Abstract
Glycogen storage disease type Ib (GSD-Ib) is caused by a deficiency in the ubiquitously expressed glucose 6-phosphate transporter (Glc-6-PT). Glc-6-PT activity has been shown to be critical in the liver and kidney where a deficiency disrupts glucose homeostasis. GSD-Ib patients also have defects in the neutrophil respiratory burst, chemotaxis, and calcium flux. They also manifest neutropenia, but whether Glc-6-PT deficiency in the bone marrow underlies myeloid dysfunctions in GSD-Ib remains controversial. To address this, we transferred bone marrow from Glc-6-PT-deficient (Glc-6-PT(-/-)) mice to wild-type mice to generate chimeric mice (BM-Glc-6-PT(-/-)). As a control, we also transferred bone marrow between wild-type mice (BM-Glc-6-PT(+/+)). While BM-Glc-6-PT(+/+) mice have normal myeloid functions, BM-Glc-6-PT(-/-) mice manifest myeloid abnormalities characteristic of Glc-6-PT(-/-) mice. Both have impairments in their neutrophil respiratory burst, chemotaxis response, and calcium flux activities and exhibit neutropenia. In the bone marrow of BM-Glc-6-PT(-/-) and Glc-6-PT(-/-) mice, the numbers of myeloid progenitor cells are increased, while in the serum there is an increase in granulocyte colony-stimulating factor and chemokine KC levels. Moreover, in an experimental model of peritoneal inflammation, local production of KC and the related chemokine macrophage inflammatory protein-2 is decreased in both BM-Glc-6-PT(-/-) and Glc-6-PT(-/-) mice along with depressed peritoneal neutrophil accumulation. The neutrophil recruitment defect was less severe in BM-Glc-6-PT(-/-) mice than in Glc-6-PT(-/-) mice. These findings demonstrate that Glc-6-PT expression in bone marrow and neutrophils is required for normal myeloid functions and that non-marrow Glc-6-PT activity also influences some myeloid functions.
Highlights
Glycogen storage disease type Ib (GSD-Ib) is caused by a deficiency in the ubiquitously expressed glucose 6-phosphate transporter (Glc-6-PT)
Since myeloid cells mature within the bone marrow in mammals [14], it is more likely that bone marrow transplantation would be able to fMLP, f-Met-Leu-Phe; MIP-2, macrophage inflammatory protein-2; PBS, phosphate-buffered saline; RT, reverse transcription; HBSS, Hanks’ balanced salt solution; PMA, phorbol 12-myristate 13-acetate; BSA, bovine serum albumin; BMT, bone marrow transplantation; colony forming units (CFU), colony forming unit(s); Hex-6-PDH, hexose-6-phosphate dehydrogenase
We show that wild-type mice receiving Glc-6-PTϪ/Ϫ bone marrow manifest the myeloid dysfunctions characteristic of GSD-Ib, which establishes that Glc-6-PT plays a functional role in bone marrow cells and is required for normal myeloid functions
Summary
Glycogen storage disease type Ib (GSD-Ib) is caused by a deficiency in the ubiquitously expressed glucose 6-phosphate transporter (Glc-6-PT). In the bone marrow of BM-Glc-6-PT؊/؊ and Glc6-PT؊/؊ mice, the numbers of myeloid progenitor cells are increased, while in the serum there is an increase in granulocyte colony-stimulating factor and chemokine KC levels.
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