MRC Mouse Network Models for Disorders of Bone and Cartilage Presentation on behalf of Bone and Cartilage Consortium: Professor R V Thakker May Professor.

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Presentation transcript:

MRC Mouse Network Models for Disorders of Bone and Cartilage Presentation on behalf of Bone and Cartilage Consortium: Professor R V Thakker May Professor of Medicine University of Oxford First meeting of MRC Mouse Network, Harwell, UK 13 th January 2012

Aims 1.To establish mouse models of bone and cartilage disorders e.g. osteoporosis, osteoarthritis, skeletal trauma, chondrocalcinosis, Paget’s disease, and skeletal dysplasia 2.To use these models for: elucidating the underlying biological mechanisms, facilitating translational research, and development of biomarkers 3.To evaluate translation of findings to the human population level by comparison to large scale GWAS data sets (GEFOS and TREAT-OA)

Why is this important? Disorders of bone and mineral homeostasis: Osteoporosis Osteoarthritis Skeletal trauma Chondrocalcinosis Gout Paget’s disease These disorders are very common, and a major burden on the health services Effective treatments and prevention strategies are required

ENDOCRINOLOGY R Thakker G Williams D Bassett RHEUMATOLOGY M Brown M Feldman S Ralston T Vincent ORTHOPAEDICS J Nanchahal HUMAN GENETICS Rivadeneira Uitterlinden Group VETERINARY SURGERY A Goodship MOUSE GENETICS S Brown R Cox P Potter BASIC SCIENCE A Boyde P Croucher J Edwards N Horwood A Pitsillides T Skerry ENGINEERING / MATERIAL SCIENCE H Gupta Consortium Members

Bone Phenotyping Primary Screen -Performed at MRC Harwell -Bone & cartilage screen fits within primary screens for other systems -Development, growth, biochemistry, body composition, whole body X-ray, DEXA – for bone mineral density Intermediate high resolution secondary screen -Faxitron – high throughput quantative analysis of bone mineral content -Micro CT – high throughput quantitative analysis of structure, mineralization and static morphometry Detailed and bespoke secondary screening -Back scattered electron scanning electron microscopy (BSE-SEM) -Quantitative BSE-SEM -Bone histology & histomorphometry -Con-focal microscopy -Mechanical testing -Nanomechanical (synchroton X-ray scattering) -Primary bone cell culture -Longitudinal studies

Collection, fixation, storage and distribution of skeletal elements between laboratories & multiple analyses per sample upholds principles of 3Rs and economy From Williams & Bassett

Bone Phenotyping Primary Screen -Performed at MRC Harwell -Bone & cartilage screen fits within primary screens for other systems -Development, growth, biochemistry, body composition, whole body X-ray, DEXA – for bone mineral density Intermediate high resolution secondary screen -Faxitron – high throughput quantative analysis of bone mineral content -Micro CT – high throughput quantitative analysis of structure, mineralization and static morphometry Detailed and bespoke secondary screening -Back scattered electron scanning electron microscopy (BSE-SEM) -Quantitative BSE-SEM -Bone histology & histomorphometry -Con-focal microscopy -Mechanical testing -Nanomechanical (synchroton X-ray scattering) -Primary bone cell culture -Longitudinal studies

Lpk/+ WT Lpk: Spondyloepiphyseal Dysplasia Congenita WT Lpk/+ Proliferating chondrocytes Hypertrophic chondrocytes Lpk/+ Humerus Ulna WT - Ser1386Pro - WT Ser1386Pro cell lysatessupernatants Antibody: anti c-Mmyc Dominant mutant Disproportionately shortened humerus and secondary osteoarthritis Flattened epyphyses and disorganized growth plate Due to Ser1386Pro Col2a1 mutation ; in C-propeptide domain ER retention of mutant Col2a1 Esapa et al, JBMR, 2012, in press

