Complete abrogation of key osteoclast markers with a membrane-anchored tissue inhibitor of metalloproteinase: A NOVEL APPROACH IN THE PREVENTION OF OSTEOCLASTOGENESIS

Meng Huee Lee, Yihe Zhang, Bingjie Jiang, Pengyuan Zhang, Sung Kau Chiu

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Abstract

Aims
Tissue inhibitors of metalloproteinases (TIMPs) are the endogenous inhibitors of the zincdependent matrix metalloproteinases (MMP) and A disintegrin and metalloproteinases
(ADAM) involved in extracellular matrix modulation. The present study aims to develop the
TIMPs as biologics for osteoclast-related disorders.
Methods
We examine the inhibitory effect of a high affinity, glycosyl-phosphatidylinositol-anchored
TIMP variant named ‘T1PrαTACE’ on receptor activator of nuclear factor kappa-Β ligand (RANKL)-
induced osteoclast differentiation.
Results
Osteoclast progenitor cells transduced with T1PrαTACE failed to form tartrate-resistant acid
phosphatase (TRAP)-positive osteoclasts or exhibit bone-resorbing activity following treatment with RANKL. At the messenger RNA level, T1PrαTACE strongly attenuated expression of
key osteoclast marker genes that included TRAP, cathepsin K, osteoclast stimulatory transmembrane protein (OC-STAMP), dendritic cell-specific transmembrane protein (DC-STAMP),
osteoclast-associated receptor (OSCAR), and ATPase H+-transporting V0 subunit d2 (ATP6V0D2) by blocking autoamplification of nuclear factor of activated T cells 1 (NFATc1), the
osteoclastogenic transcription factor. T1PrαTACE selectively extended p44/42 mitogen-activated
protein kinase activation, an action that may have interrupted terminal differentiation of osteoclasts. Inhibition studies with broad-spectrum hydroxamate inhibitors confirmed that the
anti-resorptive activity of T1PrαTACE was not reliant on its metalloproteinase-inhibitory activity.
Conclusion
T1PrαTACE disrupts the RANKL-NFATc1 signalling pathway, which leads to osteoclast dysfunction. As a novel candidate in the prevention of osteoclastogenesis, the TIMP could potentially
be developed for the treatment of osteoclast-related disorders such as osteoporosis
Original languageChinese (Simplified)
Article numberdoi: 10.1302/2046-3758.1110.BJR2022-0147.R2
Number of pages14
JournalBone and Joint Research
Volume11
Issue number10
DOIs
Publication statusAccepted/In press - Oct 2022

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