| Dr. Olena Jacenko |
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2009 Conference abstract
Altered Matrix at the Chondro-Osseous Junction Leads to Defects in the Hematopoietic Stem Cell Niche
Elizabeth Sweeney, Douglas Roberts, and Olena Jacenko
University of Pennsylvania, School of Veterinary Medicine, Division of Biochemistry, Department of Animal Biology, Philadelphia PA.
e-mail: jacenko@vet.upenn.edu
During endochondral ossification (EO), hypertrophic cartilage blueprints define all subsequent skeletal elements where a
hematopoietic marrow forms. A link between altered endochondral skeletogenesis and aberrant hematopoiesis in the marrow
was first established by the skeleto-hematopoietic disease phenotype of mice transgenic (Tg; AJP 160:2019, 2002) or null (KO;
JCB 149:983, 2000) for collagen X, a hypertrophic cartilage-specific matrix protein. In the collagen X mice, skeletal disease
manifestations involve both hypertrophic cartilage and trabecular bone, comprising the chondro-osseous junction (coj);
hematopoietic aberrations include marrow hypoplasia, altered B lymphocyte profile throughout life and both inflammatory and
hematopoietic cytokine mis-expression (Dev Dyn 237:2693, 2008). Of note, many of these altered cytokines bind heparan
sulfate proteoglycans (HSPGs), which are reduced or lacking in the coj of the collagen X mice. In vitro ELISAs and in vivo
parasite challenge confirmed an impaired immune response in all subsets of collagen X Tg and KO mice. To assess if these
hematopoietic changes are due to defects in the hematopoietic stem cell (HSC) population or in the HSC niche environment,
neonatal bone marrow transplantations and in vitro co-culture assays were used. These assays confirmed that the
hematopoietic defects in the collagen X mice result from an altered EO-derived coj environment. We present a hypothesis
depicting an EO-derived HSC niche where we propose that the collagen X/HSPG network sequesters hematopoietic cytokines and
growth factors at the coj; disruption of collagen X function and the collagen X/HSPG network causes an imbalance in cytokine
metabolism, leading to impaired hematopoiesis and immunity.
Supported by RO1-DK-057904 (OJ) and F32-AR-053804 (ES).
Altered Matrix at the Chondro-Osseous Junction Leads to Defects in the Hematopoietic Stem Cell Niche
Elizabeth Sweeney, Douglas Roberts, and Olena Jacenko
University of Pennsylvania, School of Veterinary Medicine, Division of Biochemistry, Department of Animal Biology, Philadelphia PA.
e-mail: jacenko@vet.upenn.edu
During endochondral ossification (EO), hypertrophic cartilage blueprints define all subsequent skeletal elements where a
hematopoietic marrow forms. A link between altered endochondral skeletogenesis and aberrant hematopoiesis in the marrow
was first established by the skeleto-hematopoietic disease phenotype of mice transgenic (Tg; AJP 160:2019, 2002) or null (KO;
JCB 149:983, 2000) for collagen X, a hypertrophic cartilage-specific matrix protein. In the collagen X mice, skeletal disease
manifestations involve both hypertrophic cartilage and trabecular bone, comprising the chondro-osseous junction (coj);
hematopoietic aberrations include marrow hypoplasia, altered B lymphocyte profile throughout life and both inflammatory and
hematopoietic cytokine mis-expression (Dev Dyn 237:2693, 2008). Of note, many of these altered cytokines bind heparan
sulfate proteoglycans (HSPGs), which are reduced or lacking in the coj of the collagen X mice. In vitro ELISAs and in vivo
parasite challenge confirmed an impaired immune response in all subsets of collagen X Tg and KO mice. To assess if these
hematopoietic changes are due to defects in the hematopoietic stem cell (HSC) population or in the HSC niche environment,
neonatal bone marrow transplantations and in vitro co-culture assays were used. These assays confirmed that the
hematopoietic defects in the collagen X mice result from an altered EO-derived coj environment. We present a hypothesis
depicting an EO-derived HSC niche where we propose that the collagen X/HSPG network sequesters hematopoietic cytokines and
growth factors at the coj; disruption of collagen X function and the collagen X/HSPG network causes an imbalance in cytokine
metabolism, leading to impaired hematopoiesis and immunity.
Supported by RO1-DK-057904 (OJ) and F32-AR-053804 (ES).
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online service providing access to the very best Web resources for education and research located in the UK
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