Mimicry between neurokinin-1 and fibronectin may explain the transport and stability of increased substance P immunoreactivity in patients with bone marrow fibrosis.
Bone marrow (BM) fibrosis may occur in myeloproliferative diseases, lymphoma, myelodysplastic syndrome, myeloma, and infectious diseases. In this study, 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 sera 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). It was, therefore, hypothesized that SP might be complexed with NK-1, its natural receptor, or with a molecule homologous to NK-1. To address this, 3 cDNA 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 retrieved that was 97% homologous to the ED-A region of fibronectin (FN). Furthermore, sequence analyses indicated that clone 1 shared significant homology with exon 5 of NK-1. Immunoprecipitation and Western blot analysis indicated co-migration of SP and FN in 27 of 31 patients with BM fibrosis. Computer-assisted molecular modeling suggested that similar secondary structural features between FN and NK-1 and the relative electrostatic charge might explain a complex formed between FN (negative) and SP (positive). This study suggests that SP may be implicated in the pathophysiology of myelofibrosis, though its role would have to be substantiated in future research. (Blood. 2001;97:3025-3031)
Rameshwar
P
P
Department of Medicine, UMDNJ-New Jersey Medical School, Newark, NJ 07103, USA. rameshwa@umdnj.edu
Joshi
D D
DD
Yadav
P
P
Qian
J
J
Gascon
P
P
Chang
V T
VT
Anjaria
D
D
Harrison
J S
JS
Song
X
X
D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D001665:Binding Sites; D001692:Biological Transport; D018076:DNA, Complementary / Q000737:chemistry; D004355:Drug Stability; D005353:Fibronectins / Q000097:blood* / Q000737:chemistry / Q000235:genetics; D006801:Humans; D007163:Immunosorbent Techniques; D008875:Middle Aged; D008958:Models, Molecular; D008970:Molecular Weight; D009196:Myeloproliferative Disorders / Q000150:complications; D055728:Primary Myelofibrosis / Q000097:blood* / Q000150:complications; D017510:Protein Folding; D018040:Receptors, Neurokinin-1 / Q000097:blood* / Q000737:chemistry / Q000235:genetics; D017385:Sequence Homology; D055672:Static Electricity; D013373:Substance P / Q000097:blood* / Q000737:chemistry
D018076:DNA, Complementary; D005353:Fibronectins; D018040:Receptors, Neurokinin-1; D013373:Substance P