STAT-3 regulation of CXCR4 is necessary for the prenylflavonoid Icaritin to enhance mesenchymal stem cell proliferation, migration and osteogenic differentiation

• Published in: Biochimica et biophysica acta Vol. 1862; no. 7; pp. 1680 - 1692
• Main Authors: Lim, R.Z.L., Li, L., Yong, E.L., Chew, N.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.07.2018
• Subjects: Anabolic therapeutics; Calcium - analysis; Cell Adhesion; Cell Differentiation; Cell Division; Cell Movement; Cells, Cultured; Core Binding Factor Alpha 1 Subunit - biosynthesis; Core Binding Factor Alpha 1 Subunit - genetics; Drug Evaluation, Preclinical; Flavonoids - pharmacokinetics; Humans; Icaritin; Mesenchymal Stromal Cells - drug effects; Mesenchymal Stromal Cells - metabolism; Migration; MSC; Osteoblasts - cytology; Osteogenic differentiation; Osteoporosis - drug therapy; Phosphorylation; Proliferation; Promoter Regions, Genetic; Protein Processing, Post-Translational; Receptors, CXCR4 - biosynthesis; Receptors, CXCR4 - genetics; Receptors, CXCR4 - physiology; RNA Interference; RNA, Small Interfering - genetics; STAT3 Transcription Factor - antagonists & inhibitors; STAT3 Transcription Factor - physiology; Transcription, Genetic; Up-Regulation; Proliferation; Anabolic therapeutics; MSC; Osteogenic differentiation; Migration; Icaritin
• ISSN: 0304-4165; 0006-3002; 1872-8006
• DOI: 10.1016/j.bbagen.2018.04.016

Mesenchymal stem cell (MSC) dysfunction has been implicated in the pathogenesis of osteoporosis. MSCs derived from osteoporotic subjects demonstrate significant impairment in proliferation, adhesion and chemotaxis, and osteogenic differentiation, leading to reduced functional bone-forming osteoblasts and ultimately nett bone loss and osteoporosis. Epimedium herbs and its active compound Icaritin (ICT) have been used in Chinese ethnopharmacology for the treatment of metabolic bone diseases. Using an in-vitro cell culture model, we investigated the benefits of ICT treatment in enhancing MSC proliferation, migration and osteogenic differentiation, and provide novel data to describe its mechanism of action. ICT enhances MSC proliferation, chemotaxis to stromal cell-derived factor-1 (SDF-1) and osteogenic differentiation through the activation of signal transduction activator transcription factor 3 (STAT-3), with a consequential up-regulation in the expression and activity of cysteine (C)-X-C motif chemokine receptor 4 (CXCR4). These findings provide a strong basis for future clinical studies to confirm the therapeutic potential of ICT for the prevention and treatment of osteoporosis and fragility fractures. •Icaritin enhances human MSC proliferation, motility and osteogenic differentiation.•Icaritin-induced increase of essential MSC functions is through the STAT-3/CXCR4 pathway.•Icaritin may be a potential therapeutic for improving bone health as it enhances MSC functions critical for bone formation.