期刊
JOURNAL OF BONE AND MINERAL RESEARCH
卷 16, 期 12, 页码 2339-2347出版社
WILEY
DOI: 10.1359/jbmr.2001.16.12.2339
关键词
transforming growth factor beta activation; chondrocyte maturation; matrix metalloproteases; matrix metalloprotease 13; endochondral ossification
资金
- NIAMS NIH HHS [AR45402] Funding Source: Medline
- NIDCR NIH HHS [DE11876, DE05675] Funding Source: Medline
Transforming growth factor beta (TGF-beta) has well-documented roles in chondrocyte maturation and endochondral ossification, but the mechanisms of TGF-beta activation during these processes remain unclear. In this study, we analyzed TGF-beta activation in chick embryo resting, proliferating, and hypertrophic chondrocytes in culture. We found that both levels and activation of TGF-beta increased substantially with maturation. The majority of TGF-beta produced by resting cells over culture time remained latent, but a larger portion produced by proliferating and hypertrophic cells was activated with increasing maturation. Zymography of gelatin gels revealed that matrix metalloprotease 2 (MMP-2) and MMP-9 were expressed by each population and that MMP-13 characterized hypertrophic chondrocytes and to a lesser extent proliferating chondrocytes in late cultures. Treatment with pharmacologic agents revealed that both MMPs and serine proteases are involved in activation. However, because inhibition of MMPs almost completely prevented TGF-beta activation, MMPs appear crucial for activation. During culture, inclusion of the tetracycline-derived, collagenase/gelatinase inhibitor chemically modified nonantimicrobial tetracycline (CMT-8) at concentrations specific for MMP-13 inhibition resulted in complete inhibition of TGF-beta activation by proliferating and hypertrophic chondrocytes. These results show that TGF-beta production, release, and activation are regulated developmentally in chondrocytes. Our findings point to a strict mode of regulation of this potent factor to elicit diverse and highly specific effects during chondrocyte maturation and ossification.
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