ArticleHuman molecular genetics2018
Noonan syndrome-causing SHP2 mutants impair ERK-dependent chondrocyte differentiation during endochondral bone growth.
Article in Human molecular genetics, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 41 citations in OpenAlex.
- RAS/MAPK pathway modulation with simvastatin in children with Noonan syndrome: a multicentre, randomised, double-blind, placebo-controlled phase 3 trial.EClinicalMedicine · 2026Article
- Beyond GH stimulation tests: genetic heterogeneity and treatment response in children with diagnosed GH deficiency.Journal of the Endocrine Society · 2026Article
- PTPN11 in cartilage development, adult homeostasis, and diseases.Bone research · 2025Review
- Severe generalized edema in a premature neonate: A case report and literature review.Clinical case reports · 2024Article
- Novel therapeutic perspectives in Noonan syndrome and RASopathies.European journal of pediatrics · 2024Review
- Deciphering the pathogenic role of rareFrontiers in genetics · 2024Article
- Genetic backgrounds and genotype-phenotype relationships in anthropometric parameters of 116 Japanese individuals with Noonan syndrome.Clinical pediatric endocrinology : case reports and clinical investigations : official journal of the Japanese Society for Pediatric Endocrinology · 2024Article
- Noonan syndrome: rhGH treatment and PTPN11 mutation.Molecular genetics & genomic medicine · 2023Article
- From Stem to Sternum: The Role of Shp2 in the Skeleton.Calcified tissue international · 2023Review
- The Cell-Specific Role of SHP2 in Regulating Bone Homeostasis and Regeneration Niches.International journal of molecular sciences · 2023Review
- Skeletal defects and bone metabolism in Noonan, Costello and cardio-facio-cutaneous syndromes.Frontiers in endocrinology · 2023Review
- Lymphatic anomalies during lifetime in patients with Noonan syndrome: Retrospective cohort study.American journal of medical genetics. Part A · 2022Article
- Outcomes in growth hormone-treated Noonan syndrome children: impact of PTPN11 mutation status.Endocrine connections · 2022Article
- Growth, Endocrine Features, and Growth Hormone Treatment in Noonan Syndrome.Journal of clinical medicine · 2022Review
- Targeting SHP2 phosphatase in hematological malignancies.Expert opinion on therapeutic targets · 2022Review
- Protein tyrosine phosphatases in skeletal development and diseases.Bone research · 2022Review
- Endocrine system involvement in patients with RASopathies: A case series.Frontiers in endocrinology · 2022Article
- Case report: The cardio-facio-cutaneous syndrome due to a novel germline mutation inFrontiers in pediatrics · 2022Article
- Modeling (not so) rare developmental disorders associated with mutations in the protein-tyrosine phosphatase SHP2.Frontiers in cell and developmental biology · 2022Review
- Review
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Authors and funding
12 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Growth retardation is a constant feature of Noonan syndrome (NS) but its physiopathology remains poorly understood. We previously reported that hyperactive NS-causing SHP2 mutants impair the systemic production of insulin-like growth factor 1 (IGF1) through hyperactivation of the RAS/extracellular signal-regulated kinases (ERK) signalling pathway. Besides endocrine defects, a direct effect of these mutants on growth plate has not been explored, although recent studies have revealed an important physiological role for SHP2 in endochondral bone growth. We demonstrated that growth plate length was reduced in NS mice, mostly due to a shortening of the hypertrophic zone and to a lesser extent of the proliferating zone. These histological features were correlated with decreased expression of early chondrocyte differentiation markers, and with reduced alkaline phosphatase staining and activity, in NS murine primary chondrocytes. Although IGF1 treatment improved growth of NS mice, it did not fully reverse growth plate abnormalities, notably the decreased hypertrophic zone. In contrast, we documented a role of RAS/ERK hyperactivation at the growth plate level since 1) NS-causing SHP2 mutants enhance RAS/ERK activation in chondrocytes in vivo (NS mice) and in vitro (ATDC5 cells) and 2) inhibition of RAS/ERK hyperactivation by U0126 treatment alleviated growth plate abnormalities and enhanced chondrocyte differentiation. Similar effects were obtained by chronic treatment of NS mice with statins. In conclusion, we demonstrated that hyperactive NS-causing SHP2 mutants impair chondrocyte differentiation during endochondral bone growth through a local hyperactivation of the RAS/ERK signalling pathway, and that statin treatment may be a possible therapeutic approach in NS.
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