Mimicry between neurokinin-1 and fibronectin may explain the transport andstability of increased substance P immunoreactivity in patients with bone marrow fibrosis

Bone marrow (BM) fibrosis may occur in myeloproliferative diseases, lymphom a, myelodysplastic syndrome, myeloma, and infectious diseases. In this stud y, the role of substance P (SP), a peptide with pleiotropic functions, was examined. Some of its functions-angiogenesis, fibroblast proliferation, and stimulation of BM progenitors-are amenable to inducing BM fibrosis. Indeed , a significant increase was found in SP-Immunoreactivity (SP-IR) in the se ra of patients with BM fibrosis (n = 44) compared with the sera of patients with hematologic disorders and no histologic evidence of fibrosis (n = 46) (140 +/- 12 vs 18 +/- 3; P<.01). Immunoprecipitation of sera SP indicated that this peptide exists in the form of a complex with other molecule(s). I t was, therefore, hypothesized that SP might be complexed with NK-1, its na tural receptor, or with a molecule homologous to NK-1. To address this, 3 c DNA libraries were screened that were constructed from pooled BM stroma or mononuclear cells with an NK-1 cDNA probe. A partial clone (clone 1) was re trieved that was 97% homologous to the ED-A region of fibronectin (FIN). Fu rthermore, sequence analyses indicated that clone 1 shared significant homo logy with exon 5 of NK-1. Immunoprecipitation and Western blot analysis ind icated co-migration of SP and FN in 27 of 31 patients with BM fibrosis. Com puter-assisted molecular modeling suggested that similar secondary structur al features between FN and NK-1 and the relative electrostatic charge might explain a complex formed between FN (negative) and SIR (positive). This st udy suggests that SP may be implicated in the pathophysiology of myelofibro sis, though its role would have to be substantiated in future research. (Bl ood. 2001;97:3025-3031) (C) 2001 by The American Society of Hematology.