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Potential Role of Proprotein Convertase SKI-1 in the Mineralization of Primary Bone

机译：前蛋白转化酶SKI-1在原发性骨矿化中的潜在作用

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The biochemical mechanism controlling nucleation of mineral crystals in developing bone, along with the growth and propagation of these crystals once formed, remains poorly understood. To define the nucleation mechanism, a proteomics analysis was begun on isolated biomineralization foci (BMF), sites of initial crystal nucleation in osteoblastic cell cultures and in primary bone. Comparative analyses of the protein profile for mineralized BMF with that for total osteoblast cultures revealed the latter were enriched in several proteins including BAG-75 and BSP, as well as fragments of each. When 12 protease inhibitors were added separately to UMR 106-01 osteoblastic cultures, only the serine protease inhibitor 4-(2-aminoethyl) benzenesulfonyl fluoride hydrochloride (AEBSF) blocked cleavage of BAG-75 and BSP, and prevented mineral crystal nucleation within BMF. Consideration of the specificities of the inhibitors tested and the fact that AEBSF inhibition was not dependent upon inclusion of FBS in the culture media indicated that mineral nucleation does not require serine protease plasmin, thrombin, kallikrein, urokinase, C1s or furin. In contrast, SKI-1 (S1P or site-1) is a membrane-bound serine protease inhibitable by AEBSF. We show here for the first time that mineralizing UMR 106 cells express a 98-kDa active, soluble form of SKI-1 within BMF. In contrast, nonmineralizing UMR cells appear to differentially process SKI-1 into smaller immunoreactive fragments (<35 kDa). These findings suggest that SKI-1 plays a direct or indirect role in assembly of functional nucleation complexes containing BAG-75 and BSP and their fragments, thus facilitating initial mineral nucleation within these biomineralization foci.
机译：控制发育中的骨骼中矿物晶体的成核以及这些晶体一旦形成的生长和传播的生化机制仍然知之甚少。为了定义成核机理，蛋白质组学分析开始于孤立的生物矿化灶（BMF），成骨细胞培养物中和初生骨中初始晶体成核的位点。对矿化的BMF和总成骨细胞培养物的蛋白质谱进行比较分析，发现后者富含多种蛋白质，包括BAG-75和BSP，以及每种蛋白质的片段。当将12种蛋白酶抑制剂分别添加到UMR 106-01成骨细胞培养物中时，只有丝氨酸蛋白酶抑制剂4-（2-氨基乙基）苯磺酰氟盐酸盐（AEBSF）阻止BAG-75和BSP的裂解，并阻止了BMF中矿物晶体的成核。考虑到所测试抑制剂的特异性以及AEBSF抑制不依赖于培养基中FBS的存在，这一事实表明矿物质成核不需要丝氨酸蛋白酶纤溶酶，凝血酶，激肽释放酶，尿激酶，Cls或弗林蛋白酶。相反，SKI-1（S1P或site-1）是AEBSF抑制的膜结合丝氨酸蛋白酶。我们首次在这里显示矿化的UMR 106细胞在BMF中表达98 kDa的活性，可溶形式的SKI-1。相反，未矿化的UMR细胞似乎可以将SKI-1差异化加工成较小的免疫反应性片段（<35 kDa）。这些发现表明，SKI-1在包含BAG-75和BSP及其片段的功能性成核复合体的组装中起直接或间接的作用，从而促进了这些生物矿化焦点内的初始矿物成核。

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