SHP-2 deletion in CD4Cre expressing chondrocyte precursors leads to tumor development with wrist tropism

Jeffrey T Mcnamara,Kelsey E Huntington,Laurent Brossay,Chathuraka T Jayasuriya,Samantha Borys

doi:10.1038/s41598-021-99339-0

Jeffrey T Mcnamara, Kelsey E Huntington + Show 3 more

Open Access

https://doi.org/10.1038/s41598-021-99339-0

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Abstract

Due to redundancy with other tyrosine phosphatases, the ubiquitously expressed tyrosine phosphatase SHP-2 (encoded by Ptpn11) is not required for T cell development. However, Ptpn11 gene deletion driven by CD4 Cre recombinase leads to cartilage tumors in the wrist. Using a fate mapping system, we demonstrate that wrist tumor development correlates with increased frequency and numbers of non-hematopoietic lineage negative CD45 negative cells with a bone chondrocyte stromal cell precursor cell (BCSP) phenotype. Importantly, the BCSP subset has a history of CD4 expression and a marked wrist location tropism, explaining why the wrist is the main site of tumor development. Mechanistically, we found that in SHP-2 absence, SOX-9 is no longer regulated, leading to an uncontrolled proliferation of the BCSP subset. Altogether, these results identify a unique subset of chondrocyte precursors tightly regulated by SHP-2. These findings underscore the need for the development of methods to therapeutically target this subset of cells, which could potentially have an impact on treatment of SHP-2 dysfunction linked debilitating diseases.

Highlights

Due to redundancy with other tyrosine phosphatases, the ubiquitously expressed tyrosine phosphatase Src homology region 2 domain-containing phosphatase-2 (SHP-2) is not required for T cell development
Using mice conditionally deficient for SHP-2 in the T cell lineage, we previously reported that the development and function of these lymphocytes is globally intact[13]
In contrast to the wrist tumors, tumors in other joints were mostly small. These data show that SHP-2 deletion in CD45−CD4+ cells (YFP+) lead to tumor development with a marked wrist location tropism

Summary

Introduction

Due to redundancy with other tyrosine phosphatases, the ubiquitously expressed tyrosine phosphatase SHP-2 (encoded by Ptpn11) is not required for T cell development. Our lab demonstrated that SHP-2 deletion in CD4+ cells, a canonical T cell marker expressed in all αβ T cells during thymic development, leads to skeletal tumors in mice without impacting T cell development and function[13] In support of these findings, mice deficient for SHP-2 downstream components, such as Ras guanine exchange factors (RasGEFs) SOS-1 and -214 and extracellular signal related kinase (ERK)-1 and -215 in CD4+ cells, develop skeletal tumors. Together these studies suggest a possible link to chondrocyte development, which is yet to be definitively established. The estrogen receptor triggers growth plate closure which is reduced in size in adulthood but never completely c losed[21,22]

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