title: 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.
authors.affiliation: Department of Experimental Medicine, University of L'Aquila, L'Aquila, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Rufo
authors.forename: Andrea
authors.initials: A
authors.lastname: Del Fattore
authors.forename: Mattia
authors.initials: M
authors.lastname: Capulli
authors.forename: Francesco
authors.initials: F
authors.lastname: Carvello
authors.forename: Loredana
authors.initials: L
authors.lastname: De Pasquale
authors.forename: Serge
authors.initials: S
authors.lastname: Ferrari
authors.forename: Dominique
authors.initials: D
authors.lastname: Pierroz
authors.forename: Lucia
authors.initials: L
authors.lastname: Morandi
authors.forename: Michele
authors.initials: M
authors.lastname: De Simone
authors.forename: Nadia
authors.initials: N
authors.lastname: Rucci
authors.forename: Enrico
authors.initials: E
authors.lastname: Bertini
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Bianchi
authors.forename: Fabrizio
authors.initials: F
authors.lastname: De Benedetti
authors.forename: Anna
authors.initials: A
authors.lastname: Teti
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D015519:Bone Density / Q000187:drug effects / Q000502:physiology*; D016723:Bone Remodeling / Q000187:drug effects; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D002648:Child; D016207:Cytokines / Q000097:blood / Q000235:genetics; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D051379:Mice; D009137:Muscular Dystrophy, Animal / Q000503:physiopathology*; D020388:Muscular Dystrophy, Duchenne / Q000097:blood / Q000503:physiopathology*; D009924:Organ Culture Techniques; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010012:Osteogenesis / Q000187:drug effects; D010641:Phenotype; D011859:Radiography; D015854:Up-Regulation / Q000187:drug effects; D000093242:Interleukin-6 Inhibitors
chemical_list: D019138:Antibodies, Blocking; D016207:Cytokines; D015850:Interleukin-6; D000093242:Interleukin-6 Inhibitors