A disintegrin and metalloproteinase with thrombospondin motifs 3 (ADAMTS3)

ADAMTS3 (A disintegrin and metalloproteinase with thrombospondin motifs 3) is a secreted enzyme belonging to the ADAMTS protein family characterized by metalloproteinase and thrombospondin motifs[1][2][6]. While initially thought to act primarily as a procollagen II N-propeptidase—a function now known to be minor in vivo—ADAMTS3 is now recognized as critical for the activation of VEGF-C, a growth factor necessary for lymphatic vessel development and maintenance[1]. It has additional roles in the proteolytic processing of extracellular matrix components and in brain development via cleavage of reelin[1]. Loss of function mutations in ADAMTS3 are causative for hereditary lymphedema syndromes (including Hennekam syndrome)[2][3], and deficiency may also lead to disorders of connective tissue such as dermatosparaxis[1]. As of 2025, ADAMTS3 is considered a potential therapeutic target principally in the context of lymphatic development, but no targeted drugs are clinically approved.

Other names

ADAM metallopeptidase with thrombospondin type 1 motif 3KIAA0366ADAMTS-4 (not to be confused with a distinct, separate ADAMTS4 gene)ADAM-TS 3Procollagen II N-proteinaseProcollagen II amino propeptide-processing enzymeA disintegrin-like and metalloprotease (reprolysin type) with thrombospondin type 1 motif, 3

Protease inhibitors (no specific approved inhibitor known, but theoretically, inhibitors would act by blocking ADAMTS3 enzymatic cleavage activity) Modulation of lymphangiogenesis via interference with VEGF-C activation