title: Control of megakaryocyte expansion and bone marrow fibrosis by lysyl oxidase.
abstract: Lysyl oxidase (LOX), a matrix cross-linking protein, is known to be selectively expressed and to enhance a fibrotic phenotype. A recent study of ours showed that LOX oxidizes the PDGF receptor-β (PDGFR-β), leading to amplified downstream signaling. Here, we examined the expression and functions of LOX in megakaryocytes (MKs), the platelet precursors. Cells committed to the MK lineage undergo mitotic proliferation to yield diploid cells, followed by endomitosis and acquisition of polyploidy. Intriguingly, LOX expression is detected in diploid-tetraploid MKs, but scarce in polyploid MKs. PDGFR-BB is an inducer of mitotic proliferation in MKs. LOX inhibition with β-aminopropionitrile reduces PDGFR-BB binding to cells and downstream signaling, as well as its proliferative effect on the MK lineage. Inhibition of LOX activity has no influence on MK polyploidy. We next rationalized that, in a system with an abundance of low ploidy MKs, LOX could be highly expressed and with functional significance. Thus, we resorted to GATA-1(low) mice, where there is an increase in low ploidy MKs, augmented levels of PDGF-BB, and an extensive matrix of fibers. MKs from these mice display high expression of LOX, compared with control mice. Importantly, treatment of GATA-1(low) mice with β-aminopropionitrile significantly improves the bone marrow fibrotic phenotype, and MK number in the spleen. Thus, our in vitro and in vivo data support a novel role for LOX in regulating MK expansion by PDGF-BB and suggest LOX as a new potential therapeutic target for myelofibrosis.
authors.affiliation: Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
authors.forename: Alexia
authors.initials: A
authors.lastname: Eliades
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Papadantonakis
authors.forename: Ajoy
authors.initials: A
authors.lastname: Bhupatiraju
authors.forename: Kelley A
authors.initials: KA
authors.lastname: Burridge
authors.forename: Hillary A
authors.initials: HA
authors.lastname: Johnston-Cox
authors.forename: Anna Rita
authors.initials: AR
authors.lastname: Migliaccio
authors.forename: John D
authors.initials: JD
authors.lastname: Crispino
authors.forename: Hector A
authors.initials: HA
authors.lastname: Lucero
authors.forename: Philip C
authors.initials: PC
authors.lastname: Trackman
authors.forename: Katya
authors.initials: K
authors.lastname: Ravid
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001853:Bone Marrow / Q000473:pathology*; D002455:Cell Division; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D008297:Male; D008533:Megakaryocytes / Q000166:cytology* / Q000201:enzymology; D051379:Mice; D011123:Polyploidy; D055728:Primary Myelofibrosis / Q000473:pathology* / Q000628:therapy; D008249:Protein-Lysine 6-Oxidase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; D008249:Protein-Lysine 6-Oxidase; D020797:Receptor, Platelet-Derived Growth Factor beta