Structural similarity between the bone marrow extracellular matrix protein and neurokinin 1 could be the limiting factor in the hematopoietic effects of substance P.
In the adult bone marrow (BM), immune cells are replenished through the process of definitive hematopoiesis, which is regulated by a complex process of cellular and humoral interactions. The latter include substance P (SP), a neurotransmitter that is produced by neural and nonneural cells. Neurokinin-1 (NK-1), the high-affinity SP receptor, shares structural similarity with fibronectin, a component of the BM extracellular matrix proteins. This study examines how such similarity could alter the effects of SP on the proliferation of the immature BM progenitors. In vitro studies show that 1 ng fibronectin/mL enhanced the stimulatory effect of SP on the proliferation of primitive BM progenitors. This finding was studied by computational studies: proteomics and three-dimensional molecular modeling. Use of surface-enhanced laser desorption/ionization ProteinChip technology showed that despite the induction of neutral endopeptidase, exogenous fibronectin hindered the degradation of SP to SP(1-4). These findings support a protective role for fibronectin in the digestion of SP. Since SP(1-4) is a negative regulator of hematopoiesis, this report indicates that the structural similarity between fibronectin and NK-1 could be important for maintaining hematopoietic stimulation. These studies could be extrapolated to hematological disorders that are associated with SP-fibronectin complexes.
Rameshwar
Pranela
P
Department of Medicine, UMDNJ-New Jersey Medical School, Newark 07103, USA. rameshwa@umdnj.edu
Gascon
Pedro
P
Bandari
Persis S
PS
Joshi
Deval D
DD
Fernandes
Annemarie
A
Dang
Anju
A
D001853:Bone Marrow / Q000737:chemistry* / Q000187:drug effects* / Q000378:metabolism; D002478:Cells, Cultured; D016326:Extracellular Matrix Proteins / Q000737:chemistry* / Q000378:metabolism; D005353:Fibronectins / Q000494:pharmacology; D006412:Hematopoietic Stem Cells / Q000187:drug effects; D006801:Humans; D008958:Models, Molecular; D018040:Receptors, Neurokinin-1 / Q000737:chemistry* / Q000378:metabolism; D017154:Stromal Cells / Q000737:chemistry / Q000378:metabolism; D040681:Structural Homology, Protein; D013373:Substance P / Q000378:metabolism / Q000494:pharmacology*
D016326:Extracellular Matrix Proteins; D005353:Fibronectins; D018040:Receptors, Neurokinin-1; D013373:Substance P