Dysregulation of ERK signaling in CD4-expressing cells induces osteochondromas

Abstract

Abstract ERK1 and ERK2 are serine/threonine kinases critical for the proliferation and development of many cell types. Mice with a germline deletion of Erk1 bred to mice with a conditional deletion of Erk2 mediated by CD4cre (DKOCD4 mice) exhibit a profound block in T cell development in the thymus. Surprisingly, 80% of DKOCD4 mice spontaneously developed osteochondromas by 28 weeks of age. Histological analysis of these lesions revealed excessive accumulation of hypertrophic chondrocytes originating from the growth plates in the bone, but no mononuclear infiltrate indicative of inflammation. As the majority of CD4+ cells are T cells, we investigated whether these lesions were caused by deletion of Erk2 in T cells by breeding the DKOCD4 mice to Rag1−/− mice. Unexpectedly, osteochondromas still appeared in DKOCD4Rag1−/− mice. In fact, osteochondromas developed faster and were more severe in DKOCD4Rag1−/− mice compared to DKOCD4 mice, indicating that deletion of Erk2 in other cell types mediates excess cartilage accumulation. Furthermore, the addition of T cells to DKOCD4Rag1−/− mice delayed development of osteochondromas, showing that T cells play an important role in regulating cartilage homeotstasis. Furthermore, the development of the osteochondromas appears to be influenced by changes in the microbiota, as DKOCD4 mice treated with an antibiotic cocktail have a delay in osteochondroma development, while mice housed in non-specific pathogen free conditions had accelerated onset of tumors. Together these data suggest that Erk plays a critical role in a CD4+ cell type other than T cells, possibly an innate lymphoid cell, to alter cartilage growth. In addition, we present a novel role for T cells in regulating cartilage homeostasis.