title: Increased expression of activating factors in large osteoclasts could explain their excessive activity in osteolytic diseases.
abstract: Large osteoclasts (>or=10 nuclei) predominate at sites of pathological bone resorption. We hypothesized this was related to increased resorptive activity of large osteoclasts and have demonstrated previously that larger osteoclasts are 8-fold more likely to be resorbing than small osteoclasts (2-5 nuclei). Here we ask whether these differences in resorptive activity can be explained by differences in expression of factors involved in osteoclast signaling, fusion, attachment, and matrix degradation. Authentic rabbit osteoclasts and osteoclasts derived from RAW264.7 cells showed similar increases in c-fms expression (1.7- to 1.8-fold) in large osteoclasts suggesting that RAW cells are a viable system for further analysis. We found 2- to 4.5-fold increases in the expression of the integrins alpha(v) and beta(3), the proteases proMMP9, matMMP9 and pro-cathepsinK, and in activating receptors RANK, IL-1R1, and TNFR1 in large osteoclasts. In contrast, small osteoclasts had higher expression of the fusion protein SIRPalpha1 and the decoy receptor IL-1R2. The higher expression of activation receptors and lower expression of IL-1R2 in large osteoclasts suggest they are hyperresponsive to extracellular factors. This is supported by the observation that the resorptive activity in large osteoclasts was more responsive to IL-1beta, and that this increased activity was inhibited by the IL-1 receptor antagonist, IL-1ra. This increased responsiveness of large osteoclasts to IL-1 may, in part, explain the pathological bone loss noted in inflammatory diseases. The heterogeneity in receptor expression and the differential response to cytokines and their antagonists could prove useful for selective inhibition of large osteoclasts actively engaged in pathological bone loss.
authors.affiliation: Department of Biochemistry, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada. diana.trebec@utoronto.ca
authors.forename: Diana P
authors.initials: DP
authors.lastname: Trebec
authors.forename: Divya
authors.initials: D
authors.lastname: Chandra
authors.forename: Azza
authors.initials: A
authors.lastname: Gramoun
authors.forename: Keying
authors.initials: K
authors.lastname: Li
authors.forename: Johan N M
authors.initials: JN
authors.lastname: Heersche
authors.forename: Morris F
authors.initials: MF
authors.lastname: Manolson
mesh_terms: D000135:Acid Phosphatase / Q000032:analysis; D000818:Animals; D001168:Arthritis / Q000378:metabolism* / Q000473:pathology; D002460:Cell Line; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D004792:Enzyme Precursors / Q000378:metabolism; D015151:Immunoblotting; D007249:Inflammation; D039222:Integrin alpha1beta1 / Q000378:metabolism; D053590:Interleukin 1 Receptor Antagonist Protein / Q000032:analysis / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D007527:Isoenzymes / Q000032:analysis; D016173:Macrophage Colony-Stimulating Factor / Q000032:analysis / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D010010:Osteoclasts / Q000378:metabolism*; D053245:RANK Ligand / Q000032:analysis / Q000378:metabolism; D011817:Rabbits; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000378:metabolism; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000032:analysis / Q000378:metabolism; D011971:Receptors, Immunologic / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000071681:Tartrate-Resistant Acid Phosphatase; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000378:metabolism
chemical_list: D016207:Cytokines; D004792:Enzyme Precursors; D039222:Integrin alpha1beta1; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D007527:Isoenzymes; C501922:Sirpa protein, mouse; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D011971:Receptors, Immunologic; D014409:Tumor Necrosis Factor-alpha; D016173:Macrophage Colony-Stimulating Factor; D016186:Receptor, Macrophage Colony-Stimulating Factor; D000135:Acid Phosphatase; D000071681:Tartrate-Resistant Acid Phosphatase; C120487:pro-matrix metalloproteinase 9; D020780:Matrix Metalloproteinase 9