Clinical Cell Biology (KCB), Institute of Regional Health Research (IRS), University of Southern Denmark, Vejle/Lillebælt Hospital, Kabbeltoft 25, 7100 Vejle, Denmark.
Bone Biology Group, Merck Research Laboratories, West Point, PA 19486, USA.
Biochem Biophys Res Commun. 2014 Jan 10;443(2):694-9. doi: 10.1016/j.bbrc.2013.12.036. Epub 2013 Dec 12.
The bone matrix is maintained functional through the combined action of bone resorbing osteoclasts and bone forming osteoblasts, in so-called bone remodeling units. The coupling of these two activities is critical for securing bone replenishment and involves osteogenic factors released by the osteoclasts. However, the osteoclasts are separated from the mature bone forming osteoblasts in time and space. Therefore the target cell of these osteoclastic factors has remained unknown. Recent explorations of the physical microenvironment of osteoclasts revealed a cell layer lining the bone marrow and forming a canopy over the whole remodeling surface, spanning from the osteoclasts to the bone forming osteoblasts. Several observations show that these canopy cells are a source of osteoblast progenitors, and we hypothesized therefore that they are the likely cells targeted by the osteogenic factors of the osteoclasts. Here we provide evidence supporting this hypothesis, by comparing the osteoclast-canopy interface in response to two types of bone resorption inhibitors in rabbit lumbar vertebrae. The bisphosphonate alendronate, an inhibitor leading to low bone formation levels, reduces the extent of canopy coverage above osteoclasts. This effect is in accordance with its toxic action on periosteoclastic cells. In contrast, odanacatib, an inhibitor preserving bone formation, increases the extent of the osteoclast-canopy interface. Interestingly, these distinct effects correlate with how fast bone formation follows resorption during these respective treatments. Furthermore, canopy cells exhibit uPARAP/Endo180, a receptor able to bind the collagen made available by osteoclasts, and reported to mediate osteoblast recruitment. Overall these observations support a mechanism where the recruitment of bone forming osteoblasts from the canopy is induced by osteoclastic factors, thereby favoring initiation of bone formation. They lead to a model where the osteoclast-canopy interface is the physical site where coupling of bone resorption to bone formation occurs.
骨基质通过骨吸收破骨细胞和骨形成成骨细胞的联合作用得以维持其功能，这种作用发生在所谓的骨重建单位中。这两种活性的偶联对于确保骨补充至关重要，并且涉及破骨细胞释放的成骨因子。然而，破骨细胞在时间和空间上与成熟的成骨细胞分离。因此，这些破骨细胞因子的靶细胞仍然未知。最近对破骨细胞的物理微环境的探索揭示了衬在骨髓中的细胞层，并在整个重塑表面上形成一个覆盖物，跨越从破骨细胞到成骨细胞的区域。有几个观察结果表明，这些覆盖细胞是成骨细胞祖细胞的来源，因此我们假设它们是破骨细胞成骨因子的可能靶向细胞。在这里，我们通过比较兔腰椎中两种类型的骨吸收抑制剂对破骨细胞-覆盖物界面的影响，为这一假设提供了证据。双膦酸盐阿仑膦酸盐是一种导致低骨形成水平的抑制剂，它减少了覆盖在破骨细胞上方的覆盖物的范围。这种效应与它对破骨细胞周围细胞的毒性作用一致。相比之下，odanacatib 是一种保留骨形成的抑制剂，增加了破骨细胞-覆盖物界面的范围。有趣的是，这些不同的效应与这两种抑制剂各自作用时骨吸收后骨形成的速度有关。此外，覆盖细胞表达 uPARAP/Endo180，这是一种能够结合破骨细胞释放的胶原蛋白的受体，并且据报道它介导成骨细胞的募集。总的来说，这些观察结果支持了一种机制，即破骨细胞因子诱导成骨细胞从覆盖物中募集，从而有利于骨形成的启动。它们提出了一个模型，即破骨细胞-覆盖物界面是骨吸收与骨形成偶联发生的物理部位。
