Tissue Inhibitor of Metalloproteinases 1 and 2 Directly Stimulate the Bone-Resorbing Activity of Isolated Mature Osteoclasts
Open Access
- 1 December 2001
- journal article
- research article
- Published by Oxford University Press (OUP) in Journal of Bone and Mineral Research
- Vol. 16 (12), 2205-2214
- https://doi.org/10.1359/jbmr.2001.16.12.2205
Abstract
Tissue inhibitor metalloproteinases 1 (TIMP‐1) and 2 have been reported to inhibit bone resorption. However, here, we report the direct action of both TIMP‐1 and TIMP‐2 on isolated rabbit mature osteoclasts to stimulate their bone‐resorbing activity at significantly lower concentrations (∼ng/ml) than those (∼μg/ml) required for the inhibition of bone resorption. The cell population used in this study consisted of a mature osteoclast population with >95% purity. TIMP‐1 (∼50 ng/ml) and TIMP‐2 (∼8–10 ng/ml) increased the pit area excavated by the isolated mature osteoclasts. The stimulatory effects of TIMPs were abolished by simultaneous addition of anti‐TIMP antibodies. At higher concentrations, the stimulation of bone resorption decreased reversely to the control level. The magnitude of the stimulatory effect of TIMP‐2 was more than that of TIMP‐1. Metalloproteinase inhibitors such as BE16627B and R94138 could not replace TIMPs with respect to the bone‐resorbing activity, suggesting that the osteoclast‐stimulating activity of TIMPs was independent of the inhibitory activity on matrix metalloproteinases (MMPs). TIMPs stimulated tyrosine phosphorylation of cellular proteins in the isolated mature osteoclasts. Both herbimycin A, an inhibitor of tyrosine kinases, and PD98059 and U0126, inhibitors of mitogen‐activated protein kinase (MAPK), completely blocked the TIMP‐induced stimulation of osteoclastic bone‐resorbing activity. On the plasma membrane of osteoclasts, some TIMP‐2‐binding proteins were detected by a cross‐linking experiment. These findings show that TIMPs directly stimulate the bone‐resorbing activity of isolated mature osteoclasts at their physiological concentrations and that the stimulatory action of TIMPs is likely to be independent of their activities as inhibitors of MMPs.Keywords
This publication has 77 references indexed in Scilit:
- Stromelysin (MMP-3) Synthesis Is Up-Regulated in Estrogen-Deficient Mouse Osteoblasts In Vivo and In VitroJournal of Bone and Mineral Research, 1999
- Osteoclastogenesis Inhibitory Factor (OCIF) Directly Inhibits Bone-Resorbing Activity of Isolated Mature OsteoclastsBiochemical and Biophysical Research Communications, 1998
- The Migration of Purified Osteoclasts Through Collagen Is Inhibited by Matrix Metalloproteinase InhibitorsJournal of Bone and Mineral Research, 1998
- Tyrosine phosphorylation is crucial for growth signaling by tissue inhibitors of metalloproteinases (TIMP‐1 and TIMP‐2)FEBS Letters, 1996
- Parathyroid hormone-induced resorption in fetal rat limb bones is associated with production of the metalloproteinases collagenase and gelatinase BJournal of Bone and Mineral Research, 1996
- Synthesis and Structure-Activity Relationships of Gelatinase Inhibitors Derived from Matlystatins.CHEMICAL & PHARMACEUTICAL BULLETIN, 1995
- Rabbit calvarial osteoblasts in culture constitutively synthesize progelatinase-A, and TIMP-1 and TIMP-2Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 1994
- Inhibition of metalloproteinase activity of rheumatoid arthritis synovial cells by a new inhibitor [BE16627B;l-N-(N-hydroxy-2-isobutylsuccinamoyl)-seryl-l-valine]Inflammation Research, 1993
- Inhibition of stimulated bone resorption in vitro by TIMP-1 and TIMP-2Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 1993
- Identification of osteopontin in isolated rabbit osteoclastsBiochemical and Biophysical Research Communications, 1992