title: Involvement of mitochondrial dysfunction and ER-stress in the physiopathology of equine osteochondritis dissecans (OCD).
abstract: Osteochondrosis (OC) is a developmental bone disorder affecting several mammalian species including the horse. Equine OC is described as a focal disruption of endochondral ossification, leading to osteochondral lesions (osteochondritis dissecans, OCD) that may release free bodies within the joint. OCD lesions trigger joint swelling, stiffness and lameness and affects about 30% of the equine population. OCD is considered as multifactorial but its physiopathology is still poorly understood and genes involved in genetic predisposition are still unknown. Our study compared two healthy and two OC-affected 18-month-old French Trotters diagnosed with OCD lesions at the intermediate ridge of the distal tibia. A comparative shot-gun proteomic analysis of non-wounded cartilage and sub-chondral bone from healthy (healthy samples) and OC-affected foals (predisposed samples) identified 83 and 53 modulated proteins, respectively. These proteins are involved in various biological pathways including matrix structure and maintenance, protein biosynthesis, folding and transport, mitochondrial activity, energy and calcium metabolism. Transmission electron microscopy revealed typical features of mitochondrial swelling and ER-stress, such as large, empty mitochondria, and hyper-dilated rough endoplasmic reticulum, in the deep zone of both OC lesions and predisposed cartilage. Abnormal fibril organization surrounding chondrocytes and abnormal features at the ossification front were also observed. Combining these findings with quantitative trait loci and whole genome sequencing results identified about 140 functional candidate genes carrying putative damaging mutations in 30 QTL regions. In summary, our study suggests that OCD lesions may result from defective hypertrophic terminal differentiation associated with mitochondrial dysfunction and ER-stress, leading to impaired cartilage and bone biomechanical properties, making them prone to fractures. In addition, 11 modulated proteins and several candidate mutations located in QTL regions were identified, bringing new insight into the molecular physiopathology and genetic basis of OCD.
authors.affiliation: INRA, UMR1313, Biologie Intégrative et Génétique Animale, Jouy-en-Josas, France. Electronic address: clemence.desjardin@jouy.inra.fr.
authors.forename: Clémence
authors.initials: C
authors.lastname: Desjardin
authors.affiliation: INRA, UR 1197 Génomique et Physiologie de la Lactation, Jouy-en-Josas, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Chat
authors.affiliation: INRA, UMR1313, Biologie Intégrative et Génétique Animale, Jouy-en-Josas, France.
authors.forename: Mailys
authors.initials: M
authors.lastname: Gilles
authors.affiliation: INRA, UMR1313, Biologie Intégrative et Génétique Animale, Jouy-en-Josas, France.
authors.forename: Rachel
authors.initials: R
authors.lastname: Legendre
authors.affiliation: INRA, UMR1313, Biologie Intégrative et Génétique Animale, Jouy-en-Josas, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Riviere
authors.affiliation: INRA, UMR1313, Biologie Intégrative et Génétique Animale, Jouy-en-Josas, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Mata
authors.affiliation: INRA, PAPPSO, UMR 0320/UMR8120 Génétique Végétale, Gif-sur-Yvette, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Balliau
authors.affiliation: INRA, GeT Genomics Facility, UMR444 Laboratoire de Génétique Cellulaire, Castanet-Tolosan, France.
authors.forename: Diane
authors.initials: D
authors.lastname: Esquerré
authors.affiliation: INRA, UMR1313, Biologie Intégrative et Génétique Animale, Jouy-en-Josas, France.
authors.forename: Edmond P
authors.initials: EP
authors.lastname: Cribiu
authors.affiliation: Clinique Equine de Meheudin, Ecouché, France.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Betch
authors.affiliation: INRA, UMR1313, Biologie Intégrative et Génétique Animale, Jouy-en-Josas, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Schibler
mesh_terms: D000818:Animals; D002356:Cartilage / Q000503:physiopathology / Q000648:ultrastructure; D019902:Chondrocytes / Q000473:pathology / Q000648:ultrastructure; D059865:Endoplasmic Reticulum Stress; D006736:Horses; D007596:Joints / Q000503:physiopathology / Q000648:ultrastructure; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000473:pathology* / Q000648:ultrastructure; D010008:Osteochondritis Dissecans / Q000235:genetics / Q000503:physiopathology* / Q000662:veterinary*; D010012:Osteogenesis; D040901:Proteomics; D040641:Quantitative Trait Loci; D013977:Tibia / Q000503:physiopathology / Q000648:ultrastructure
keywords: Cartilage; Equine osteochondrosis; Proteomic shotgun analysis; Sub-chondral bone; TEM