Department of Experimental Medicine, Division of Pharmacology "Leonardo Donatelli", University of Campania "Luigi Vanvitelli", 80138 Naples. Italy.
Department of Women, Child and General and Specialist Surgery, University of Campania "Luigi Vanvitelli", 80138 Naples. Italy.
Curr Cancer Drug Targets. 2017;17(7):650-656. doi: 10.2174/1568009616666161215163426.
Osteosarcoma is the most frequent malignant bone tumor in childhood and young adulthood. Long-term survivors of osteosarcoma patients show high prevalence of osteoporosis and fractures. The immunomodulatory mifamurtide, which modulates macrophages activity, improves disease outcome.
To evaluate the role of mifamurtide on macrophage component of bone, the osteoclasts, during chemotherapy in children with osteosarcoma.
Osteoclasts, obtained from peripheral blood cells of healthy donors were harvested in the presence or not of mifamurtide. Moreover, osteoclast cultures were obtained from osteosarcoma patients, at onset and during chemotherapy, alone or with mifamurtide. Pro-osteoporotic tartrateresistant acid phosphatase (TRAP), phosphokinase-β-2 (PKCβ2), vanilloid receptor type 1 (TRPV1), and anti-osteoporotic cannabinoid receptor type 2 (CB2) biomarkers were analyzed by bio-molecular (qPCR), biochemical (Western Blotting), and morphological (TRAP assay) approaches.
Osteoclasts from osteosarcoma patients show significant increase of TRAP and decrease of CB2 with respect to osteoclasts from healthy donors. This osteoclast hyperactivity is more evident in osteoclasts from osteosarcoma patients during chemotherapy. Mifamurtide reduces pro-osteoporotic TRAP, PKCβ2, TRPV1 levels and increases CB2 in osteoclasts from healthy donors. Moreover, chemotherapy-induced effects on bone resorption markers are fully reverted in osteoclasts derived from osteosarcoma patients in chemotherapy plus mifamurtide.
Our data suggest a new therapeutic role for mifamurtide as possible anti-resorption agent in chemotherapy-induced osteoporosis in children with osteosarcoma.
骨肉瘤是儿童和青少年中最常见的恶性骨肿瘤。骨肉瘤患者的长期幸存者骨质疏松症和骨折的患病率很高。免疫调节剂米夫单抗可调节巨噬细胞的活性，改善疾病的预后。
评估米夫单抗在儿童骨肉瘤化疗过程中对骨巨噬细胞（破骨细胞）的作用。
从健康供者的外周血细胞中获取破骨细胞，在存在或不存在米夫单抗的情况下进行培养。此外，还从骨肉瘤患者在发病时和化疗期间获得破骨细胞培养物，单独或联合使用米夫单抗。通过生物分子（qPCR）、生化（Western Blotting）和形态学（TRAP 测定）方法分析促骨质疏松症的耐酒石酸盐酸性磷酸酶（TRAP）、磷酸激酶-β-2（PKCβ2）、香草素受体 1（TRPV1）和抗骨质疏松症的大麻素受体 2（CB2）生物标志物。
与健康供者的破骨细胞相比，骨肉瘤患者的破骨细胞中 TRAP 显著增加，CB2 减少。骨肉瘤患者在化疗期间的破骨细胞活性更为明显。米夫单抗降低了健康供者破骨细胞中的促骨质疏松症 TRAP、PKCβ2 和 TRPV1 水平，并增加了 CB2。此外，在化疗加米夫单抗的骨肉瘤患者来源的破骨细胞中，完全逆转了化疗引起的骨吸收标志物的作用。
我们的数据表明，米夫单抗在儿童骨肉瘤化疗引起的骨质疏松症中具有作为潜在抗吸收剂的新治疗作用。
