Heparanase regulation of osteolysis in multiple myeloma.

描述（由申请人提供）：骨髓瘤是一种无法治愈的恶性肿瘤，过度的骨破坏是骨髓瘤患者发病的主要原因。然而，骨髓瘤诱导骨病发病的生物学机制尚不清楚。肝素酶是一种酶，它可以切割蛋白质多糖的硫酸肝素链，在多种人类肿瘤中，包括骨髓瘤中，它的表达都是上调的。我之前已经证明肝素酶促进骨髓瘤肿瘤的生长并支持自发骨转移。此外，我最近有一个惊人的发现，骨髓瘤肿瘤细胞中肝素酶的表达是溶骨表型的主要决定因素，它有力地促进了局部和全身的骨溶解。该项目的目标是确定肝素酶如何促进骨髓瘤诱导的骨病，并确定抑制肝素酶治疗骨髓瘤骨病的潜力。NF-?受体激活因子激活骨吸收破骨细胞的形成和功能B配体（RANKL），受骨保护素（OPG）抑制。活化的破骨细胞分泌基质金属蛋白酶-9 (MMP-9)，降解骨组织。我和我的同事们首次发现，肝素酶可以显著提高骨髓瘤细胞中RANKL、MMP-9和转录因子Runx2的表达。此外，肝素酶增加RANKL，降低成骨细胞前体中OPG的表达。在这里，我假设肝素酶通过上调Runx2，增加骨髓瘤细胞中RANKL和MMP-9的表达和分泌，从而促进骨髓瘤骨溶解。我进一步假设肝素酶调节成骨细胞前体以增强其作为破骨细胞支持细胞的作用。因此，骨髓瘤骨病可以通过抑制肝素酶得到改善。为了验证这一新的假设，目的1和目的2将关注肝素酶如何通过影响骨髓瘤细胞和成骨细胞/基质细胞来促进骨髓瘤骨破坏。目的3将研究抑制肝素酶是否可以保护骨髓瘤诱导的骨病。该项目将确定肝素酶在促进骨髓瘤骨性破坏特征中的作用，并进一步了解肝素酶抑制剂用于骨髓瘤和其他溶骨性肿瘤的治疗。

DESCRIPTION (provided by applicant): Myeloma is an incurable malignancy, and excessive bone destruction is a major cause of morbidity in myeloma patients. However, the biologic mechanisms involved in the pathogenesis of myeloma-induced bone disease are poorly understood. Heparanase, an enzyme that cleaves the heparan sulfate chains of proteoglycans, is upregulated in a variety of human tumors, including myeloma. I have previously demonstrated that heparanase promotes robust myeloma tumor growth and supports spontaneous metastasis to bone. In addition, I have recently made the striking discovery that the expression of heparanase by myeloma tumor cells is a major determinant of the osteolytic phenotype where it potently promotes both local and systemic osteolysis. The goal of this project is to determine how heparanase promotes myeloma-induced bone disease and to determine the potential of heparanase inhibition for the treatment of myeloma bone disease. The formation and function of bone resorbing osteoclasts is activated by Receptor Activator of NF-?B Ligand (RANKL) and inhibited by osteoprotegerin (OPG). Activated osteoclasts secrete matrix metalloproteinase-9 (MMP-9), degrading bone tissue. I and my colleagues have found, for the first time, that heparanase significantly elevates the expression of RANKL, MMP-9, and transcription factor Runx2 in myeloma cells. In addition, heparanase increases RANKL and decreases OPG expression in osteoblast precursors. Here I hypothesize that heparanase drives myeloma osteolysis by increasing the expression and secretion of RANKL and MMP-9 in myeloma cells via the upregulation of Runx2. I further postulate that heparanase modulates osteoblast precursors to enhance their role as osteoclast- support cells. Thus, myeloma bone disease can be ameliorated by the inhibition of heparanase. To test this novel hypothesis, Aims 1 and 2 will focus on how heparanase promotes myeloma bone destruction by affecting myeloma cells and osteoblasts/stromal cells. Aim 3 will investigate whether inhibiting heparanase can protect bone from myeloma-induced bone disease. This project will determine the role of heparanase in promoting the osteolytic bone destruction characteristic of myeloma and provide further insight into the use of heparanase inhibitors as treatment for myeloma and other osteolytic tumors.