title: Blood-derived human osteoclast resorption activity is impaired by Hyaluronan-CD44 engagement via a p38-dependent mechanism.
abstract: The control of bone resorption is crucial in osteolytic diseases. Once attached to bone, osteoclasts (OCs) initiate the resorption process through the activation of a complex cascade of morphological and biochemical changes. Hyaluronan (HA), an extracellular glycosaminoglycan long non-branching polysaccharide, is expressed in bone matrices. Here we demonstrate that HA counter-balances the erosion activity of human mature OCs by significantly reducing their degradative potential. HA treatment of fully differentiated OCs derived from human peripheral blood monocytes inhibited migration on collagen as well as bone resorption. HA-mediated effects were primarily due to TRAcP, MMP-9, and cathepsin K down-regulation and to the increased levels of TIMP-1, a natural MMP-9 inhibitor. Binding of HA to mature OCs was entirely mediated by CD44: function-blocking anti-CD44 antibodies fully abrogated HA effects, and the engagement of HA receptor caused a rapid de-phosphorylation of Ser325 in the CD44 cytoplasmic tail. The inhibitory action by HA was associated with a transient up-phosphorylation of Pyk2, a novel persistent phosphorylation of p38 and the down-regulation of NFATc1 transcription factor. Our results provide a direct evidence for the involvement of CD44 in the HA-dependent regulation of OC activity and suggest a signaling pathway that could be unique in OC function inhibition.
authors.affiliation: Experimental Oncology 2, CRO, IRCCS, National Cancer Institute, Aviano, PN, Italy.
authors.forename: Eliana
authors.initials: E
authors.lastname: Pivetta
authors.forename: Martina
authors.initials: M
authors.lastname: Scapolan
authors.forename: Bruna
authors.initials: B
authors.lastname: Wassermann
authors.forename: Agostino
authors.initials: A
authors.lastname: Steffan
authors.forename: Alfonso
authors.initials: A
authors.lastname: Colombatti
authors.forename: Paola
authors.initials: P
authors.lastname: Spessotto
mesh_terms: D000135:Acid Phosphatase / Q000378:metabolism; D001862:Bone Resorption / Q000097:blood* / Q000201:enzymology*; D002454:Cell Differentiation / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D048430:Cell Shape / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D006820:Hyaluronic Acid / Q000494:pharmacology*; D007527:Isoenzymes / Q000378:metabolism; D008954:Models, Biological; D050778:NFATC Transcription Factors / Q000378:metabolism; D010010:Osteoclasts / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology*; D011485:Protein Binding / Q000187:drug effects; D000071681:Tartrate-Resistant Acid Phosphatase; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D018960:Hyaluronan Receptors; D007527:Isoenzymes; D050778:NFATC Transcription Factors; D006820:Hyaluronic Acid; D048051:p38 Mitogen-Activated Protein Kinases; D000135:Acid Phosphatase; D000071681:Tartrate-Resistant Acid Phosphatase