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Brittle bone disease research suggests new approach to therapy

2017-05-18

May 18, 2017, SALZBURG, AUSTRIA. Press Dispensary. A study by research scientists from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) in Bethesda, Maryland, is suggesting that autophagy of misfolded procollagen plays an important role in the progress of brittle bone disease (osteogenesis imperfecta), and might be targeted for therapeutic intervention.

The outcome of the study was announced today by Elena Makareeva, of the NICHD, at ECTS 2017, the 44th European Calcified Tissue Society Congress being held in Salzburg, Austria.

Dr Makareeva said
: "We had already found through previous studies that osteoblast malfunction caused by an accumulation of misfolded procollagen inside the cell is a major factor in bone disease and that cells degrade misfolded procollagen by autophagy. In this study, we assessed how modulation of autophagy by genetic tools would affect bone characteristics.

autophagy of misfolded procollagen plays an important role in brittle bone disease. It might be ... targeted for therapeutic intervention
Elena Makareeva

"The G610C mouse with a Gly610 to Cys substitution in the α2(I) chain produces moderately severe osteogenesis imperfecta (OI) in heterozygous animals and lethal OI in homozygous animals. To modulate autophagy, we crossed G610C with Atg5flox/flox (MGI:3663625) mice and then generated G610C;Atg5flox/flox;osteocalcin-Cre animals by breeding with osteocalcin-Cre mice (MGI:2446069).

"Even without introducing Cre recombinase, we found Atg5 mRNA and protein expression to be 2-5 times lower in all tested tissues of Atg5flox/flox compared to Atg5+/+ animals (p less than 0.05). Lower expression of the Atg5 protein, which is required for autophagosome membrane formation, significantly increased the frequency and severity of skeletal deformities in newborn G610C-het pups and reduced survival of the pups by 30-50% without affecting their wild type littermates.

"Skeletal staining of newborn pups revealed undermineralization of calvaria, in-utero rib fractures, severe rib and scapula deformities, and long bones deformities and fractures. The conditional knockout of Atg5 in osteoblasts had no significant additional effect on G610C-het pup survival or relative growth curve. Yet, it further increased the frequency and severity of the skeletal deformities and bone fractures in newborns and affected bone development and maintenance in mice up to 4 months age."

Dr Makareeva concluded: "Combined with our other observations, this study suggests that autophagy of misfolded procollagen plays an important role in brittle bone disease. It might be responsible for variable severity of the same mutation in different individuals and be targeted for therapeutic intervention."

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Notes for editors

About the study
The study, titled "Genetic modulation of autophagy alters osteogenesis imperfecta severity in mice with gly610 to cys substitution in the triple helical region of the α2(i) collagen chain", was carried out by Elena Makareeva, Shakib Omari, Anna Roberts-Pilgrim, Ed Mertz, Laura Gorrell, Lynn Mirigian and Sergey Leikin of the National Institute Of Child Health And Human Development, National Institutes of Health, Bethesda, Maryland, USA.

The objective was to assess how autophagy modulation by genetic tools affects bone phenotype and the conclusion was that the study, combined with the researchers' other observations, suggests that autophagy of misfolded procollagen plays an important role in OI bone pathology. It might be responsible for variable severity of the same mutation in different individuals and be targeted for therapeutic intervention.

About ECTS 2017 (http://ects2017.org)
ECTS 2017 is the 44th European Calcified Tissue Society Congress, held from 13 to 16 May 2017 in the Austrian city of Salzburg.

ECTS serves as a forum for researchers and clinicians working in the musculoskeletal field to join forces, discover and discuss the latest advances and controversies in research and in the daily care of patients.

About The European Calcified Tissue Society (http://www.ectsoc.org/)
The European Calcified Tissue Society (ECTS) is the major organisation in Europe for researchers and clinicians working in the field of calcified tissues and related fields. ECTS acts as a forum for the dissemination of high quality research through its annual meeting, the European Symposium on Calcified Tissues, and through training courses and workshops.

Calcified tissues are central to a healthy skeleton and to bone disorders - such as osteoporosis, back pain and fractures - that make life a misery for countless people. Children can inherit some forms of bone diseases causing bone pain, shortness and deformed limbs.

For further information please contact
Roberta Mugnai, ECTS executive director
European Calcified Tissue Society (ECTS)
Tel: + 32 476 520 716
Email:
Site: www.ectsoc.org

ECTS 2017: http://ects2017.org
Facebook: ECTSoc
Twitter: @ECTS_soc
Event hashtag: #ECTS2017

Media contacts

Roberta Mugnai, ECTS executive director
Tel: + 32 476 520 716
Email:
Site: www.ectsoc.org

ECTS 2017: http://ects2017.org
Facebook: ECTSoc
Twitter: @ECTS_soc
Event hashtag: #ECTS2017

Keywords/tags
Brittle bone therapy ECTS ECTS Congress 2017 European Calcified Tissue Society NICHD Eunice Kennedy Shriver Elena Makareeva

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