Icariin promotes osteogenic differentiation of mesenchymal stem cells through upregulating HOTTIP

doi:10.5246/jcps.2026.06.038

Abstract

Abstract:

Mesenchymal stem cells (MSCs) have emerged as a highly promising strategy in tissue repair engineering owing to their robust self-renewal capacity and multidirectional differentiation potential. Among the regulatory factors governing MSC fate determination, the long non-coding RNA (lncRNA) HOTTIP has been identified as a pivotal modulator of osteogenic differentiation and the maintenance of bone homeostasis. Mechanistically, HOTTIP regulates osteogenic commitment through orchestrating chromatin remodeling and transcriptional activation of key osteogenesis-related genes, highlighting its potential value as a therapeutic target in bone regeneration strategies. Icariin (ICA), a bioactive flavonoid glycoside isolated from Epimedium, has been reported to promote osteogenic differentiation and enhance bone metabolic activity. However, the precise molecular interplay between ICA and lncRNA-mediated epigenetic regulation during osteogenesis remains largely unexplored, and further investigation is required to elucidate their potential synergistic roles in bone tissue engineering. In the present study, our results demonstrated that ICA exerted no significant cytotoxic effects on bone marrow-derived mesenchymal stem cells (BMSCs) at concentrations below 50 μM. Treatment with 5 and 10 μM ICA markedly enhanced alkaline phosphatase (ALP) activity and Alizarin Red S (ARS) staining intensity, accompanied by a significant upregulation of osteogenic-related gene expression, collectively indicating that ICA effectively promoted osteogenic differentiation. Notably, we further observed that lncRNA HOTTIP expression was upregulated in a dose-dependent manner following ICA treatment, and the pro-osteogenic effects of ICA were effectively abolished in HOTTIP-depleted MSCs. In addition, the expression level of β-catenin, a core component of the canonical Wnt/β-catenin signaling pathway, was markedly reduced in HOTTIP-depleted MSCs. While ICA significantly promoted β-catenin expression in MSCs from wild-type (WT) mice, this stimulatory effect was absent in HOTTIP-deficient MSCs. Taken together, these findings indicated that ICA promoted osteogenic differentiation of MSCs through the upregulation of β-catenin signaling via enhanced expression of lncRNA HOTTIP, thereby revealing a previously unrecognized lncRNA-mediated epigenetic mechanism underlying ICA-induced osteogenesis.

Key words: Icariin, LncRNA HOTTIP, Bone marrow mesenchymal stem cells, Osteogenic differentiation, Wnt/β-catenin

Supporting:

Jiang Shao, Jinfang Zhang, Yage Zhang, Dongxiang Zhan. Icariin promotes osteogenic differentiation of mesenchymal stem cells through upregulating HOTTIP[J]. Journal of Chinese Pharmaceutical Sciences, 2026, 35(6): 538-551.

Figures/Tables 7

References 38

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