Downregulation of calcitonin receptor mRNA expression by calcitonin during human osteoclast-like cell differentiation.

Abstract

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 (the calcitonin "escape phenomenon"). The molecular basis for calcitonin "escape" is unclear. To determine the regulatory mechanisms controlling calcitonin receptor (CTR) expression in osteoclasts and their precursors, we treated immature mononuclear precursors for human osteoclast-like multinucleated cells (MNC) formed in vitro with 1,25-(OH)2D3, to induce their differentiation to committed mononuclear precursors, and mature multinucleated osteoclasts, and used reverse transcriptase (RT)-PCR to assess expression of CTR mRNA in both committed mononuclear precursors and MNC. The PCR fragment produced was cloned and sequenced to confirm that it was derived from CTR mRNA. CTR mRNA expression was detected in mononuclear MNC precursors after 7 d of 1,25-(OH)2D3 treatment. It was also present in osteoclast-like MNC and highly purified giant cells from osteoclastomas, but not in monocytes or macrophage polykaryons formed in vitro. Calcitonin markedly decreased CTR but not actin mRNA expression in giant cells and MNC after 12 h, and removal of calcitonin restored CTR mRNA expression. Similarly, calcitonin 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) expression of CTR mRNA occurs in mononuclear osteoclast precursors within 7 d after exposure to 1,25-(OH)2D3. (J. Clin. Invest. 1995. 95:167-171.)

Osteoporotic Vertebral Compression Fractures: Surgery versus Non-Operative Management

“…34 Calcitonin was also used for pain relief. Elcatonin has been used for many years to treat osteoporosis and osteoporotic fractures as it provides excellent pain relief, suppresses the activity of osteoclasts and increases bone density.…”

“…35 − 37 There are, however, some disadvantages of using elcatonin in clinical applications. Longterm usage may lead to escape phenomenon 34 H Tang, J Zhao, C Hao Management of osteoporotic vertebral compression fractures morphology, thereby losing its role in bone resorption. Calcitonin does not relieve pain immediately, so another analgesic may be needed in the acute phase following fracture.…”

Pharmacological Topics of Bone Metabolism: Antiresorptive Microbial Compounds That Inhibit Osteoclast Differentiation, Function, and Survival

“…Continuous treatment with calcitonin eventually leads to decreased inhibitory effects on osteoclastic bone resorption (escape phenomenon). This escape phenomenon is known to involve downregulation of the calcitonin receptor, which is derived from activation of the PKA pathway (17,18). Compounds that exert calcitonin-like activity without affecting the PKA pathway would be viewed as new types of antiresorptive agents.…”

Osteoclast differentiation antigen, distinct from receptor activator of nuclear factor kappa B, is involved in osteoclastogenesis under calcitonin-regulated conditions

“…It has been shown that the accumulation of calcitonin in the Golgi apparatus of osteoclasts is related to the down-regulation of CTR (Ikegame et al 1994). It has also been demonstrated that the synthesis of CTR is suppressed at the transcription level when osteoclast-like multinucleated cells (MNCs) are treated with calcitonin (Takahashi et al 1995, Findlay & Martin 1997. Such prolonged down-regulation of the CTR appears to be an important molecular aspect of the escape phenomenon.…”