Inhibition of osteoclastogenesis by mechanically stimulated osteoblasts is attenuated during estrogen deficiency
Abstract
Osteoporotic bone loss and fracture have long been regarded to arise upon depletion of circulating estrogen, which increases osteoclastogenesis and bone resorption. Osteoblasts from human osteoporotic patients also display deficient osteogenic responses to mechanical loading. However, while osteoblasts play an important role in regulating osteoclast differentiation, how this relationship is affected by estrogen deficiency is unknown. This study seeks to determine how mechanically stimulated osteoblasts regulate osteoclast differentiation and matrix degradation under estrogen deficiency. Here, we report that osteoblast-induced osteoclast differentiation (indicated by TRAP, CTSK, NFATc1) and matrix degradation was inhibited by estrogen treatment and mechanical loading. However, estrogen deficient osteoblasts exacerbated osteoclast formation and matrix degradation through conditioned media and co-culture experiments. This was accompanied by higher COX-2 and M-CSF expression, but not OPG, by osteoblasts under estrogen deficiency. Interestingly, this response was exacerbated under conditions that block the Rho-ROCK signalling pathway. Together this study provides an important, but previously unrecognised, insight into bone loss in postmenopausal osteoporosis whereby estrogen deficient osteoblasts fail to produce inhibitory OPG after mechanical stimulation, but upregulate M-CSF and COX-2 expression and thus leave osteoclast activity unconstrained.
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