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From Stem to Sternum: The Role of Shp2 in the Skeleton

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Abstract

Src homology-2 domain-containing phosphatase 2 (SHP2) is a ubiquitously expressed phosphatase that is vital for skeletal development and maintenance of chondrocytes, osteoblasts, and osteoclasts. Study of SHP2 function in small animal models has led to insights in phenotypes observed in SHP2-mutant human disease, such as Noonan syndrome. In recent years, allosteric SHP2 inhibitors have been developed to specifically target the protein in neoplastic processes. These inhibitors are highly specific and have great potential for disease modulation in cancer and other pathologies, including bone disorders. In this review, we discuss the importance of SHP2 and related signaling pathways (e.g., Ras/MEK/ERK, JAK/STAT, PI3K/Akt) in skeletal development. We review rodent models of pathologic processes caused by germline mutations that activate SHP2 enzymatic activity, with a focus on the skeletal phenotype seen in these patients. Finally, we discuss SHP2 inhibitors in development and their potential for disease modulation in these genetic diseases, particularly as it relates to the skeleton.

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Acknowledgements

This work was supported by the Biomedical Laboratory Research and Development Program of the Department of Veterans Affairs (VA Merit Award to A.C.L., BX000333 and BX005168).

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  1. Nathaniel R. Jensen and Ryan R. Kelly have contributed equally to this work.

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  1. Department of Pediatrics, Washington University in St. Louis, St. Louis, MO, USA

    Nathaniel R. Jensen

  2. Ralph H. Johnson VA Health Care System, Research Service, Charleston, SC, USA

    Ryan R. Kelly, Kirsten D. Kelly, Stephanie K. Khoo, Sara J. Sidles & Amanda C. LaRue

  3. Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC, USA

    Ryan R. Kelly, Sara J. Sidles & Amanda C. LaRue

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Jensen, N.R., Kelly, R.R., Kelly, K.D. et al. From Stem to Sternum: The Role of Shp2 in the Skeleton. Calcif Tissue Int 112, 403–421 (2023). https://doi.org/10.1007/s00223-022-01042-3

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