Complete abrogation of key osteoclast markers with a membrane-anchored tissue inhibitor of metalloproteinase: a novel approach in the prevention of osteoclastogenesis

Bone & Joint Research

article

Yihe Zhang¹  Bingjie Jiang¹  Pengyuan Zhang¹  Sung K. Chiu²  Meng H. Lee¹ 

[1]Department of Biological Sciences/Academy of Pharmacy, Xi’an Jiaotong-Liverpool University

[2]Shanghai XP Biomed Ltd

关键词: Osteoclasts;    Osteoclastogenesis;    Cathepsin K;    TRAP;    TIMP;    osteoclasts;    tissue inhibitors of metalloproteinases (TIMPs);    progenitor cells;    matrix metalloproteinases (MMP);    RNA;    tartrate-resistant acid phosphatase;    osteoporosis;    extracellular matrix;    staining;    mRNA;   

DOI  :  10.1302/2046-3758.1111.BJR-2022-0147.R2

学科分类：骨科学

来源: British Editorial Society Of Bone And Joint Surgery

【 摘 要 】

AimsTissue inhibitors of metalloproteinases (TIMPs) are the endogenous inhibitors of the zinc-dependent 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.MethodsWe 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.ResultsOsteoclast 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.ConclusionT1PrαTACE 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.

【 授权许可】

CC BY-NC