OSTM1 bone defect reveals an intercellular hematopoietic crosstalk.
The most severe form of bone autosomal recessive osteopetrosis both in humans and in the gray-lethal (gl/gl) mouse is caused by mutations in the Ostm1 gene. Although osteopetrosis is usually associated with a defect in the hematopoietic-derived osteoclast cells, this study determined that Ostm1 is expressed in many hematopoietic cells of the myeloid and lymphoid B- and T-lineages. Hematopoiesis in gl/gl mice is characterized by a marked expansion of the osteoclast lineage but also by deregulation of the lymphoid lineages with a decrease in B-lymphoid cell populations and altered distribution in T-lymphoid double and single CD4 CD8-positive cells. In committed gl/gl osteoclasts, specific Ostm1 transgene targeting showed a requirement of additional factors and/or cells for normal osteoclast function, and importantly, defined the gl osteopetrotic defect as non-cell autonomous. By contrast, gl/gl osteoclast, B- and T-lymphoid lineage phenotypes were rescued when Ostm1 is expressed under PU.1 regulation from a bacterial artificial chromosome transgene, which established an essential role for Ostm1 in hematopoietic cells in addition to osteoclasts. Together these experiments are the first to demonstrate the existence of hematopoietic crosstalk for the production of functional and active osteoclasts.
Pata
Monica
M
Department of Cellular Interactions and Development, Faculté de Médecine de l'Université de Montréal, Québec H2W 1R7, Canada.
Héraud
Céline
C
Vacher
Jean
J
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism / Q000473:pathology; D022202:Chromosomes, Artificial, Bacterial / Q000235:genetics; D030342:Genetic Diseases, Inborn / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006410:Hematopoiesis / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D010010:Osteoclasts / Q000378:metabolism* / Q000473:pathology; D010022:Osteopetrosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D019076:Transgenes / Q000235:genetics; D000099232:Proto-Oncogene Protein Spi-1
D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1; C509143:OSTM1 protein, mouse
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