Chi3L1 is a therapeutic target in bone metabolism and a potential clinical marker in patients with osteoporosis. (October 2022)

• Record Type: Journal Article
• Authors: Park, Kyung-Ran; Park, Jae-Il; Lee, Seongsoo; Yoo, Kyeongwon; Kweon, Gi-Ryang; Kwon, Il Keun; Yun, Hyung-Mun; Hong, Jin Tae
• Is Part Of: Pharmacological research. Volume 184(2022)
• Publication Date: 2022-10
• Subjects: BMP2 -- BMPRIa -- Bone metabolism -- Chi3L1 -- Osteoporosis; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2022.106423
• Languages: English
• ISSNs: 1043-6618

Abstract

Abstract: BMP2 is clinically used as an ectopic bone inducer and plays a significant role in bone development, formation, and diseases. Chitinase 3-like 1 protein (Chi3L1) is found in the skeletal system. However, Chi3L1-mediated bone metabolism and aging-related bone erosion via BMP2 signaling have not yet been demonstrated. Herein, Chi3L1 increased BMP2-induced osteoblast differentiation in mesenchymal precursor cells and human primary osteoblasts. Chi3L1 KO(-/-) showed abnormal bone development, and primary osteoblasts isolated from Chi3L1 KO(-/-) exhibited impaired osteoblast differentiation and maturation. Chi3L1 also potentiated BMP2 signaling and RUNX2 expression in primary osteoblasts. Chi3L1 interacted with BMPRIa, which increased the surface expression of BMPRIa and promoted BMP2 signaling to induce osteoblast differentiation. Chi3L1 KO(-/-) mice showed bone formation reduced with a decrease in RUNX2 expression in calvarial defects. Chi3L1 KO(-/-) mice exhibited aging-related osteoporotic bone loss with decreases in the levels of RUNX2 and OPG, while serum PYD level and osteoclast number increased. Chi3L1 increased OPG via non-canonical BMP2 signaling in osteoblasts, which suppressed osteoclastogenesis in BMMs. Furthermore, ROC analysis showed that serum Chi3L1 level clinically decreased in osteoporosis patients. Our findings demonstrate that Chi3L1 promotes bone formation, suppresses osteoclastogenesis, and prevents aging-related osteoporosis. Graphical Abstract: ga1 Highlights: Chi3L1–mediated BMP2 signaling increases osteoblast differentiation and bone formation via interaction with BMPRIa. Chi3L1 inhibits osteoclastogenesis and bone resorption through the induction of RUNX2 and OPG expression in osteoblasts. Chi3L1 is an important regulator in bone metabolism between osteoblasts and osteoclasts. Chi3L1 is an ideal target for the development of therapeutic agents with clinically used BMP2, and a potential biomarker.