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Triple helix formation of procollagen after the assembly of three α-chains at the C-propeptide is a prerequisite for refined structures such as fibers and meshworks. Hsp47 is an ER-resident stress inducible glycoprotein that specifically and transiently binds to newly synthesized procollagens. However, the real function of Hsp47 in collagen biosynthesis has not been elucidated in vitro or in vivo. Here, we describe the establishment of Hsp47 knockout mice that are severely deficient in the mature, propeptide-processed form of α1(I) collagen and fibril structures in mesenchymal tissues. The molecular form of type IV collagen was also affected, and basement membranes were discontinuously disrupted in the homozygotes. The homozygous mice did not survive beyond 11.5 days postcoitus (dpc), and displayed abnormally orientated epithelial tissues and ruptured blood vessels. When triple helix formation of type I collagen secreted from cultured cells was monitored by protease digestion, the collagens of Hsp47+/+ and Hsp47+/− cells were resistant, but those of Hsp47−/− cells were sensitive. These results indicate for the first time that type I collagen is unable to form a rigid triple-helical structure without the assistance of molecular chaperone Hsp47, and that mice require Hsp47 for normal development.

n animal model for accelerated senescence named the Senescence-Accelerated Mouse (SAM) was developed in our laboratory (Department of Senescence Biology, formerly Department of Pathology, Chest Disease Research Institute, Kyoto University) beginning in 1970. In this review, the circumstances related to development of SAM, characteristics of aging, pathologic phenotypes, and genetic background of this model are described. CIRCUMSTANCES OF DEVELOPMENTSeveral pairs of the AKR/J strain of mice were donated by the Jackson Laboratory (Bar Harbor, Maine, USA) to the Department of Pathology, Chest Disease Research Institute, Kyoto University, Japan, in 1968.' While continuing the sister-brother mating to maintain this inbred strain, we became aware of the presence of certain litters in which most of the mice showed a moderate to severe degree of loss of activity, hair loss and lack of glossiness, skin coarseness, periophthalmic lesions,* increased lordokyphosis of the spine, and shortened life span despite the relatively low incidence of thymic lymphoma. We were also aware of inheritance of these phenotypes by the following generations ( Figure 1). As the progenitor of senescence-prone series (P series), five litters with severe exhaustion were selected. Litters in which the aging process was normal were also selected as the progenitors of the senescenceresistant series (R series).' Selecting these progenitors, normal was defined a5 follows: for the preceding three generations, the mean life span had to be more than 16 months and the grading score of senescence less than 2.0 at 8 months of age.3Thereafter, in addition to the routine sister-brother mating, selective breeding was applied based on the data of the grading score of senescence, life span, and pathologic phenotypes. From each of the selected litters with severe exhaustion, five different series designated

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