Regulation of extracellular matrix structure as a biological response to chemical stimuli and irradiation

乙酰肝素酶最初被鉴定为内切β-葡萄糖醛酸酶，其切割硫酸乙酰肝素蛋白聚糖，并且该酶的病理作用在癌症生物学领域中被广泛研究。在本研究中，我们研究了乙酰肝素酶在免疫系统中的功能相关性以及对化学刺激和辐射的生物反应。乙酰肝素酶参与单核细胞对基底膜的降解。细胞表面分子的帽化和随后在前沿的重新分布是导致降解的原因。制备了一系列抗小鼠乙酰肝素酶的单克隆抗体，并用于检测该酶在细胞内的分布。在皮肤肥大细胞和炎症微血管中的中性粒细胞中检测到颗粒中的乙酰肝素酶积聚。肝素酶参与肝素加工和调节颗粒功能进行了检查。当乙酰肝素酶基因或重组蛋白掺入MST肥大细胞瘤细胞，活性乙酰肝素酶定位于颗粒。在这些修饰的MST细胞中，颗粒状肝素被切割成较小的分子大小，颗粒状酶的活性似乎受到低分子量肝素的调节。乙酰肝素酶介导的硫酸乙酰肝素和肝素的裂解可能调节免疫系统中细胞功能所必需的过程，并因此极大地参与对化学刺激和辐射的生物反应。

Heparanase was originally identified as an endo-beta-glucuronidase which cleaves heparan sulfate proteoglycan, and the enzyme' s pathological roles were extensively investigated in the field of cancer biology. In the present study, we examined functional relevance of heparanase in the immune system and biological responses to chemical stimuli and irradiation. Heparanase is involved in degradation of the basement membranes by monocytes. Capping of the molecule on the cell surface and subsequent redistribution at the leading edge are responsible for the degradation. A series of anti-mouse heparanase monoclonal antibodies were established and used to examine the intracellular distribution of the enzyme. Heparanase accumulation in the granules was detected in skin mast cells and in neutrophils in the inflamed microvasculature. Involvement of heparanase in heparin processing and modulation of granular function was examined. When heparanase gene or recombinant proteins were incorporated into MST mastcytoma cells, active heparanase was localized to the granules. In these modified MST cells, granular heparin was cleaved into a smaller molecular size and activity of granular enzymes seemed to be modulated by the low-molecular-weight heparin. Heparanase-mediated cleavage of heparan sulfate and heparin is likely to regulate processes essential to the functions of cells in the immune system and there by greatly involved in biological responses to chemical stimuli and irradiation.