Bone Phenotyping Primary Screen -Performed at MRC Harwell -Bone & cartilage screen fits within primary screens for other systems -Development, growth, biochemistry, body composition, whole body X-ray, DEXA – for bone mineral density Intermediate high resolution secondary screen -Faxitron – high throughput quantative analysis of bone mineral content -Micro CT – high throughput quantitative analysis of structure, mineralization and static morphometry Detailed and bespoke secondary screening -Back scattered electron scanning electron microscopy (BSE-SEM) -Quantitative BSE-SEM -Bone histology & histomorphometry -Con-focal microscopy -Mechanical testing -Nanomechanical (synchroton X-ray scattering) -Primary bone cell culture -Longitudinal studies

Faxitron: deiodinase mutants have increased bone mineral Bassett et al, 2010, PNAS

Bone Phenotyping Primary Screen -Performed at MRC Harwell -Bone & cartilage screen fits within primary screens for other systems -Development, growth, biochemistry, body composition, whole body X-ray, DEXA – for bone mineral density Intermediate high resolution secondary screen -Faxitron – high throughput quantative analysis of bone mineral content -Micro CT – high throughput quantitative analysis of structure, mineralization and static morphometry Detailed and bespoke secondary screening -Back scattered electron scanning electron microscopy (BSE-SEM) -Quantitative BSE-SEM -Bone histology & histomorphometry -Con-focal microscopy -Mechanical testing -Nanomechanical (synchroton X-ray scattering) -Primary bone cell culture -Longitudinal studies

Adult D2KO and D1/D2KO mice have brittle bones Biomechanical characteristics and strength properties determined by destructive 3 point bend testing 16w Yield load Maximum load Fracture load D2KO WT Stiffness * * ** * Bassett et al, 2010, PNAS

Bone Phenotyping Primary Screen -Performed at MRC Harwell -Bone & cartilage screen fits within primary screens for other systems -Development, growth, biochemistry, body composition, whole body X-ray, DEXA – for bone mineral density Intermediate high resolution secondary screen -Faxitron – high throughput quantative analysis of bone mineral content -Micro CT – high throughput quantitative analysis of structure, mineralization and static morphometry Detailed and bespoke secondary screening -Back scattered electron scanning electron microscopy (BSE-SEM) -Quantitative BSE-SEM -Bone histology & histomorphometry -Con-focal microscopy -Mechanical testing -Nanomechanical (synchroton X-ray scattering) -Primary bone cell culture -Longitudinal studies

BC D D T = 0 s T = 240 s Wild type Hpr 1 week 4 weeks 7 weeks 10 weeks 16 weeks Mineral coating Collage n fibril d l b L i. Wild-typeii. Hpr Karunaratne et al, JBMR, 2012, in press

1 week old mice scapula 10 weeks old wild type mice scapula 10 weeks old Hpr mice scapula Mineral particle orientated along the muscle force direction Mineral particles are randomly orientated due to the low muscle forces and less activity levels in 1 week old mice Due to the disturbed local mechanical and structural environment mineral particles are randomly orientated WT HPR Disruption of muscle stress-mediated mineral orientation at the nanoscale in the flat scapular bones of rahictic mice (HPR) Karunaratne et al, in preparation

Summary – Phenotyping by Bone & Cartilage Consortium Primary Screen -Performed at MRC Harwell -Bone & cartilage screen fits within primary screens for other systems -Development, growth, biochemistry, body composition, whole body X-ray, DEXA – for bone mineral density Intermediate high resolution secondary screen -Faxitron – high throughput quantative analysis of bone mineral content -Micro CT – high throughput quantitative analysis of structure, mineralization and static morphometry Detailed and bespoke secondary screening -Back scattered electron scanning electron microscopy (BSE-SEM) -Quantitative BSE-SEM -Bone histology & histomorphometry -Con-focal microscopy -Mechanical testing -Nanomechanical (synchroton X-ray scattering) -Primary bone cell culture -Longitudinal studies