Data from ADAMTS-1–null mice obtained in this study show that ADAMTS-1 is necessary for normal growth and the structure and function of the kidneys, adrenal glands, and female reproductive organs. The lack of severe renal failure with azotemia or major metabolic disturbance suggests that the ADAMTS-1 gene is pleiotropic, and that ADAMTS-1 has multiple and nonredundant functions throughout the body.
ADAMTS-1 is a member of the ADAM protein family that is involved in proteolytic modification of cell-surface proteins and extracellular matrices. The unique structure of ADAMTS-1, characterized by the presence of thrombospondin type I motifs, is shared by other newly identified proteins in mammals and in C. elegans
, which constitute the ADAMTS subfamily that may perform well-conserved biological functions (21
). ADAMTS-1 is anchored to the extracellular matrix by an interaction between its carboxyl-terminal spacing region together with its thrombospondin type I motifs, and sulfated glycosaminoglycans such as heparan sulfate (14
). ADAMTS-1 may, therefore, serve as a local factor processing as-yet unknown substrates by protease activity (15
). It is notable that among the tissues we examined, the urinary epithelium at the ureteropelvic junction expressed the highest levels of ADAMTS-1 protein. The renal abnormalities involving the calyces and corticomedullary structure in ADAMTS-1–/–
mice might be secondary to the structural abnormalities of the urinary tract. Thus ADAMTS-1 produced by the urinary epithelium may contribute to normal development or remodeling of the underlying fibrous tissue in the ureteropelvic junction and ureter.
Interestingly, mice lacking angiotensinogen, angiotensin-converting enzyme, or angiotensin type I receptor have a very similar renal phenotype (23
). In these mice, hypoplastic ureteral smooth muscle and impaired ureteropelvic peristalsis are thought to cause functional obstruction of the urinary tract (23 and S. Okubo, personal communication). In contrast, ADAMTS-1–/–
mice exhibit accumulation of excessive fibrous tissue and deformity of smooth muscle cells at the ureteropelvic junction and ureter, which could lead to both organic and functional obstruction. Electron microscopy showing the accumulation of collagen fibers suggests that processing of collagen and related matrix substances may be impaired in ADAMTS-1–/–
mice. In this respect, it is noteworthy that ADAMTS-1 shares unique structural features with procollagen I N-proteinase and aggrecanase-1, other ADAM proteins that contain four thrombospondin type I motifs (16
). This supports the notion that ADAMTS-1 may process collagen or related substrates (e.g., proteoglycans) that are important for the organization of organ structures.
The mechanisms responsible for growth retardation, female infertility with histological changes in the uterus and ovaries, and disrupted adrenomedullary architecture remain unknown. It is difficult to infer the molecular substrate or substrates of ADAMTS-1 that are common to the organs affected in knockout mice because the characteristics of histological changes seem to be different among organs. The discovery of physiologically relevant substrates of ADAMTS-1 would be expected to pave the way for further understanding of growth, fertility, and organ morphogenesis.
Recently, METH-1, the human orthologue of ADAMTS-1, was shown to suppress FGF-2–induced vascularization in the cornea pocket assay and to inhibit VEGF-induced angiogenesis in the chorioallantoic membrane assay (19
). Consistent with this inhibitory effect on angiogenesis, METH-1 inhibits endothelial cell proliferation, but not fibroblast or smooth muscle growth (19
). On the other hand, the lack of adrenomedullary capillary network formation in ADAMTS-1–/–
mice suggests that ADAMTS-1 may be necessary for the capillary formation of the adrenal medulla. It is presently unclear how these contradictory findings could be reconciled. It is possible that the effect of ADAMTS-1 on angiogenesis may be different among tissues, developmental stages, and pathophysiological conditions. It is also possible that the lack of a capillary network in the adrenal medulla of ADAMTS-1–/–
mice is not the direct effect of the ADAMTS-1
null mutation. Further studies are necessary to clarify the role of ADAMTS-1 in angiogenesis and its molecular mechanism, which potentially involves extracellular matrices.
This study also has significant clinical implications. The renal phenotype of ADAMTS-1–/–
mice resembles human ureteropelvic junction obstruction, which is the most common cause of congenital hydronephrosis and is recognized in nearly 1 in 500 live births (27
). This disease is characterized by abnormal collagen and smooth muscle components at the ureteropelvic junction that contribute to mechanical or functional obstruction of urinary flow (27
). Interestingly, the structural abnormalities in ADAMTS-1–/–
mice are responsible for the same dysfunctions described in cases of congenital ureteropelvic junction obstruction and primary obstructive megaureter in humans (29
). Thus, the ADAMTS-1
–null mouse may represent a useful new disease model for clarification of the pathogenesis of congenital ureteropelvic junction obstruction.