Icariin attenuates methotrexate chemotherapy‐induced bone marrow microvascular damage and bone loss in rats

• Published in: Journal of cellular physiology Vol. 234; no. 9; pp. 16549 - 16561
• Main Authors: Hassanshahi, Mohammadhossein, Su, Yu‐Wen, Khabbazi, Samira, Fan, Chia‐Ming, Tang, Qian, Wen, Xuesen, Fan, Jian, Chen, Ke‐Ming, Xian, Cory J.
• Format: Journal Article
• Language: English
• Published: 01.09.2019
• Subjects: angiogenesis; bone loss; bone marrow sinusoids; icariin; methotrexate
• ISSN: 0021-9541; 1097-4652
• DOI: 10.1002/jcp.28326

Methotrexate (MTX), a widely used antimetabolite in paediatric cancer to treatment, has been widely reported to cause bone loss and bone marrow (BM) microvascular (particularly sinusoids) damage. Investigations must now investigate how MTX‐induced bone loss and microvasculature damage can be attenuated/prevented. In the present study, we examined the potency of icariin, an herbal flavonoid, in reducing bone loss and the dilation/damage of BM sinusoids in rats caused by MTX treatment. Groups of young rats were treated with five daily MTX injections (0.75 mg/kg) with and without icariin oral supplementation until Day 9 after the first MTX injection. Histological analyses showed a significant reduction in the bone volume/tissue volume (BV/TV) fraction (%) and trabecular number in the metaphysis trabecular bone of MTX‐treated rats, but no significant changes in trabecular thickness and trabecular spacing. However, the BV/TV (%) and trabecular number were found to be significantly higher in MTX + icariin‐treated rats than those of MTX alone‐treated rats. Gene expression analyses showed that icariin treatment maintained expression of osteogenesis‐related genes but suppressed the induction of adipogenesis‐related genes in bones of MTX‐treated rats. In addition, icariin treatment attenuated MTX‐induced dilation of BM sinusoids and upregulated expression of endothelial cell marker CD31 in the metaphysis bone of icariin + MTX‐treated rats. Furthermore, in vitro studies suggest that icariin treatment can potentially enhance the survival of cultured rat sinusoidal endothelial cells against cytotoxic effect of MTX and promote their migration and tube formation abilities, which is associated with enhanced production of nitric oxide. Methotrexate (MTX), a widely used antimetabolite in paediatric cancer treatment, has been widely reported to cause bone loss and bone marrow (BM) microvascular (particularly sinusoids) damage, for which there are no preventative treatments. Using a rat model, the current study showed that icariin can prevent MTX treatment‐induced bone loss by stimulation of osteoblast differentiation/maturation and suppression of MTX‐induced adipogenic differentiation of BM stromal/stem cells, and that icariin may reduce the MTX‐induced BM sinusoidal damage potentially via direct effect on survival and migration/tube formation functions of BM sinusoidal endothelial cells probably via activation of eNOS/NO axis.