Abstract
Cancer chemotherapy has been shown to induce long-term skeletal side effects such as osteoporosis and fractures; however, there are no preventative treatments. This study investigated the damaging effects of anti-metabolite methotrexate (MTX) subcutaneous injections (0.75 mg/kg BW) for five days and the potential protective benefits of daily oral gavage of fish oil at 0.5 mL/100 g BW (containing 375 mg of n-3 PUFA/100 g BW), genistein (2 mg/100 g BW), or their combination in young adult rats. MTX treatment alone significantly reduced primary spongiosa height and secondary spongiosa trabecular bone volume. Bone marrow stromal cells from the treated rats showed a significant reduction in osteogenic differentiation but an increase in adipogenesis ex vivo. Consistently, stromal cells had significantly higher mRNA levels of adipogenesis-related proliferator activator activated receptor-γ (PPAR-γ) and fatty acid binding protein (FABP4). MTX significantly increased the numbers of bone-resorbing osteoclasts and marrow osteoclast precursor cell pool while significantly enhancing the mRNA expression of receptor activator for nuclear factor kappa B ligand (RANKL), the RANKL/osteoprotegerin (OPG) ratio, interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) in the bone. Supplementary treatment with fish oil and/or genistein significantly preserved trabecular bone volume and osteogenesis but suppressed MTX-induced adipogenesis and increases in osteoclast numbers and pro-osteoclastogenic cytokine expression. Thus, Fish oil and/or genistein supplementation during MTX treatment enabled not only preservation of osteogenic differentiation, osteoblast number and bone volume, but also prevention of MTX treatment-induced increases in bone marrow adiposity, osteoclastogenic cytokine expression and osteoclast formation, and thus bone loss.
Highlights
Both clinical and animal studies have reported that chemotherapy causes adverse effects on bone, negatively impacting on bone remodeling and bone mass [1,2,3,4,5,6,7]
The current study investigated the damaging effects in osteogenesis, osteoclastogenesis and adipogenesis in long bones caused by MTX treatment and examined the protective effects and potential action mechanisms of supplementary treatments with fish oil and genistein
All supplemented groups (MTX+fish oil (FO), MTX+Gen, MTX+fish oil and genistein in combination (FO+Gen)) were considerably higher than the MTX alone group and were not statistically different from the Sal+H2O, only MTX+Gen group was significantly higher than the MTX alone group (P,0.05) (Fig. 1A–1D, 1F)
Summary
Both clinical and animal studies have reported that chemotherapy causes adverse effects on bone, negatively impacting on bone remodeling and bone mass [1,2,3,4,5,6,7]. Anti-metabolite methotrexate (MTX) is a widely used chemotherapeutic agent in treatment for acute lymphoblastic leukaemia (ALL), non-Hodgkin’s lymphoma, and at lower doses for rheumatoid arthritis and psoriatic arthritis [8]. Previous studies using rat models have demonstrated that MTX decreases trabecular bone volume, which is associated with increased adipogenesis, enhanced osteoclastogenesis, and decreased osteogenesis potential within the bone marrow, and a lower osteoblast number but a higher osteoclast density on the bone surface as well as a higher adipocyte density in the bone marrow [1,3,13,14,15]. The underlying mechanisms for MTX chemotherapyinduced bone loss and marrow require further investigations
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