Bone mineralization and turnover in children with congenital neutropenia, and its relationship to treatment with recombinant human granulocyte‐colony stimulating factor

Fewtrell, Mary; Kinsey, Sally; Williams, Denise; Bishop, Nick

doi:10.1046/j.1365-2141.1997.1302945.x

Cited by 17 publications

(8 citation statements)

References 8 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Previous studies have established that chronic treatment with G‐CSF leads to increased osteoclast number and activity.

^{(^{(4–6,23,24)})}

Although there is evidence that G‐CSF can directly activate the osteoclast lineage,

^{(^{(8)})}

the potent suppressive effect of G‐CSF on osteoblasts suggests another possibility. Namely, because osteoblasts contribute to the regulation of osteoclastogenesis, the reduced number of osteoblasts during G‐CSF treatment may secondarily activate osteoclasts.…”

Section: Resultsmentioning

confidence: 99%

Granulocyte Colony-Stimulating Factor Induces Osteoblast Apoptosis and Inhibits Osteoblast Differentiation

Christopher

Link

2008

Journal of Bone and Mineral Research

116

View full text Add to dashboard Cite

Long-term treatment of mice or humans with granulocyte colony-stimulating factor (G-CSF) is associated with a clinically significant osteopenia characterized by increased osteoclast activity and number. In addition, recent reports have observed a decrease in number of mature osteoblasts during G-CSF administration. However, neither the extent of G-CSF's suppressive effect on the osteoblast compartment nor its mechanisms are well understood. Herein, we show that short-term G-CSF treatment in mice leads to decreased numbers of endosteal and trabecular osteoblasts. The effect is specific to mature osteoblasts, because bone-lining cells, osteocytes, and periosteal osteoblasts are unaffected. G-CSF treatment accelerates osteoblast turnover in the bone marrow by inducing osteoblast apoptosis. In addition, whereas G-CSF treatment sharply increases osteoprogenitor number, differentiation of mature osteoblasts is impaired. Bone marrow transplantation studies show that G-CSF acts through a hematopoietic intermediary to suppress osteoblasts. Finally, G-CSF treatment, through suppression of mature osteoblasts, also leads to a marked decrease in osteoprotegerin expression in the bone marrow, whereas expression of RANKL remains relatively constant, suggesting a novel mechanism contributing to the increased osteoclastogenesis seen with long-term G-CSF treatment. In sum, these findings suggest that the hematopoietic system may play a novel role in regulating osteoblast differentiation and apoptosis during G-CSF treatment.

show abstract

“…Previous studies have established that chronic treatment with G‐CSF leads to increased osteoclast number and activity.

^{(^{(4–6,23,24)})}

Although there is evidence that G‐CSF can directly activate the osteoclast lineage,

^{(^{(8)})}

Section: Resultsmentioning

confidence: 99%

Granulocyte Colony-Stimulating Factor Induces Osteoblast Apoptosis and Inhibits Osteoblast Differentiation

Christopher

Link

2008

Journal of Bone and Mineral Research

116

View full text Add to dashboard Cite

show abstract

“…Osteoporosis 45 and other bone mineralization defects 46, 47 are seen in SCN, although they may be a side effect of treatment with rhG-CSF 48, 49 . G-CSF administration reduces bone mineral density by activating osteoclasts 50 and inhibiting osteoblasts 51 .…”

Section: Functional Deficiency Of Neutrophils In Addition To Neutropeniamentioning

confidence: 99%

ELANE Mutations in Cyclic and Severe Congenital Neutropenia

Horwitz

Corey

Grimes

et al. 2013

Hematology/Oncology Clinics of North America

107

103

View full text Add to dashboard Cite

There are two main forms of hereditary neutropenia: cyclic and severe congenital neutropenia (SCN). Cyclic neutropenia is an autosomal dominant disorder in which neutrophil counts fluctuate between nearly normal levels and close to zero with 21-day periodicity. In contrast, SCN, also known as Kostmann syndrome, consists of chronic and profound neutropenia, with a characteristic promyelocytic maturation arrest in the bone marrow. Unlike cyclic neutropenia, SCN displays frequent acquisition of somatic mutations in the gene, CSF3R, encoding the Granulocyte Colony-Stimulating Factor Receptor (G-CSFR), and a strong predisposition to developing myelodysplasia (MDS) and/or acute myeloid leukemia (AML). Cyclic neutropenia is caused by heterozygous mutations in the gene, ELANE (formerly known as ELA2), encoding the neutrophil granule serine protease, neutrophil elastase. SCN is genetically heterogeneous, but it is most frequently associated with ELANE mutations. While some of the different missense mutations in ELANE exhibit phenotype-genotype correlation, the same mutations are sometimes found in patients with either form of inherited neutropenia. The mutations lead to production of a mutant polypeptide, but no common biochemical abnormality, including effects on proteolysis, has been identified. Two non-mutually exclusive theories have been advanced to explain how the mutations might produce neutropenia. The mislocalization hypothesis states that mutations within neutrophil elastase or involving other proteins responsible for its intracellular trafficking cause neutrophil elastase to accumulate in inappropriate subcellular compartments. The misfolding hypothesis proposes that mutations prevent the protein from properly folding, thereby inducing the stress response pathway within the endoplasmic reticulum (ER). We discuss how the mutations themselves provide clues into pathogenesis, describe supporting and contradictory observations for both theories, and highlight outstanding questions relating to pathophysiology of neutropenia.

show abstract

“…Despite concern, there is little evidence that the use of G-CSF is contributory. 35 All patients with SCN should have their bone mineral density regularly evaluated. Routine radiological imaging may miss osteopenia and osteoporosis and so imaging modalities such as dexa-scanning and Q-CT, which appear to be more sensitive in early disease, should be considered.…”

Section: Osteopenia Osteoporosismentioning

confidence: 99%

The investigation and management of chronic neutropenia in children

James

Kinsey

2006

Archives of Disease in Childhood

View full text Add to dashboard Cite

Unravelling the cause of a neutropenia poses a complex diagnostic challenge. The differential diagnosis ranges from life threatening disease to transient benign causes of little clinical significance. This review offers a practical guide to investigating the neutropenic child, and highlights features that merit specialist referral. Therapeutic options, the role of long term follow up, and the complications of severe chronic neutropenia are considered.

show abstract

Bone mineralization and turnover in children with congenital neutropenia, and its relationship to treatment with recombinant human granulocyte‐colony stimulating factor

Cited by 17 publications

References 8 publications

Granulocyte Colony-Stimulating Factor Induces Osteoblast Apoptosis and Inhibits Osteoblast Differentiation

Granulocyte Colony-Stimulating Factor Induces Osteoblast Apoptosis and Inhibits Osteoblast Differentiation

ELANE Mutations in Cyclic and Severe Congenital Neutropenia

The investigation and management of chronic neutropenia in children

Contact Info

Product

Resources

About