Osteosclerosis in advanced chronic idiopathic myelofibrosis is associated with endothelial overexpression of osteoprotegerin.
Advanced chronic idiopathic myelofibrosis (IMF) with osteosclerosis and increase and thickening of bone trabeculae is typically contrasted by the absence or sparse presence of osteoclasts. Because osteoclast formation can be inhibited by osteoprotegerin (OPG) we investigated OPG expression in IMF with severe fibrosis and osteosclerosis, which expressed significantly higher (up to 71-fold) OPG mRNA levels when compared with prefibrotic cellular IMF and control cases. The receptor activator of nuclear factor kappaB ligand (RANKL), a positive regulator of osteoclast differentiation and putative antagonist of OPG was overexpressed by up to 34-fold exclusively in advanced IMF. Case-specific calculation of the RANKL/OPG ratio in advanced IMF showed a wide range without significant differences when compared with the prefibrotic IMF and non-neoplastic haematopoiesis. Immunohistochemical detection of OPG protein revealed strong labelling of endothelial cells within proliferating vessels in fibrotic IMF and heterogeneously labelled megakaryocytes, and fibroblasts. Osteosclerosis and impaired osteoclast function in IMF appears to be associated with upregulated endothelial OPG expression but concomitant reduction of the antagonist RANKL could not be demonstrated. We conclude that osteosclerosis in IMF is associated with increased endothelial OPG expression without concomitant RANKL downregulation.
Bock
Oliver
O
Institute of Pathology, Medizinische Hochschule Hannover, Hannover, Germany. bock.oliver@mh-hannover.de
Loch
Gero
G
Schade
Ulrika
U
Büsche
Guntram
G
Wasielewski
Reinhard
R
Wiese
Birgitt
B
Kreipe
Hans
H
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001856:Bone Marrow Examination; D002352:Carrier Proteins / Q000235:genetics; D042783:Endothelial Cells / Q000737:chemistry / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000737:chemistry; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D008533:Megakaryocytes / Q000737:chemistry; D008562:Membrane Glycoproteins / Q000235:genetics; D008875:Middle Aged; D010010:Osteoclasts / Q000473:pathology; D053244:Osteoprotegerin; D010026:Osteosclerosis / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D055728:Primary Myelofibrosis / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D053245:RANK Ligand; D012333:RNA, Messenger / Q000032:analysis; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D002352:Carrier Proteins; D006023:Glycoproteins; D008562:Membrane Glycoproteins; D053244:Osteoprotegerin; D053245:RANK Ligand; D012333:RNA, Messenger; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; C505686:TNFRSF11A protein, human; C506030:TNFRSF11B protein, human; C505688:TNFSF11 protein, human