CD36 and macrophage scavenger receptor a modulate foam cell formation via inhibition of lipid-laden platelet phagocytosis.

CD34 (+) progenitor cells are a promising source of regeneration in atherosclerosis or ischemic heart disease. However, as recently published, CD34(+) progenitor cells have the potential to differentiate not only into endothelial cells but also into foam cells upon interaction with platelets. The mechanism of platelet-induced differentiation of progenitor cells into foam cells is as yet unclear. In the present study we investigated the role of scavenger receptor (SR)-A and CD36 in platelet-induced foam cell formation. Human CD34(+) progenitor cells were freshly derived from human umbilical veins and were co-incubated with platelets (2 x 10(8)/mL) up to 14 days resulting in large lipid-laden foam cells. Developing macrophages expressed SR-A, CD36, and Lox-1 as measured by fluorescent-activated cell sorting analysis. The presence of a blocking anti-CD36 or anti-SR-A antibody nearly abrogated foam cell formation, whereas anti-Lox-1 did not affect foam cell formation. Consistently blocking either anti-CD36 or anti-SR-A antibody significantly reduced the phagocytosis of lipid-laden platelets by macrophages. We conclude that CD36 and SR-A play an important role in platelet-induced foam cell formation from CD34(+) progenitor cells and thus represent a promising target to inhibit platelet-induced foam cell formation.

Identification of a novel mutation in the coding region of the grey-lethal gene OSTM1 in human malignant infantile osteopetrosis.

Autosomal recessive malignant infantile osteopetrosis (ARO) is characterized by severe osteosclerosis, pathologic fractures, hepatosplenomegaly, and pancytopenia. The pathophysiological basis is inadequate bone resorption due to osteoclast dysfunction. In the majority of cases, mutations in either of two human genes cause this fatal disorder: TCIRG1, encoding a subunit of the osteoclast H(+)-ATPase, and the voltage-gated chloride channel gene CLCN7. We excluded both genes in a small inbred family with malignant infantile osteopetrosis and undertook linkage analysis of several candidate loci that are involved in murine osteopetrosis. A region spanning more than 20 cM between the markers D6S1717 and D6S1608 on chromosome 6q21 was found to be homozygous in the affected child. This locus is syntenic to the genomic region harboring the gene for the osteopetrotic mutant mouse grey-lethal (gl). Recently, mutations in a novel gene of unknown function were described in the grey-lethal mouse and in one human patient. Mutation screening of the grey-lethal gene (OSTM1), revealed a homozygous 2-bp deletion in exon 2 (c.415_416delAG) in the affected child. No mutations could be found in six independent ARO patients who had tested negative for mutations in TCIRG1 and CLCN7. In summary, we describe the identification of a novel mutation in the coding sequence of the human grey-lethal gene, which is the second OSTM1 mutation found in human ARO, confirming the involvement of this gene in the pathogenesis of this severe bone disease.