title: Bone marrow osteoblast vulnerability to chemotherapy.
abstract: 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 (VP16) and melphalan, on murine osteoblasts at distinct stages of maturation. VP16 and melphalan delayed maturation of preosteoblasts and altered CXCL12 protein levels, a key regulator of hematopoietic cell homing to the bone marrow. Sublethal concentrations of VP16 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.
authors.affiliation: Alexander B. Osborn Hematopoietic Malignancy and Transplantation Program of the Mary Babb Randolph Cancer Center, Robert C. Byrd Health Sciences Center, West Virginia University School of Medicine, Morgantown, WV 26506-9300, USA.
authors.forename: Marieta
authors.initials: M
authors.lastname: Gencheva
authors.forename: Ian
authors.initials: I
authors.lastname: Hare
authors.forename: Susan
authors.initials: S
authors.lastname: Kurian
authors.forename: Jim
authors.initials: J
authors.lastname: Fortney
authors.forename: Debbie
authors.initials: D
authors.lastname: Piktel
authors.forename: Robert
authors.initials: R
authors.lastname: Wysolmerski
authors.forename: Laura F
authors.initials: LF
authors.lastname: Gibson
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D002460:Cell Line; D054377:Chemokine CXCL12 / Q000378:metabolism; D024042:Collagen Type I / Q000378:metabolism; D000090602:Collagen Type I, alpha 1 Chain; D005047:Etoposide / Q000494:pharmacology*; D005109:Extracellular Matrix / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D008558:Melphalan / Q000494:pharmacology*; D051379:Mice; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism*; D015675:Osteocalcin / Q000378:metabolism; D053495:Osteopontin / Q000378:metabolism; D055153:Stem Cell Niche / Q000187:drug effects*
chemical_list: D018906:Antineoplastic Agents, Alkylating; D000972:Antineoplastic Agents, Phytogenic; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; C515256:Cxcl12 protein, mouse; C506896:Spp1 protein, mouse; D015675:Osteocalcin; D053495:Osteopontin; D005047:Etoposide; D008558:Melphalan
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