Mechanisms inducing low bone density in duchenne muscular dystrophy in mice and humans

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

Skeletal Fragility in Children with Chronic Disease

“…Chronic inflammation is reported in animal models and humans with DMD and contributes in part to the skeletal deficits, together with a reduction in muscle function before GC [65]. Femoral neck BMD was already low during the ambulatory phase in boys with DMD not treated with GC and declined with follow-up [66].…”

The Use of Bisphosphonates in Pediatrics

“…Disuse osteoporosis is a severe complication in patients with acute and chronic neurogenic diseases with palsy or severely handicapped children with cerebral damage, myelomeningoceles and muscular dystrophies [35,36]. Prevalence rates for fragility fractures have been estimated at 20% in nonambulatory children [37].…”

Osteoclast Genetic Diseases

“…They have been instrumental for the understanding of the mechanisms by which osteoclasts form and resorb bone and contributed to shed light on the pathogenesis of more frequent bone diseases, including osteoporosis and bone inflammatory disorders, such as osteoarthritis and rheumatoid arthritis (Tanaka et al, 2005). Further investigation on osteoclast genetic diseases is expected to help increase our knowledge about the recently identified relationships between the bone and other systems, including the immune system (Takayanagi, 2010), the nervous system (Kumar et al, 2010), the endocrine system Fukumoto & Martin, 2009;Karsenty & Oury, 2010), the reproductive system (Oury et., 2011) and the skeletal muscle system (Rufo et al, 2011), in which osteoclasts may be implicated. Therefore, in the next future we are likely to assist to flourishing novel insights into the osteoclast biology, physiology and pathology, which could represent the basis for a better prophylaxis and more effective treatments of bone diseases.…”