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Glucocorticoid regulation of transforming growth factor beta 1 activity and binding in osteoblast-enriched cultures
M Centrella1, T L McCarthy, E Canalis
1Department of Research, Saint Francis Hospital and Medical Center, Hartford, Connecticut 06105.
Abstract:
Transforming growth factor beta (TGF-beta) enhances replication and bone matrix protein synthesis and associates with distinct binding sites in osteoblast-enriched cultures from fetal rat bone. In the organism high levels of or sustained exposure to glucocorticoids alters bone cell activity and decreases bone mass, effects that may be mediated in part by changes in local TGF-beta actions in skeletal tissue. Preexposure of osteoblast-enriched cultures to 100 nM cortisol reduced the stimulatory effects of TGF-beta 1 on DNA and collagen synthesis by 40 to 50%. Binding studies showed that cortisol moderately enhanced total TGF-beta 1 binding, but chemical cross-linking and polyacrylamide gel electrophoretic analysis revealed an increase only within Mr 250,000 (type III) TGF-beta-binding complexes, which are thought to represent extracellular TGF-beta storage sites. In contrast, a decrease in TGF-beta 1 binding was detected in Mr 65,000 (type I) and 85,000 (type II) complexes, which have been implicated as signal-transducing TGF-beta receptors. Our present studies therefore indicate that glucocorticoids can decrease the anabolic effects of TGF-beta 1 in bone, and these may occur in part by a redistribution of its binding toward extracellular matrix storage sites. Alterations of this sort could contribute to bone loss associated with glucocorticoid excess.
Insights
Glucocorticoids, like cortisol, reduce the bone-building effects of transforming growth factor beta (TGF-beta). This occurs by shifting TGF-beta binding away from receptors towards storage sites, potentially contributing to bone loss.
Area of Science:
- Bone Biology
- Endocrinology
- Cell Signaling
Background:
- Transforming growth factor beta (TGF-beta) is crucial for bone formation and matrix synthesis.
- Glucocorticoids are known to negatively impact bone mass and cellular activity.
- The interaction between glucocorticoids and TGF-beta in bone is not fully understood.
Purpose of the Study:
- To investigate how glucocorticoids affect the anabolic actions of TGF-beta in bone cells.
- To determine the impact of cortisol on TGF-beta binding to its receptors and storage sites.
Main Methods:
- Osteoblast-enriched cultures from fetal rat bone were used.
- Cells were pre-exposed to cortisol before TGF-beta 1 stimulation.
- TGF-beta 1 effects on DNA and collagen synthesis were measured.
- TGF-beta binding studies utilized chemical cross-linking and gel electrophoresis.
Main Results:
- Cortisol pre-exposure reduced TGF-beta 1-stimulated DNA and collagen synthesis by 40-50%.
- Cortisol increased TGF-beta 1 binding to Mr 250,000 complexes (extracellular storage).
- Cortisol decreased TGF-beta 1 binding to Mr 65,000 (type I) and 85,000 (type II) complexes (receptors).
Conclusions:
- Glucocorticoids diminish the anabolic effects of TGF-beta 1 in bone cells.
- This may be mediated by a shift in TGF-beta 1 binding towards extracellular matrix storage.
- These alterations could contribute to the bone loss observed with excess glucocorticoid exposure.