (木村―須田) 公立千歳科学技術大学, 理工学部, 教授 (00574857) 古川潤一北海道大学, 医学研究院, 特任准教授 (30374193)
Project Period (FY)	2017-04-01 – 2021-03-31
Project Status	Completed (Fiscal Year 2020)
Budget Amount *help	¥17,030,000 (Direct Cost: ¥13,100,000、Indirect Cost: ¥3,930,000) Fiscal Year 2020: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000) Fiscal Year 2019: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000) Fiscal Year 2018: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000) Fiscal Year 2017: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
Keywords	破骨細胞 / 骨吸収 / 免疫受容体 / 骨粗鬆症 / 骨破壊性疾患 / Siglec-15 / シグレック１５ / 骨吸収抑制剤 / ステロイド / 糖鎖 / 骨吸収抑制薬 / 免疫グロブリン様受容体
Outline of Final Research Achievements	While existing bone resorptive agents have a strong inhibitory effect on osteoclasts, they inhibit physiological bone resorption and bone growth by strongly suppressing bone metabolism and bone resorption in the bone growth plate. In this study, we conducted an exploratory study of therapeutic targets that selectively suppress pathological bone resorption without adversely affecting bone remodeling and bone growth. Among the immunoglobulin-like receptor molecules (IgLR) that are important for osteoclast differentiation and activation, Siglec-15 has a therapeutic effect on postmenopausal osteoporosis in which the bone remodeling balance is disturbed, and also on pediatric steroid-induced osteoporosis without causing growth disorders.
Academic Significance and Societal Importance of the Research Achievements	破骨細胞の分化や活性化に必須の免疫受容体チロシン活性化モチーフ(ITAM)依存性共刺激シグナル制御機構にはまだ不明な点が多い。本研究は、この経路を賦活化する複数の免疫受容体IgRLがそれぞれ異なる役割をもつことを示すとともに、その中でSiglec-15がもっとも重要な役割をもつことを明らかにした。Siglec-15は高齢者に生じる骨粗鬆症だけでなく、ステロイドや先天性疾患などによって生じる小児骨粗鬆症に対しても適応可能なきわめて有望な治療ターゲットであることを明らかにした。