Osteitis fibrosa is mediated by Platelet-Derived Growth Factor-A via a phosphoinositide 3-kinase-dependent signaling pathway in a rat model for chronic hyperparathyroidism.
Abnormal secretion of PTH by the parathyroid glands contributes to a variety of common skeletal disorders. Prior studies implicate platelet-derived growth factor-A (PDGF-A) as an important mediator of selective PTH actions on bone. The present studies used targeted gene profiling and small-molecule antagonists directed against candidate gene products to elucidate the roles of specific PTH-regulated genes and signaling pathways. A group of 29 genes in rats continuously infused with PTH and cotreated with the PDGF receptor antagonist trapidil were differentially expressed compared with PTH treatment alone. Several of the identified genes were functionally clustered as regulators of fibroblast differentiation and extracellular matrix modeling, including the matrix cross-linking enzyme lysyl oxidase (LOX). Treatment with beta-aminopropionitrile, an irreversible inhibitor of LOX activity, dramatically reduced diffuse mineralization but had no effect on PTH-induced fibrosis. In contrast, the receptor tyrosine kinase inhibitor Gleevec and the phosphoinositide 3-kinase inhibitor wortmannin each reduced bone marrow fibrosis. In summary, the present studies support the hypotheses that PTH-induced bone marrow fibrosis is mediated by PDGF-A via a phosphoinositide 3-kinase-dependent signaling pathway and that increased LOX gene expression plays a key role in abnormal mineralization, a hallmark of chronic hyperparathyroidism.
Lowry
Malcolm B
MB
Department of Microbiology, Oregon State University, Corvallis, Oregon 97331, USA. malcolm.lowry@oregonstate.edu
Lotinun
Sutada
S
Leontovich
Alexey A
AA
Zhang
Minzhi
M
Maran
Avudaiappan
A
Shogren
Kristen L
KL
Palama
Brett K
BK
Marley
Kevin
K
Iwaniec
Urszula T
UT
Turner
Russell T
RT
D000818:Animals; D002908:Chronic Disease; D016000:Cluster Analysis; D004195:Disease Models, Animal; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D006961:Hyperparathyroidism / Q000150:complications* / Q000235:genetics / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D010002:Osteitis Fibrosa Cystica / Q000209:etiology* / Q000235:genetics; D010281:Parathyroid Hormone / Q000008:administration & dosage / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D010982:Platelet-Derived Growth Factor / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology
D010281:Parathyroid Hormone; D010982:Platelet-Derived Growth Factor; C075278:platelet-derived growth factor A; D019869:Phosphatidylinositol 3-Kinases