Abstract
Patients affected by Duchenne muscular dystrophy (DMD) and dystrophic MDX mice were investigated in this study for their bone phenotype and systemic regulators of bone turnover. Micro–computed tomographic (µCT) and histomorphometric analyses showed reduced bone mass and higher osteoclast and bone resorption parameters in MDX mice compared with wild-type mice, whereas osteoblast parameters and mineral apposition rate were lower. In a panel of circulating pro-osteoclastogenic cytokines evaluated in the MDX sera, interleukin 6 (IL-6) was increased compared with wild-type mice. Likewise, DMD patients showed low bone mineral density (BMD) Z-scores and high bone-resorption marker and serum IL-6. Human primary osteoblasts from healthy donors incubated with 10% sera from DMD patients showed decreased nodule mineralization. Many osteogenic genes were downregulated in these cultures, including osterix and osteocalcin, by a mechanism blunted by an IL-6-neutralizing antibody. In contrast, the mRNAs of osteoclastogenic cytokines IL6, IL11, inhibin-βA, and TGFβ2 were increased, although only IL-6 was found to be high in the circulation. Consistently, enhancement of osteoclastogenesis was noted in cultures of circulating mononuclear precursors from DMD patients or from healthy donors cultured in the presence of DMD sera or IL-6. Circulating IL-6 also played a dominant role in osteoclast formation because ex vivo wild-type calvarial bones cultured with 10% sera of MDX mice showed increase osteoclast and bone-resorption parameters that were dampen by treatment with an IL-6 antibody. These results point to IL-6 as an important mediator of bone loss in DMD and suggest that targeted anti-IL-6 therapy may have a positive impact on the bone phenotype in these patients. © 2011 American Society for Bone and Mineral Research
Highlights
Duchenne muscular dystrophy (DMD) is an X-linked disorder owing to mutations in the gene encoding dystrophin.[1]
Our results suggest that the defective bone mass in DMD is secondary to the failure in muscular traction and to the marked uncoupling of osteoclast and osteoblast activity potentially caused by imbalanced circulating and local cytokines, among which we point to interleukin 6 (IL-6) as a crucial systemic mediator of bone loss.[23]. These results are in keeping with a recent report by Nakagaki and colleagues,(31) who demonstrated reduced bone mass and altered bone mechanical and biochemical properties in MDX mice at 21 days of life, when histologic sections and Evans blue staining showed no muscle fiber damage, but are in disagreement with Montgomery and colleagues,(32) who evidenced increased femoral bone mineral density (BMD) in 4-month-old MDX mice
There is evidence that the bone tissue is significantly affected in DMD and that low bone mass and increased frequency of fractures may be complications even at an early stage of the disease.[18,19,20,21,22,34] Many cytokines and other local regulators are involved in the control of bone remodeling with a high degree of redundancy,(35,36) and many cell types take part in this process, including osteoblasts, osteoclasts, inflammatory cells, and cells of the immune system.[37,38]
Summary
Duchenne muscular dystrophy (DMD) is an X-linked disorder owing to mutations in the gene encoding dystrophin.[1]. Dystrophin is localized especially at the sarcolemma, assembled with several other glycoproteins, such as dystroglicans, syntrophins, dystrobrevins, sarcoglycans, and sarcospan, all together making the dystrophin glycoprotein complex, whose integrity is critical for linking the actin cytoskeleton to the extracellular matrix.[4,5] Deficiency of dystrophin expression affects formation of the dystrophin glycoprotein complex, causing disruption of the molecular bridge, with resulting membrane instability, increased susceptibility to mechanical stress, and altered cellular metabolism.[6,7,8,9,10] These events favor myofiber necrosis, which is believed to be the pivotal trigger of the state of inflammation that characterizes skeletal muscle in DMD patients. We report that a cytokine imbalance appears to contribute to the bone loss in DMD and point to interleukin 6 (IL-6) as a possible systemic mediator of the damage induced by chronic inflammation in bone, which could be subjected to therapeutic neutralization
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