Disruption of biomineralization suppression mechanisms by chronic inflammation

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K09472
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 56020:Orthopedics-related
• Research Institution: Hokkaido University
• Principal Investigator: Ota Masahiro 北海道大学, 医学研究院, 客員研究員 (70823334)
• Co-Investigator(Kenkyū-buntansha): 高畑 雅彦 北海道大学, 医学研究院, 准教授 (40374368)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: 異所性石灰化 / 慢性炎症 / 石灰化抑制機構 / 炎症アンプ / IL-6 / ピロリン酸代謝 / 靭帯 / 線維芽細胞

Outline of Final Research Achievements

We tested whether local disruption of biomineralization suppression mechanisms by chronic inflammation is involved in ectopic calcification of tendons and ligaments. TNF-alpha and IL-6-stimulated fibroblasts from human ossified lesion of ligamentum flavum decreased the concentration of pyrophosphate, a calcification inhibitory molecule, but the results could not be explained solely by the behavior of ENPP1, ANK, and TNAP, which regulate pyrophosphate. When fibroblasts were cultured in the presence of TNFalpha or IL-6 in osteogenic induction medium, calcification was enhanced in the IL-6 group, while TNF-alpha stimulation inhibited calcification. In a rat Achilles tendon rupture model, ectopic calcification/osteogenesis was induced, and ossification showed a suppressive trend by anti-inflammation therapy.

Free Research Field

骨代謝学

Academic Significance and Societal Importance of the Research Achievements

生体内の様々な臓器にリン酸カルシウム結晶（ハイドロキシアパタイト）が沈着する『異所性石灰化』は痛みや臓器機能障害を引き起こす。リン酸カルシウム結晶はさらなる炎症を引き起すと考えられており、炎症アンプ（増強）がその障害を慢性化、重症化させる可能性がある。現在、この病態に対する治療薬はなく、unmet medical needsのひとつといえる。本研究ではIL-6刺激がこの異所性石灰化あるいは骨化と、その慢性化に関わる可能性が示されたことから、この経路を遮断するような治療法が症状悪化を防ぐ治療法になりうると考えられた。