Time course of “escape” from calcitonin-induced inhibition of motility and resorption of disaggregated osteoclasts

Kanehisa, Junya

doi:10.1016/8756-3282(89)90010-0

Cited by 25 publications

(8 citation statements)

References 17 publications

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“…In isolated osteoclasts, calcitonin induced immediate quiescence and gradual contraction of osteoclasts, as well as inhibition of bone resorption. After 4-8 h, osteoclasts regained cytoplasmic motility and resumption of bone resorption (35). These data suggest a direct effect of calcitonin on osteoclasts.…”

Section: Discussionmentioning

confidence: 59%

“…This phenomenon has been ascribed to secondary hyperparathyroidism (32) and formation of neutralizing antibodies to calcitonin (15). However, in vitro cultures have shown that osteoclasts lose responsiveness to calcitonin (33)(34)(35), and in rat bone or mouse calvaria, the inhibitory effect of calcitonin on bone resorption lasts only 48-96 h (33,34). In isolated osteoclasts, calcitonin induced immediate quiescence and gradual contraction of osteoclasts, as well as inhibition of bone resorption.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 1995

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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.)

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Section: Discussionmentioning

confidence: 59%

Section: Discussionmentioning

confidence: 99%

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

et al. 1995

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“…Our experience of mammalian osteoclast viability has R J 19% WILEY-LISs, INC been different. In cultures of rat osteoclasts maintained for at least 48 h, we have seen continuous resorption and the ability to recover partially from the effects of calcitonin (Murrills et al, 1990b; Fitton and Arnett, 1990) as have other workers using this assay (Fenton et al., 1991) and those studying individual osteoclasts (Kanehisa, 1989;Lakkakorpi and Vaananen, 1990).We therefore examined the time-course of pH-stimulated resorption by rat osteoclasts with the following aims: 1) to confirm and extend the previous report of stimulation of rat osteoclasts by low pH using a different means of altering pH, 2) to determine whether this…”

mentioning

confidence: 81%

Stimulation of bone resorption and osteoclast clear zone formation by low pH: A time‐course study

Murrills

Stein

Dempster

1993

Journal Cellular Physiology

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The significance of low pH-induced stimulation of osteoclastic bone resorption has recently been questioned following the finding that embryonic chick osteoclasts were only weakly stimulated by extremely low pH (6.5) and that the effect was transient, apparently due to cytotoxicity. Although low pH in the range 6.8-7.2 is known to stimulate rat osteoclasts over 24 h, the long-term effects of low pH on mammalian osteoclasts are not known. We have therefore conducted time-course studies over 72 h on the effect of pH in the range 6.3-7.3 on bone resorption and cytotoxicity in both rat and chick osteoclasts. In neonatal rat osteoclasts, lowering extracellular pH produced a powerful and significant stimulation of resorption over 24 h. Detailed analysis of the resorption focus revealed that this was due mainly to a higher proportion of active osteoclasts at lower pH. In addition, osteoclasts excavated slightly larger pits at low pH. Stimulation was no longer significant at 72 h, however, due to a pH-dependent slowing of resorption at acid pH associated 1) with cytotoxicity primarily of nonosteoclastic cells and 2) with an acceleration of bone resorption after 24 h at more alkaline pH. Resorption stimulated by low pH was associated with the formation of actin-rich "clear zones" within the osteoclast. Chick osteoclasts were less sensitive to low pH than rat osteoclasts but nonetheless showed a consistently higher level of resorption at low pH over 24-72 h. These results suggest that protons play an important regulatory role in neonatal rat osteoclasts, and stimulate the formation of clear zones. The lower sensitivity of the chick osteoclast to acid pH may be due to a species difference or the chick osteoclast's higher basal level of resorption.

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“…In the first 4 days of culture, ipriflavone reduced the number of preexisting TRAP(+)-MNCs, but CT did not. Furthermore, in long-term culture, ipriflavone caused continuous inhibition of pit formation, differing from CT because the disappearance of the inhibitory effect on bone resorption, called the escape phenomenon, was observed in ours and other studies [21,22]. In addition, Azria et al [23] also reported the difference between the action of ipriflavone and that of CT on the cell motility and the adhesion properties of isolated osteoclasts.…”

Section: Discussionmentioning

confidence: 49%

Inhibitory effect of ipriflavone on osteoclast-mediated bone resorption and new osteoclast formation in long-term cultures of mouse unfractionated bone cells

Notoya

Yoshida²,

Taketomi³

et al. 1993

Calcif Tissue Int

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To study the effect of ipriflavone on osteoclast-mediated bone resorption and new osteoclast formation, we used an unfractionated bone cell culture system containing mature osteoclasts from femur and tibia of newborn mice. Ipriflavone (10(-5) M) inhibited pit formation on dentin slices and caused a decrease in the number of tartrate-resistant acid phosphatase (TRAP)-positive (+) multinucleate cells (MNCs) in a 4-day culture period in which no increase in the number of TRAP(+)-MNCs was observed in the presence of 5% fetal bovine serum (FBS) and 10(-8) M 1 alpha,25-dihydroxy-vitamin D3 (1 alpha,25(OH)2D3). During the following 12 days, both the total area of the pits and the number of TRAP(+)-MNCs increased in the control. Continuous treatment with ipriflavone also inhibited the increase in pit area during this period. These effects of ipriflavone were reversible. Furthermore, the differentiation of osteoclasts was examined when preexisting TRAP(+)-MNCs were removed by incubation in the absence of 1 alpha,25(OH)2D3 for the initial 4 days in culture dishes without dentin slices. When 1 alpha,25(OH)2D3 and ipriflavone were added to the medium on the 4th day, ipriflavone inhibited new TRAP(+)-MNC formation stimulated by 1 alpha,25(OH)2D3 in a dose-dependent manner. However, pretreatment of the cells with ipriflavone before the addition of 1 alpha,25(OH)2D3 did not inhibit TRAP(+)-MNC formation. These results indicate that ipriflavone inhibits both the activation of mature osteoclasts and the formation of new osteoclasts without affecting growth of TRAP-negative progenitor cells.

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Time course of “escape” from calcitonin-induced inhibition of motility and resorption of disaggregated osteoclasts

Cited by 25 publications

References 17 publications

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

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

Stimulation of bone resorption and osteoclast clear zone formation by low pH: A time‐course study

Inhibitory effect of ipriflavone on osteoclast-mediated bone resorption and new osteoclast formation in long-term cultures of mouse unfractionated bone cells

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