ESPE Abstracts (2015) 84 P-1-152

Noonan Syndrome-Causing SHP2 Mutants Inhibit Murine Growth Plate Chondrogenesis and Bone Development: Role of Ras/MAPK Hyperactivation

Armelle Yarta, Mylène Tajana, Florence Capillab, Nicolas Betonc, Jean-Luc Davignonc, Maithé Tauberc,d, Jean-Pierre Sallesc,d & Thomas Edouardc,d


aINSERM UMR1048, Institute of Cardiovascular and Metabolic Diseases (I2MC), University of Toulouse Paul Sabatier, Toulouse, France; bINSERM, US006, ANEXPLO/CREFRE, Histopathology Unit, Purpan Hospital, Toulouse, France; cINSERM UMR 1043, Centre of Pathophysiology of Toulouse Purpan (CPTP), University of Toulouse Paul Sabatier, Toulouse, France; dEndocrine, Bone Diseases, and Genetics Unit, Children’s Hospital, Toulouse University Hospital, Toulouse, France


Background: Growth retardation affects more than 80% of patients with Noonan syndrome (NS; MIM#163950), one of the most common developmental disorders, but its origin remains poorly understood. We have demonstrated that mutations of the tyrosine phosphatase SHP2, that are responsible for half the cases of NS, impair the systemic production of Insulin-like growth factor 1 (IGF1), the biological mediator of GH acting on growth plate, through a hyperactivation of the Ras/Mitogen-Activated Protein Kinase (MAPK) signalling pathway. This is in accordance with clinical data suggesting partial GH insensitivity in NS patients. However, the direct impact of NS-causing mutations on growth plate and bone has never been explored.

Objectives: To evaluate the impact of NS-causing mutations on growth plate and bone development and to determinate the contribution of GH insensitivity.

Methods: In vivo and in vitro analyses were performed in a mouse model of NS (SHP2 D61G/+ mice) and in chondrogenic ATDC5 cells expressing NS-causing SHP2 mutants respectively.

Results: Compared with their WT littermates, male SHP2 D61G/+ mice exhibited homogeneous postnatal growth retardation and alteration of trabecular bone of femur and vertebra. At the growth plate level, the length of the hypertrophic zone was decreased in SHP2 D61G/+ mice, whereas the length of the proliferating zone was unaffected. Proliferation and apoptosis were similar in WT and SHP2 D61G/+ mice. Expression of NS-associated SHP2 mutants results in ERK1/2 hyperactivation in chondrocytes in vitro and in vivo. Chronic inhibition of ERK1/2 activation in young mice alleviates growth plate abnormalities, which is associated with significant growth improvement in NS mice. Interestingly, IGF1 treatment of SHP2 D61G/+ mice increased the length of the proliferating zone without modifying hypertrophic zone abnormalities.

Conclusion: In conclusion, NS-causing SHP2 mutants inhibit chondrocyte differentiation through Ras/MAPK hyperactivation, a mechanism that could contribute to growth retardation. This also provides interesting insights into the development specific therapeutic options targeting the Ras/MAPK pathway to improve growth in NS patients.

Funding: This work was supported by the 2012 ASPIRE Young Investigator Research Awards in Endocrinology from Pfizer (reference number WS2385803, 2012).