INCREASED PROLIFERATION OF BONE-MARROW-DERIVED FIBROBLASTS IN PRIMITIVE HYPERTROPHIC OSTEOARTHROPATHY WITH SEVERE MYELOFIBROSIS

Pachydermoperiostosis or primary hypertrophic osteoarthropathy (HOA) i s a rare congenital growth disorder of connective tissue, We report a case of severe myelofibrosis in a patient with HOA. When cultured in v itro, patient bone marrow-derived fibroblasts displayed a high prolife rative potential with a shortened doubling time (24 hours v 36 to 48 h ours for normal fibroblasts). The role of platelet-derived growth fact or (PDGF), previously implicated in the pathogenesis of secondary acqu ired myelofibrosis, was studied, HOA fibroblasts expressed an increase d number of PDGF-BB binding sites (300,000 sites/cell v 200,000 sites/ cell for normal fibroblasts) without any modification of affinity. The increased expression of PDGF-R beta appeared to result from an accele rated rate of PDGF-R beta resynthesis with normal kinetics of endocyto sis, As a consequence, a several-fold increase of PDGF-R beta tyrosine kinase activity was observed, No autocrine mechanism of growth was su spected as neither spontaneous PDGF-R beta autophosphorylation nor mit ogenic activity in HOA fibroblast-conditioned medium was detected. Pat ient serum and platelet lysate were less potent than controls in induc ing [H-3]thymidine incorporation into HOA fibroblasts. This was incons istent with a paracrine mechanism of growth, In vitro, human serum or PDGF-BB were not more mitogenic for HOA than normal fibroblasts. High levels of cyclin D1, a putative oncogene, were detected in serum-depri ved HOA fibroblasts, Cyclin D1 overexpression could be implicated in t he accelerated growth of these cells. Our results suggest that the mec hanism of fibroblastic proliferation observed in this case of myelofib rosis might differ from those reported in other acquired myeloprolifer ative syndromes and could be associated with an intrinsic abnormality of HOA fibroblast growth. (C) 1995 by The American Society of Hematolo gy.