Dysregulation of ERK signaling in CD4-expressing cells induces osteochondromas (IRC8P.441)

Abstract

Abstract ERK1 and ERK2 are serine/threonine kinases critical for the proliferation and development of T cells. Loss of ERK signaling in T cells, mediated by conditional deletion of Erk2 (CD4Cre) on an Erk1-/- background (DKOCD4), results in a block in the thymic development of T cells. Surprisingly, 80% of DKOCD4 mice spontaneously developed visible osteochondromas by 28 weeks of age. Histological analysis of these lesions revealed excessive accumulation of hypertrophic chondrocytes originating from the growth plates, but no mononuclear infiltrate indicative of inflammation. To determine if these lesions were caused by deletion of Erk in T cells, DKOCD4 mice were bred to Rag1-/- mice. Unexpectedly, osteochondromas still appeared in DKOCD4Rag1-/- mice, indicating deletion of Erk2 in other cell types mediates excess cartilage accumulation. Moreover, the addition of T cells delayed development of osteochondromas, which is a previously unknown level of regulation in cartilage homeostasis. Osteochondromas also appear to be influenced by alterations in the microbiota, as DKOCD4 mice treated with an antibiotic cocktail have a delay in osteochondroma development, which can be accelerated by housing the mice in non-specific-pathogen free conditions. Together these data suggest that Erk plays a critical role in a CD4+ cell type other than T cells, possibly an innate-like lymphocyte, to alter cartilage homeostasis. Finally, we present a novel role for T cells in regulating this process.