S. Takahashi et al., DOWN-REGULATION OF CALCITONIN RECEPTOR MESSENGER-RNA EXPRESSION BY CALCITONIN DURING HUMAN OSTEOCLAST-LIKE CELL-DIFFERENTIATION, The Journal of clinical investigation, 95(1), 1995, pp. 167-171
Calcitonin inhibits both osteoclast formation and bone resorption, and
is a primary treatment for patients with hypercalcemia and increased
bone turnover. However, the clinical utility of calcitonin is limited
because patients become refractory to calcitonin after several days (t
he calcitonin ''escape phenomenon''). The molecular basis for calciton
in ''escape'' is unclear. To determine the regulatory mechanisms contr
olling calcitonin receptor (CTR) expression in osteoclasts and their p
recursors, we treated immature mononuclear precursors for human osteoc
last-like multinucleated cells (MNC) formed in vitro with 1,25-(OH)(2)
D-3, to induce their differentiation to committed mononuclear precurso
rs, and mature multinucleated osteoclasts, and used reverse transcript
ase (RT)-PCR to assess expression of CTR mRNA in both committed mononu
clear precursors and MNC. The PCR fragment produced was cloned and seq
uenced to confirm that it was derived from CTR mRNA. CTR mRNA expressi
on was detected in mononuclear MNC precursors after 7 d of 1,25-(OH)(2
)D-3 treatment. It was also present in osteoclast-like MNC and highly
purified giant cells from osteoclastomas, but not in monocytes or macr
ophage polykaryons formed in vitro. Calcitonin markedly decreased CTR
but not actin mRNA expression in giant cells and MNC after 12 h, and r
emoval of calcitonin restored CTR mRNA expression. Similarly, calciton
in decreased calcitonin-induced adenylate cyclase activity. These data
suggest: (a) downregulation of CTR gene expression by calcitonin may
in part explain the calcitonin ''escape phenomenon'' and (b) expressio
n of CTR mRNA occurs in mononuclear osteoclast precursors within 7 d a
fter exposure to 1,25-(OH)(2)D-3.