Molecular and cellular mechanisms of skeletal disease mediated by plasma cell dyscrasias

骨的溶骨性和骨质疏松性病变是原发性和继发性骨癌（包括血液来源的癌症）的常见后遗症。现在有强有力的证据表明，肿瘤细胞扰乱了骨吸收和骨形成之间的局部平衡，并且在骨质溶解的情况下，导致破骨细胞（OC）介导的骨吸收增加，而没有匹配的骨形成量。这一提议源于我们在多发性骨髓瘤（MM）以及其他骨骼肿瘤方面的广泛临床和基础科学经验，以及我们在OC和成骨细胞生物学方面的强大背景。MM是一种以浆细胞恶液质为特征的血液恶性肿瘤，其通常导致骨骼的进行性和严重破坏，伴随骨痛、骨折，最后是恶性肿瘤的高钙血症。两种相关疾病，MGUS和POEMS，已被选择用于研究，因为它们与MM的关键相似性和差异性，并且可能为MM在骨骼中的活动提供新的线索。MGUS不会引起可识别的骨缺损，而POEMS可引起溶骨性和骨质疏松性病变。这些条件的比较将使我们能够研究为什么这些看似相关的肿瘤能够介导不同的骨骼疾病状态。首先，由于目前MM的治愈性疗法很少，我们提出的研究旨在确定治疗这种疾病最严重表现（即骨组织破坏）的治疗靶点。

Osteolytic and osteosclerotic lesions of bone are common sequelae of primary and secondary bone cancers, including cancers of hematological origin. There is now strong evidence that tumor cells perturb the local balance between bone resorption and formation, and in cases of osteolysis, cause increased osteoclast (OC)-mediated bone resorption without a matching amount of bone formation. This proposal arises from our extensive clinical and basic science experience with multiple myeloma (MM) in addition to other skeletal tumors, and our strong background in both OC and osteoblast biology. MM is a hematological malignancy characterised by plasma cell dyscrasia, which typically causes progressive and severe destruction of the skeleton, with accompanying bone pain, fracture and finally, hypercalcaemia of malignancy. Two related diseases, MGUS and POEMS, have been chosen for study because of their key similarities and differences with MM, and are likely to shed new light on the activities of MM in the bone. MGUS does not cause identifiable bone defects, whereas POEMS can give rise to both osteolytic and osteosclerotic lesions. Comparison of these conditions will uniquely enable us to examine why these seemingly related neoplasms are able to mediate disparate skeletal disease states. Primarily, and since there are few curative therapies for MM at present, our proposed studies are designed to identify targets for therapy that will treat the most serious manifestation of this disease, namely its destruction of bone tissue.