Mechanistically linking skeletogenesis and hematopoiesis

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This proposal will characterize the link between endochondral ossification, where hypertrophic cartilage is replaced by bone and marrow, and the development of a functional immune system. To do this, collagen X transgenic (Tg) and knock-out mice (KO) mice will be used since the disease phenotype involves growth plate defects, which lead to an altered marrow environment and aberrant hematopoiesis. It is proposed that collagen X and other matrix molecules, e.g. glycosaminoglycans and heparan sulfate proteoglycans, provides a structural network that sequesters cytokines in hypertrophic cartilage, and disruption of this network may cause inappropriate signaling at the growth plate/marrowjunction leading to an altered marrow environment and defective hematopoiesis. To test this, 1) The involvement of the bone marrow resident cells, e.g. stromal cells, hypertrophic cartilage, and/or osteoblasts, from the collagen X mice in the disease phenotype will be confirmed with bone marrow transplants, 2) Further, the collagen X mouse marrow environment will be assayed for support of hematopoiesis in vitro, function of lymphocytes will be tested, and the marrow resident cells will be assayed individually for the ability to support hematopoiesis. 3) Finally, a mechanism will be explored that links aberrant cytokine expression, due to decompartmentalization of the hypertrophic network, to altered hematopoiesis via real-time RT-PCR of growth plate and marrow tissue from collagen X mice. Resulting data may elucidate how a hematopoietic marrow is established, and which skeletal defects might contribute to marrow alterations and hematopoietic disorders. Understanding the relationship between skeletal development and hematopoiesis may reveal which skeletal defects contribute to marrow alterations, leading to hematopoietic disorders and impaired immunity, such as bone marrow failure and immune dysfunction (e.g. aplastic anemia, rheumatoid arthritis), autoimmunity, as well as certain cancers (e.g. leukemia, lymphoma).