Oxygen-derived free radicals stimulate osteoclastic bone resorption in rodent bone in vitro and in vivo.

Abstract

The mechanisms by which bone resorbing osteoclasts form and are activated by hormones are poorly understood. We show here that the generation of oxygen-derived free radicals in cultured bone is associated with the formation of new osteoclasts and enhanced bone resorption, identical to the effects seen when bones are treated with hormones such as parathyroid hormone (PTH) and interleukin 1 (IL-1). When free oxygen radicals were generated adjacent to bone surfaces in vivo, osteoclasts were also formed. PTH and IL-1-stimulated bone resorption was inhibited by both natural and recombinant superoxide dismutase, an enzyme that depletes tissues of superoxide anions. We used the marker nitroblue tetrazolium (NBT) to identify the cells that were responsible for free radical production in resorbing bones. NBT staining was detected only in osteoclasts in cultures of resorbing bones. NBT staining in osteoclasts was decreased in bones coincubated with calcitonin, an inhibitor of bone resorption. We also found that isolated avian osteoclasts stained positively for NBT. NBT staining in isolated osteoclasts was increased when the cells were incubated with bone particles, to which they attach. We confirmed the formation of superoxide anion in isolated avian osteoclasts using ferricytochrome c reduction as a method of detection. The reduction of ferricytochrome c in isolated osteoclasts was inhibited by superoxide dismutase.Our results "suggest that oxygen-derived free radicals, and particularly the superoxide anion, are intermediaries in the formation and activation of osteoclasts. (J. Clin. Invest. 1990.

Characterization of skeletal alterations in a model of prematurely aging mice

“…Relative intensities of corresponding β-catenin and sclerostin signals to α-tubulin are indicated decrease in the number of trabecular osteoblasts in the femur of these mice, suggesting a predominance of bone resorption in these animals. In any event, this proinflammation status in long bones of adult PAM recapitulates that previously observed in aging bone (Garrett et al 1990;Cao et al 2005).…”

“…Moreover, oxidative stress interferes with osteoblastic, osteoclastic, and vascular differentiation, and thus, it has been proposed as a good candidate to explain bone loss occurring from the third decade of life, before sex hormone reduction (Garrett et al 1990;Mody et al 2001;Bai et al 2004;Manolagas 2010). Among the defensive mechanisms against oxidative stress, forkhead box O (FoxO) transcription factor family is involved in the response to ROS by driving the transcription of several antioxidant genes like catalase and growth arrest and DNA damage 45 (Gadd45) (Kops et al 2002;Tran et al 2002).…”

Aseptic Loosening Of Total Hip Replacement: Macrophage Expression Of Inducible Nitric Oxide Synthase And Cyclo-oxygenase-2, Together With Peroxynitrite Formation, As A Possible Mechanism For Early Prosthesis Failure

“…29 NO can inactivate superoxide dismutase leading to an increased accumulation of superoxide anion, which itself can stimulate bone resorption, and also interfere with the glutathione-glutathione peroxidase system resulting in an increased production of hydrogen peroxide, a reactive oxygen species able to activate bone resorption. 30 There is therefore considerable potential for cellular injury in diseases characterised by high-output NO production states. In this study, we hypothesise that the expression of iNOS and COX-2 is induced in activated periprosthetic macrophages associated with aseptic loosening and that peroxynitrite-induced protein nitrosylation can also be detected.…”

Life-long caloric restriction does not alter the severity of age-related osteoarthritis

“…The beneficial effect of CR on bone properties could be potentially due to the downregulation of reactive oxygen species, particularly the ones generated by osteoclasts (Brochmann et al 2003). These oxygen-related free radicals have been shown to stimulate osteoclast differentiation and bone resorption (Garrett et al 1990).…”