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/marrow junction 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). ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32AR053804-01A1
Application #
7223094
Study Section
Special Emphasis Panel (ZRG1-F10-H (20))
Program Officer
Sharrock, William J
Project Start
2006-12-01
Project End
2009-11-30
Budget Start
2006-12-01
Budget End
2007-11-30
Support Year
1
Fiscal Year
2006
Total Cost
$48,796
Indirect Cost
Name
University of Pennsylvania
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Sweeney, Elizabeth; Roberts, Douglas; Lin, Angela et al. (2013) Defective endochondral ossification-derived matrix and bone cells alter the lymphopoietic niche in collagen X mouse models. Stem Cells Dev 22:2581-95
Sweeney, Elizabeth; Roberts, Douglas; Corbo, Tina et al. (2010) Congenic mice confirm that collagen X is required for proper hematopoietic development. PLoS One 5:e9518
Sweeney, E; Campbell, M; Watkins, K et al. (2008) Altered endochondral ossification in collagen X mouse models leads to impaired immune responses. Dev Dyn 237:2693-704