Secreted ADAMTS-like proteins as regulators of connective tissue function

The extracellular matrix (ECM) determines functional properties of connective tissues through structural components, such as collagens, elastic fibers, or proteoglycans. The ECM also instructs cell behavior through regulatory proteins, including proteases, growth factors, and matricellular proteins, which can be soluble or tethered to ECM scaffolds. The secreted a disintegrin and metalloproteinase with thrombospondin type 1 repeats/motifs-like (ADAMTSL) proteins constitute a family of regulatory ECM proteins that are related to ADAMTS proteases but lack their protease domains. In mammals, the ADAMTSL protein family comprises seven members, ADAMTSL1-6 and papilin. ADAMTSL orthologs are also present in the worm, Caenorhabditis elegans, and the fruit fly, Drosophila melanogaster. Like other matricellular proteins, ADAMTSL expression is characterized by tight spatiotemporal regulation during embryonic development and early postnatal growth and by cell type- and tissue-specific functional pleiotropy. Although largely quiescent during adult tissue homeostasis, reexpression of ADAMTSL proteins is frequently observed in the context of physiological and pathological tissue remodeling and during regeneration and repair after injury. The diverse functions of ADAMTSL proteins are further evident from disorders caused by mutations in individual ADAMTSL proteins, which can affect multiple organ systems. In addition, genome-wide association studies (GWAS) have linked single nucleotide polymorphisms (SNPs) in ADAMTSL genes to complex traits, such as lung function, asthma, height, body mass, fibrosis, or schizophrenia. In this review, we summarize the current knowledge about individual members of the ADAMTSL protein family and highlight recent mechanistic studies that began to elucidate their diverse functions.