CD47, also called integrin-associated protein, plays a critical role in the innate immune response and is an atypical member of the immunoglobulin superfamily that interacts with and activates B3 integrins. B3 integrin-/- mice have defective platelet and osteoclast function and are protected from bone metastasis. The role of CD47 in skeletal homeostasis and bone metastasis has not been described. CD47-/- mice had increased bone mass and defective osteoclast function in vivo. Although the number of functional osteoclasts formed by differentiating CD47-/- bone marrow macrophages was decreased, high doses of RANKL rescued differentiation and function of CD47-/- osteoclasts ex vivo and rescued the osteoclast defect in CD47-/- mice. Inhibition of nitric oxide (NO) synthase, which is expressed at higher levels in CD47-/- osteoclasts, also rescued the osteoclast defect in CD47-/- cells. We then examined the consequences of this osteoclast defect in bone metastasis. In a model of tumor metastasis to bone, bone tumor burden was decreased in the CD47-/- mice compared with wild-type (WT) controls, with no decrease in s.c. tumor growth in CD47-/- mice. There was decreased tumor-associated bone destruction in the CD47-/- mice compared with WT controls, consistent with a defect in osteoclast function that was not rescued by the presence of tumor. Our data show that CD47 regulates osteoclastogenesis, in part, via regulation of NO production, and its disruption leads to a decrease in tumor bone metastasis. CD47 is a novel therapeutic target to strengthen bone mass and diminish metastatic tumor growth in bone.
CD47-/- mice have decreased tumor burden and bone loss in an intracardiac metastasis model. (A) B16-FL cells were injected into the left ventricular chamber of WT (n = 3) and CD47-/- (n = 3) mice. Tumor burden in the femur/tibia (P = 0.003) and the mandible (P = 0.05) as measured by bioluminescence imaging 7, 10, and 12 d after tumor cell injection. (B) representative images of bioluminescence and of tibial histologic bone sections. M, marrow; T, tumor.
Uluçkan O, Becker SN, Deng H, Zou W, Prior JL, Piwnica-Worms D, Frazier WA, Weilbaicher KN. CD47 Regulates Bone Mass and Tumor Metastasis to Bone. Cancer Res 2009; 69(7): 3196-3204.