Cathepsin K is required for maintenance and regeneration of lymphopoiesis in vivo

Cathepsin K (CTSK) is a major collagen-degrading protease in osteoclasts. Defects in CTSK activity are directly linked to skeletal abnormalities such as osteoporosis and osteopetrosis. The role of CTSK in cell types other than osteoclasts is poorly understood. Stromal cells, which maintain hematopoietic stem cells (HSCs) during in vitro culture, show high transcription of the Ctsk gene. Here, we investigated the influence of the absence of Ctsk on the hematopoietic system. We found that in vitro cultures with Lineage- SCA1+ KIT+ (LSK) cells on Ctsk deficient stromal cells display reduced colony formation and proliferation, with increased differentiation, whilst subsequent in vivo experiments show impaired HSC maintenance of lymphopoiesis of in vitro cultured cells. In vivo, deletion of Ctsk does not show gross effects on early hematopoiesis or myelopoiesis. But, in the bone marrow (BM), T cell numbers are significantly reduced. Lymphocyte deregulation is also found in transplantation experiments, which revealed that Ctsk is required for optimal regeneration not only of T cells, but also of B cells. Interestingly, environmental Ctsk is involved in both B- and T-lymphopoiesis, but T cell development in the bone marrow additionally requires an intrinsic Ctsk-dependent process. Thus, our study shows that Ctsk is required for the maintenance of HSCs and proper lymphopoiesis in vitro and in vivo.