Premium
Bone marrow osteoblast vulnerability to chemotherapy
Author(s) -
Gencheva Marieta,
Hare Ian,
Kurian Susan,
Fortney Jim,
Piktel Debbie,
Wysolmerski Robert,
Gibson Laura F.
Publication year - 2013
Publication title -
european journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.904
H-Index - 84
eISSN - 1600-0609
pISSN - 0902-4441
DOI - 10.1111/ejh.12109
Subject(s) - bone marrow , osteoblast , haematopoiesis , osteopontin , microbiology and biotechnology , biology , cancer research , chemistry , immunology , stem cell , biochemistry , in vitro
Osteoblasts are a major component of the bone marrow microenvironment, which provide support for hematopoietic cell development. Functional disruption of any element of the bone marrow niche, including osteoblasts, can potentially impair hematopoiesis. We have studied the effect of two widely used drugs with different mechanisms of action, etoposide ( VP 16) and melphalan, on murine osteoblasts at distinct stages of maturation. VP 16 and melphalan delayed maturation of preosteoblasts and altered CXCL 12 protein levels, a key regulator of hematopoietic cell homing to the bone marrow. Sublethal concentrations of VP 16 and melphalan also decreased the levels of several transcripts which contribute to the composition of the extracellular matrix ( ECM ) including osteopontin ( OPN ), osteocalcin ( OCN ), and collagen 1A1 (Col1a1). The impact of chemotherapy on message and protein levels for some targets was not always aligned, suggesting differential responses at the transcription and translation or protein stability levels. As one of the main functions of a mature osteoblast is to synthesize ECM of a defined composition, disruption of the ratio of its components may be one mechanism by which chemotherapy affects the ability of osteoblasts to support hematopoietic recovery coincident with altered marrow architecture. Collectively, these observations suggest that the osteoblast compartment of the marrow hematopoietic niche is vulnerable to functional dysregulation by damage imposed by agents frequently used in clinical settings. Understanding the mechanistic underpinning of chemotherapy‐induced changes on the hematopoietic support capacity of the marrow microenvironment may contribute to improved strategies to optimize patient recovery post‐transplantation.