Osteoclastogenesis inhibitory factor exhibits hypocalcemic effects in normal mice and in hypercalcemic nude mice carrying tumors associated with humoral hypercalcemia of malignancy.
Osteoclastogenesis inhibitory factor (OCIF) is a novel secreted protein that inhibits osteoclastogenesis both in vitro and in vivo. In this study, we examined the effects of OCIF on serum calcium (Ca) concentrations in normal mice and in hypercalcemic nude mice carrying tumors associated with humoral hypercalcemia of malignancy. In normal mice, a single intraperitoneal injection of OCIF reduced serum Ca levels in a dose-dependent manner. Significant decrease in serum Ca (by 1.6 +/- 0.3 mg/dL, n = 5) was observed 2 h after the injection of OCIF at 20 mg/kg and the hypocalcemic effect continued for up to 12 h. Serum phosphate (Pi) concentrations also decreased in response to OCIF. Urinary excretion of Ca, Pi, and creatinine did not change significantly after injection of OCIF or vehicle. In hypercalcemic, tumor-bearing nude mice, a single intraperitoneal injection of OCIF at 20 mg/kg resulted in a dramatic decrease in serum Ca (maximal decrease 2.8 +/- 0.37 mg/dL, n = 11), which continued for up to 24 h. The results suggest that OCIF decreased serum Ca through its inhibitory effect on bone resorption. Furthermore, it is suggested that OCIF has therapeutic potential for the treatment of hypercalcemic conditions such as malignancy-associated hypercalcemia.
Akatsu
T
T
Third Department of Internal Medicine, National Defense Medical College, Tokorozawa, Saitama, Japan. akatsu@ndmc.ac.jp
Murakami
T
T
Ono
K
K
Nishikawa
M
M
Tsuda
E
E
Mochizuki
S I
SI
Fujise
N
N
Higashio
K
K
Motoyoshi
K
K
Yamamoto
M
M
Nagata
N
N
D000818:Animals; D002118:Calcium / Q000097:blood*; D003404:Creatinine / Q000652:urine; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006023:Glycoproteins / Q000627:therapeutic use*; D006934:Hypercalcemia / Q000097:blood / Q000188:drug therapy* / Q000209:etiology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000378:metabolism; D009374:Neoplasms, Experimental / Q000097:blood / Q000188:drug therapy* / Q000209:etiology; D053244:Osteoprotegerin; D044162:Parathyroid Hormone-Related Protein; D010710:Phosphates / Q000097:blood; D011506:Proteins / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000627:therapeutic use; D016211:Transforming Growth Factor alpha / Q000378:metabolism
D006023:Glycoproteins; D009363:Neoplasm Proteins; D053244:Osteoprotegerin; D044162:Parathyroid Hormone-Related Protein; D010710:Phosphates; D011506:Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins; C506031:Tnfrsf11b protein, mouse; D016211:Transforming Growth Factor alpha; D003404:Creatinine; D002118:Calcium