Fluid Shear Stress Increases Osteocyte and Inhibits Osteoclasts via Downregulating Receptor-Activator of Nuclear Factor κB (RANK)/Osteoprotegerin Expression in Myeloma Microenvironment

Abstract

Background The aim of this study was to determine the effects of myeloma cells exposed to fluid shear stress on osteocytes and osteoclasts, and clarify the potential underlying mechanisms. Material/methods A flow and a non-flow model were established using a flow fluid chamber. The myeloma cell line U266 and murine osteocytic MLO-Y4 cells were cultured in vitro . The osteocytes and osteoclasts were examined under a microscope. Osteoclasts were stained for tartrate-resistant acid phosphatase (TRAP) activity. RANKL and osteoprotegerin (OPG) gene expression were detected using reverse transcription-quantitative polymerase chain reaction. Results Compared with the controls, Y4 cells cultured with U266 culture supernatant showed altered morphology, fewer osteocytes, increased RANKL gene expression, a higher RANKL/OPG gene ratio, and a greater number of TRAP-positive osteoclasts ( P <0.05 for all). Compared to the no-flow model, the flow model showed a higher number of Y4 cells, increased OPG gene expression, decreased RANKL gene expression, a lower RANKL/OPG gene ratio, and fewer TRAP-positive osteoclasts ( P <0.05 for all). Conclusions Our study revealed that fluid shear stress ameliorated the inhibitory effects of myeloma cells on osteocyte growth and inhibited osteoclast proliferation by means of decreasing RANKL/OPG gene expression. This may have clinical implications in patients with multiple myeloma in that mechanical loading with low-intensity vibration or mild exercise may prevent the progression of myeloma bone disease.

Impact of whole-body vibration exercise on physical performance and bone turnover in patients with monoclonal gammopathy of undetermined significance

“…Recent in-vitro studies suggest that mechanical stimulation ameliorates the inhibitory effect of the MM microenvironment on osteocyte growth and a previous animal model confirmed that low intensity vibration protects bone quantity and quality and mitigates progression in a murine model of MM [45] , [46] . In wistar rats mechanical vibration increases bone density dependent of the vibration stimulus frequencies [47] .…”

Raloxifene Prevents Early Periprosthetic Bone Loss for Postmenopausal Women after Uncemented Total Hip Arthroplasty: A Randomized Placebo‐Controlled Clinical Trial

“…As a result, the bone in Gruen zone 7 bears less load and thereafter bone mass decreased significantly according to Wolff's law of mechanics 20 . Mechanical stress inhibited osteoclast proliferation through decreasing RANKL/OPG gene expression 21 . Raloxifene can bind to estrogen receptors and inhibit the activity of osteoclasts and, thus, make the bone density increase 10,12 .…”

“…However, the adverse effects were accompanied by its benefits, such as breast cancer and abnormal uterine bleeding. Fortunately, raloxifene, as a kind of SERM, has the potential to retain most of the beneficial effects of estrogen while avoiding most of the adverse effects 21 . Our results showed that using raloxifene for 2 years after THA did not increase adverse events, including cardiac events, stroke, venous thromboembolism, and gynecological cancer, and even decreased the odds of breast cancer, which is consistent with the descriptions in previous studies 18,19 .…”

How the mechanical microenvironment of stem cell growth affects their differentiation: a review

“…Therefore, the effects of different mechanical forces on osteoblasts and osteoclasts were investigated. Fluid shear stress reduced RANKL expression and increased OPG expression in cells, which significantly reduced the RANKL/OPG ratio, upregulating the expression of osteoblast marker genes [ 90 ] (Fig. 1 ).…”