Parathyroid hormone and calcitonin interactions in bone: Irradiation-induced inhibition of escape in vitro

Krieger, Nancy S.; Feldman, Roy S.; Tashjian, Armen H.

doi:10.1007/bf02411233

Cited by 29 publications

(10 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Recently, Kreiger et al (28) found that x-irradiation did not inhibit PTH from stimulated calcium release from newborn mouse calvarial cultures or from increasing osteoclast number after 48 h of culture. However, in contrast to our results, they did not find x-irradiation to decrease unstimulated levels of bone resorption.…”

Section: Discussionmentioning

confidence: 99%

DNA synthesis is not necessary for osteoclastic responses to parathyroid hormone in cultured fetal rat long bones.

Lorenzo¹,

Raisz²,

Hock³

1983

J. Clin. Invest.

View full text Add to dashboard Cite

A B S T R A C T Osteoclasts, the principal cells mediating bone resorption, are believed to increase their size, number, and resorbing activity in response to parathyroid hormone (PTH) through mechanisms dependent upon the fusion of specific mononuclear precursor cells into either new or existing multinucleated osteoclasts. To address the question of whether these actions of PTH are dependent on the replication of osteoclast precursor cells, we examined the ability of an inhibitor of DNA synthesis, hydroxyurea (HU), to alter bone resorption, osteoclast formation, and DNA synthesis in cultured fetal rat bones treated with PTH. We found that HU significantly reduced [3H]thymidine incorporation into the bones and labeling of osteoclast nuclei by >90%, but did not prevent PTH from stimulating bone resorption, measured as the release of 45Ca, or from increasing the number of osteoclasts in the bones. In bones cultured without PTH, HU decreased the rate of bone resorption, but not the number of osteoclasts per bone.We conclude that in fetal rat bone cultures, PTH can increase osteoclast number and stimulate bone resorption by affecting existing osteoclasts and osteoclast precursors, and that replication of osteoclast precursor cells is not necessary for PTH to stimulate a resorptive response. In unstimulated cultures it appears that HU inhibits bone resorption by affecting mechanisms that are independent of changes in osteoclast number and that may be influenced by cell replication or other unknown factors.Dr. Lorenzo's current address is Newington VA Hospital, Newington, CT 06111.

show abstract

Section: Discussionmentioning

confidence: 99%

DNA synthesis is not necessary for osteoclastic responses to parathyroid hormone in cultured fetal rat long bones.

Lorenzo¹,

Raisz²,

Hock³

1983

J. Clin. Invest.

View full text Add to dashboard Cite

show abstract

“…This phenomenon has been reported in both in vivo [41,42] and in vitro [43,44] systems. Possible mechanisms include the recruitment of osteoclasts that are insensitive to calcitonin [45,46] and/or downregulation of CTRs on osteoclasts [44]. In mature osteoclasts, even short-term treatment with low concentrations of calcitonin produced down-regulation of the CTR expression.…”

Section: Discussionmentioning

confidence: 99%

Calcitonin induces expression of the inducible cAMP early repressor in osteoclasts

Yang

Kream

2008

Endocr

View full text Add to dashboard Cite

The cAMP response element modulator gene (Crem) encodes a variety of transcriptional regulators including the inducible cAMP early repressor, ICER. We previously showed that Crem knockout mice, which are deficient in CREM and ICER factors, display slightly increased long bone mass and decreased osteoclast number. These data are consistent with the notion that Crem regulates bone mass in part through an effect on osteoclast formation and/or function. Since ICER is strongly induced by cAMP, we asked whether the calcium-regulating hormone calcitonin, which stimulates cAMP production and inhibits osteoclastic bone resorption, could induce ICER in osteoclasts. The monocytic cell line RAW264.7 was treated with receptor activator of NF-κB ligand (RANKL) to induce osteoclast formation. Calcitonin caused a time-and dose-dependent induction of ICER mRNA and an increase in ICER protein abundance in RANKL-treated RAW264.7 cells. Calcitonin also induced ICER mRNA and protein in osteoclasts derived from primary mouse bone marrow cell cultures. Calcitonin-treated osteoclasts showed immunoreactivity with an anti-CREM antibody. Calcitonin decreased the activity of wild type and Crem knockout osteoclasts in vitro, and this inhibitory effect was greater in Crem knockout osteoclasts. Furthermore, calcitonin decreased calcitonin receptor mRNA expression in wild type osteoclasts but not in Crem knockout osteoclasts. These data suggest that calcitonin induction of ICER in osteoclasts might regulate osteoclast activity.

show abstract

“…However, the "escape phenomenon" cannot be explained solely on receptor internalization, because many other receptors such as the insulin receptor also are internalized (38), and forskolin, an adenylate cyclase activator, induced similar effects in osteoclasts, including the "escape phenomenon" and inhibition of bone resorption (39). Furthermore, inhibition of DNA synthesis in rodent organ cultures can block calcitonin escape (40). Another possible explanation for the "escape phenomenon" is that phosphorylation of the intracellular region of the receptor results in desensitization of the intracellular signaling pathway (41).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 1995

View full text Add to dashboard Cite

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.)

show abstract

Parathyroid hormone and calcitonin interactions in bone: Irradiation-induced inhibition of escape in vitro

Cited by 29 publications

References 18 publications

DNA synthesis is not necessary for osteoclastic responses to parathyroid hormone in cultured fetal rat long bones.

DNA synthesis is not necessary for osteoclastic responses to parathyroid hormone in cultured fetal rat long bones.

Calcitonin induces expression of the inducible cAMP early repressor in osteoclasts

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

Contact Info

Product

Resources

About