ADAMTS-12: a multifaced metalloproteinase in arthritis and inflammation

Abstract

ADAMTS-12 is a member of a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) family of proteases, which were known to play important roles in various biological and pathological processes, such as development, angiogenesis, inflammation, cancer, arthritis, and atherosclerosis. In this review, we briefly summarize the structural organization of ADAMTS-12; concentrate on the emerging role of ADAMTS-12 in several pathophysiological conditions, including intervertebral disc degeneration, tumorigenesis and angioinhibitory effects, pediatric stroke, gonad differentiation, trophoblast invasion, and genetic linkage to schizophrenia and asthma, with special focus on its role in arthritis and inflammation; and end with the perspective research of ADAMTS-12 and its potential as a promising diagnostic and therapeutic target in various kinds of diseases and conditions.

Figure 1

A schematic representation of ADAMTS-12's multiple functions.

Figure 2

Domain structure and organization of ADAMTS-12. ADAMTS-12 N-terminal consists of a signal peptide, prodomain, and metalloprotease domain. The ADAMTS-12 C-terminal contains a disintegrin domain, the first thrombospondin type 1 repeat (TSP1), Cys-rich domain, and 7 additional TSP1 repeats interspaced with two spacer domains. The second spacer domain is also a mucin-like domain.

Figure 3

Regulation of ADAMTS-12 by PTHrP signaling in chondrocyte differentiation. ADAMTS-12 acts as a downstream molecule of PTHrP/PTHLH signaling and is regulated by c-Maf transcription factor in the course of chondrogenesis. Abbreviations: PTHrP/PTHLH: parathyroid hormone-like hormone; ADAMTS: a disintegrin and metalloproteinase with thrombospondin motifs.

Figure 4

The interplay network in the degradation of extracellular matrix mediated by ADAMTS-12 in arthritis. ADAMTS-12 mediated proteolysis of aggrecan and COMP is positively modulated by TNF-α and inhibited by α ₂ M and GEP. Abbreviations: yellow arrows indicate a stimulatory effect; perpendicular lines indicate an inhibitory effect; α ₂ M: alpha-2-macroglobulin; ADAMTS: a disintegrin and metalloproteinase with thrombospondin motifs; TNF: tumor necrosis factor; COMP: cartilage oligomeric matrix protein; GEP: granulin-epithelin precursor.