Role of interleukin-6 in uncoupling of bone in vivo in a human squamous carcinoma coproducing parathyroid hormone-related peptide and interleukin-6.
OCC tumor has been established from a human squamous carcinoma associated with humoral hypercalcemia of malignancy (HHM) and shown to overproduce parathyroid hormone-related peptide (PTHrP) and cause aggressive hypercalcemia when implanted into nude rats. In the present study, we have demonstrated by reverse transcription-polymerase chain reaction and Northern blot analysis that OCC tumor also overexpressed interleukin 6 (IL-6) mRNA and that tumor-bearing animals exhibited a marked increase in plasma IL-6 as well as PTHrP concentrations. When a monoclonal antibody against human IL-6 was injected to block the activities of tumor-derived IL-6, bone loss in tumor-bearing animals was significantly prevented. Quantitative bone histomorphometric analysis revealed that treatment with anti-IL-6 antibody caused a substantial decrease in both osteoclast number and eroded surface (as parameters of bone resorption) and also a significant increase in the mineral apposition rate, but little effect on the osteoblastic surface. These results provide in vivo evidence suggesting that in tumors coproducing IL-6 and PTHrP, IL-6 is involved not only in the acceleration of osteoclastic bone resorption but also, at least in part, in the suppression of osteoblastic functions in HHM syndrome.
Nagai
Y
Y
Biomedical Research Laboratories, Kureha Chemical Industry, Co., Ltd., Tokyo, Japan.
Yamato
H
H
Akaogi
K
K
Hirose
K
K
Ueyama
Y
Y
Ikeda
K
K
Matsumoto
T
T
Fujita
T
T
Ogata
E
E
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D016723:Bone Remodeling / Q000187:drug effects; D001862:Bone Resorption / Q000517:prevention & control; D002294:Carcinoma, Squamous Cell / Q000097:blood / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D006801:Humans; D006934:Hypercalcemia / Q000097:blood / Q000378:metabolism*; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000276:immunology; D008297:Male; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D010006:Osteoblasts / Q000187:drug effects; D010010:Osteoclasts / Q000187:drug effects; D010281:Parathyroid Hormone / Q000096:biosynthesis*; D044162:Parathyroid Hormone-Related Protein; D014176:Protein Biosynthesis; D051381:Rats; D011922:Rats, Mutant Strains; D011923:Rats, Nude
D000911:Antibodies, Monoclonal; D015850:Interleukin-6; D009363:Neoplasm Proteins; C470121:PTHLH protein, human; D010281:Parathyroid Hormone; D044162:Parathyroid Hormone-Related Protein