Abstract
A review of the available literature was performed in order to summarize the existing evidence between osteoblast dysfunction and clinical features in non-hereditary sclerosing bone diseases. It has been known that proliferation and migration of osteoblasts are concerted by soluble factors such as fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), transforming growth factor (TGF), bone morphogenetic protein (BMP) but also by signal transduction cascades such as Wnt signaling pathway. Protein kinases play also a leading role in triggering the activation of osteoblasts in this group of diseases. Post-zygotic changes in mitogen-activated protein kinase (MAPK) have been shown to be associated with sporadic cases of Melorheostosis. Serum levels of FGF and PDGF have been shown to be increased in myelofibrosis, although studies focusing on Sphingosine-1-phosphate receptor was shown to be strongly expressed in Paget disease of the bone, which may partially explain the osteoblastic hyperactivity during this condition. Pathophysiological mechanisms of osteoblasts in osteoblastic metastases have been studied much more thoroughly than in rare sclerosing syndromes: striking cellular mechanisms such as osteomimicry or complex intercellular signaling alterations have been described. Further research is needed to describe pathological mechanisms by which rare sclerosing non hereditary diseases lead to osteoblast dysfunction.
Highlights
Sclerosing bone diseases are a heterogeneous group of skeletal alterations that share the process of impaired bone ossification
Impaired levels of soluble factors influencing osteoblast (Ob) metabolism such as fibroblast growth factor (FGF), platelet-derived growth factor (PDGF) or bone morphogenetic protein (BMP) or alterations of intracellular pathways such as Wnt signaling, Mitogen-activated protein kinase (MAPK) signaling, Receptor activator of NF-κB (RANK)/ RANK ligand (RANKL)/ Osteoprotegerin (OPG) pathway have been described in this group of diseases
Somatic mosaicisms for mitogen-activated protein kinase (MAP2K1)-activating mutations are involved in the pathogenesis of melorheostosis; it has been shown that SMAD3 p.S264 substitutions increase transforming growth factor β (TGF-β) signaling, which in turn leads to an increased Ob proliferation and a consequent bone sclerosis [17,18]
Summary
Sclerosing bone diseases are a heterogeneous group of skeletal alterations that share the process of impaired bone ossification. They are mostly rare diseases that are usually classified in hereditary and non-hereditary bone diseases. Non-hereditary sclerosing bone diseases include intramedullary osteosclerosis, melorheostosis, Paget disease of bone, Erdheim-Chester disease, myelofibrosis and sickle cell disease. Ob metastases showed peculiar mechanisms inducing osteosclerosis such as cross-talk between cancer cells and Ob. The aim of this review is to describe the main clinical features in non-hereditary sclerosing bone diseases and to review the existing evidence concerning the Ob dysfunction involved in the physiopathological mechanism of these disorders
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