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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.

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.

Osteochondromatosis is the most frequent tumor of the skeletal system. Although these bone tumors are benign, they create deformities resulting in impaired use of the affected joints, severe pain, and potential paralysis due to nerve compression. Patients often have a single tumor, although a disorder characterized by the presence of multiple osteochondromas is well established. Surprisingly, mice with a germline deficiency in Erk1 bred to mice with a conditional deletion of Erk2 in the T cell lineage (Erk1-/-.Erk2fl/fl.CD4cre) [DKO] developed multiple osteochondromas by 28 weeks of age. Gross protrusions of the spine and carpus were visible in the DKO mice, and radiological imaging revealed boney abnormalities in the spine, carpus, and sternum. Histological analysis of these protrusions showed an excessive proliferation of cartilage originating from the growth plates, but no mononuclear infiltrate indicative of inflammation. Moreover, we did not find autoantibodies in the serum of the DKO mice. Flow cytometric analysis indicated that an innate-like population of cells was more prominent in the DKO mice compared to littermate controls. These data suggest that the presence of Erk2 in a CD4-expressing, non-T cell population may play a central role in preventing the development of osteochondromas.