Hou Peng, Troen Tine, Ovejero Maria C, Kirkegaard Tove, Andersen Thomas L, Byrjalsen Inger, Ferreras Mercedes, Sato Takuya, Shapiro Steven D, Foged Niels T, Delaissé Jean-Marie
Nordic Bioscience/Center for Clinical and Basic Research, Herlev, Ballerup, Denmark.
Bone. 2004 Jan;34(1):37-47. doi: 10.1016/j.bone.2003.08.011.
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.
破骨细胞需要基质金属蛋白酶（MMP）活性和组织蛋白酶K来吸收骨质，但关键的MMP尚未确定。破骨细胞表达MMP - 9和MMP - 14，它们似乎对吸收过程没有限制作用，其他MMP的表达情况尚不清楚。MMP - 12，也称为金属弹性蛋白酶，仅在少数细胞中报道过，包括组织巨噬细胞和肥大软骨细胞。MMP - 12在诸如动脉瘤和肺气肿等病理状态的侵袭和破坏过程中起关键作用。在本研究中，我们证明破骨细胞能够表达MMP - 12，尽管只是在某些情况下。Northern印迹显示，培养的高度纯化的兔破骨细胞表达MMP - 12的水平与巨噬细胞相同，而对兔骨进行的原位杂交显示，无论何种骨类型，破骨细胞中均未显示出任何MMP - 12表达。相反，对小鼠骨进行的原位杂交显示，在颅骨和长骨的破骨细胞中有MMP - 12表达。我们还证明，重组MMP - 12可切割骨桥蛋白和骨唾液蛋白的假定功能结构域，这两种骨基质蛋白对破骨细胞的活动，如黏附、铺展和吸收有强烈影响。此外，我们通过在已知依赖MMP活性的特殊培养模型以及卵巢切除模型中比较MMP - 12基因敲除小鼠和野生型小鼠，研究了MMP - 12在骨吸收和破骨细胞募集中的作用，我们没有发现任何迹象表明MMP - 12在这些过程中起限制作用。总之，我们发现破骨细胞能够表达MMP - 12，但MMP - 12似乎对破骨细胞的募集或吸收并不关键。迄今为止在破骨细胞中鉴定出的MMP均未显示出对吸收有限制作用，这一事实支持了一种假说，即溶解骨质的关键MMP是由非破骨细胞产生的。
