Strain-Dependent Differences in Bone Development, Myeloid Hyperplasia, Morbidity and Mortality in Ptpn2-Deficient Mice

Single nucleotide polymorphisms in the gene encoding the protein tyrosine phosphatase TCPTP (encoded by PTPN2) have been linked with the development of autoimmunity. Here we have used Cre/LoxP recombination to generate Ptpn2(ex2−/ex2−) mice with a global deficiency in TCPTP on a C57BL/6 background and compared the phenotype of these mice to Ptpn2(−/−) mice (BALB/c-129SJ) generated previously by homologous recombination and backcrossed onto the BALB/c background. Ptpn2(ex2−/ex2−) mice exhibited growth retardation and a median survival of 32 days, as compared to 21 days for Ptpn2(−/−) (BALB/c) mice, but the overt signs of morbidity (hunched posture, piloerection, decreased mobility and diarrhoea) evident in Ptpn2(−/−) (BALB/c) mice were not detected in Ptpn2(ex2−/ex2−) mice. At 14 days of age, bone development was delayed in Ptpn2(−/−) (BALB/c) mice. This was associated with increased trabecular bone mass and decreased bone remodeling, a phenotype that was not evident in Ptpn2(ex2−/ex2−) mice. Ptpn2(ex2−/ex2−) mice had defects in erythropoiesis and B cell development as evident in Ptpn2(−/−) (BALB/c) mice, but not splenomegaly and did not exhibit an accumulation of myeloid cells in the spleen as seen in Ptpn2(−/−) (BALB/c) mice. Moreover, thymic atrophy, another feature of Ptpn2(−/−) (BALB/c) mice, was delayed in Ptpn2(ex2−/ex2−) mice and preceded by an increase in thymocyte positive selection and a concomitant increase in lymph node T cells. Backcrossing Ptpn2(−/−) (BALB/c) mice onto the C57BL/6 background largely recapitulated the phenotype of Ptpn2(ex2−/ex2−) mice. Taken together these results reaffirm TCPTP's important role in lymphocyte development and indicate that the effects on morbidity, mortality, bone development and the myeloid compartment are strain-dependent.