title: Matrix metalloproteinase-12 (MMP-12) in osteoclasts: new lesson on the involvement of MMPs in bone resorption.
abstract: Osteoclasts require matrix metalloproteinase (MMP) activity and cathepsin K to resorb bone, but the critical MMP has not been identified. Osteoclasts express MMP-9 and MMP-14, which do not appear limiting for resorption, and the expression of additional MMPs is not clear. MMP-12, also called metalloelastase, is reported only in a few cells, including tissue macrophages and hypertrophic chondrocytes. MMP-12 is critical for invasion and destruction in pathologies such as aneurysm and emphysema. In the present study, we demonstrate that osteoclasts express MMP-12, although only in some situations. Northern blots show that highly purified rabbit osteoclasts in culture express MMP-12 at the same level as macrophages, whereas in situ hybridizations performed on rabbit bone do not show any MMP-12 expression in osteoclasts whatever the bone type. In contrast, in situ hybridizations performed on mouse bone show MMP-12 expression in osteoclasts in calvariae and long bones. We also demonstrate that recombinant MMP-12 cleaves the putative functional domains of osteopontin and bone sialoprotein, two bone matrix proteins that strongly influence osteoclast activities, such as attachment, spreading and resorption. Furthermore, we investigated the role of MMP-12 in bone resorption and osteoclast recruitment by comparing MMP-12 knockout and wild-type mice in specialized culture models known to depend on MMP activity, as well as in the ovariectomy model, and we did not find any indication for a limiting role of MMP-12 in these processes. In conclusion, we found that osteoclasts are able to express MMP-12, but MMP-12 did not appear critical for osteoclast recruitment or resorption. The fact that none of the MMPs identified so far in osteoclasts appears limiting for resorption, gives strength to the hypothesis that the critical MMP for bone solubilization is produced by non-osteoclastic cells.
authors.affiliation: Nordic Bioscience/Center for Clinical and Basic Research, Herlev, Ballerup, Denmark.
authors.forename: Peng
authors.initials: P
authors.lastname: Hou
authors.forename: Tine
authors.initials: T
authors.lastname: Troen
authors.forename: Maria C
authors.initials: MC
authors.lastname: Ovejero
authors.forename: Tove
authors.initials: T
authors.lastname: Kirkegaard
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Andersen
authors.forename: Inger
authors.initials: I
authors.lastname: Byrjalsen
authors.forename: Mercedes
authors.initials: M
authors.lastname: Ferreras
authors.forename: Takuya
authors.initials: T
authors.lastname: Sato
authors.forename: Steven D
authors.initials: SD
authors.lastname: Shapiro
authors.forename: Niels T
authors.initials: NT
authors.lastname: Foged
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Delaissé
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015152:Blotting, Northern; D001857:Bone Matrix / Q000378:metabolism; D001862:Bone Resorption / Q000201:enzymology* / Q000378:metabolism; D002478:Cells, Cultured; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000235:genetics; D005260:Female; D053508:Matrix Metalloproteinase 12; D008666:Metalloendopeptidases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D010010:Osteoclasts / Q000166:cytology / Q000201:enzymology* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011817:Rabbits; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment
chemical_list: D018076:DNA, Complementary; D012333:RNA, Messenger; D011994:Recombinant Proteins; D008666:Metalloendopeptidases; D053508:Matrix Metalloproteinase 12