Abstract
Defects in cartilage homeostasis can give rise to various skeletal disorders including osteochondromas. Osteochondromas are benign bone tumors caused by excess accumulation of chondrocytes, the main cell type of cartilage. The extracellular signal-regulated kinase (ERK) pathway is a major signaling node that functions within chondrocytes to regulate their growth and differentiation. However, it is not known whether the ERK pathway in other cell types regulates cartilage homeostasis. We show here that mice with a germline deficiency of Erk1 and a conditional deletion of Erk2 in cells that express CD4, or expressed CD4 at one point in development, unexpectedly developed bone deformities. The bone lesions were due to neoplastic outgrowths of chondrocytes and disordered growth plates, similar to tumors observed in the human disease, osteochondromatosis. Chondrocyte accumulation was not due to deletion of Erk2 in the T cells. Rather, CD4cre was expressed in cell types other than T cells, including a small fraction of chondrocytes. Surprisingly, the removal of T cells accelerated osteochondroma formation and enhanced disease severity. These data show for the first time that T cells impact the growth of osteochondromas and describe a novel model to study cartilage homeostasis and osteochondroma formation.
Highlights
The differentiation and proliferation of cartilage cells is a highly ordered and tightly regulated process that is essential for bone growth
Due to the requirement of extracellular signalregulated kinase (ERK) signaling in T cell development, DKOCD4 mice have a significant reduction in the number of T cells in the spleen and lymph nodes (Figures S1A,B in Supplementary Material) [8, 9]
While there was a reduction in the total number of regulatory T cells, a higher proportion of the CD4+ T cells expressed Foxp3 in the DKOCD4 mice compared to wild-type mice (Figure S1C in Supplementary Material), which is consistent with the fact that ERK2 signaling suppresses Foxp3 expression [12]
Summary
The differentiation and proliferation of cartilage cells is a highly ordered and tightly regulated process that is essential for bone growth. Defects in this process can cause a variety of disorders including osteochondromas, which are the most common type of benign bone tumor. These tumors are caused by excess accumulation of chondrocytes that erupt from the growth plate and are associated with significant pain, restriction of movement, impingement of blood vessels and nerves, and severe deformities. The molecular and cellular mechanisms that maintain cartilage homeostasis and prevent osteochondroma formation are incompletely understood
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