Parathyroid hormone-like adenylate cyclase-stimulating activity from a human carcinoma is associated with bone-resorbing activity

We found previously that a human renal carcinoma cell line derived from a hypercalcemic patient induces humoral hypercalcemia when grown as allografts in the nude mouse and secretes a protein that activates adenylate cyclase via the PTH receptor. The purpose of this study was to examine the conditioned medium of this cell line for bone-resorbing activity in vitro. Processed conditioned medium produced dosedependent stimulation of bone resportion in cultured fetal rat limb bone explants. Two PTH antagonists were used to assess the PTH receptor dependence of this bone-resorbing activity. Neither [⁸Nle,¹⁸Nle,³⁴Tyr]bovine (b) PTH-(3–34) amide nor [³⁴Tyr]bPTH-(7–34)amide inhibited bone resorption or limb bone cAMP accumulation induced by either processed conditioned medium or equivalent concentrations of bPTH-(l–34). As an alternate means to assess whether this tumor-derived PTH-like protein had intrinsic bone-resorbing activity, the latter was measured during partial purification of PTH-like adenylate cyclase-stimulating activity (ACSA) from conditioned medium by consecutive gel filtration and reverse phase HPLC. The bone-resorbing activity in conditioned medium could not be resolved from PTH-like ACSA by these two separation techniques, indicating that the activities may be intrinsic to the same protein. These results are consistent with the view that a tumorderived protein with PTH-like ACSA and bone-resorbing activity may be responsible for hypercalcemia in vivo.