M. Ono et al.

articular cartilage were positive for IGF1 and IGF-1 receptor in all animals withosteoarthritis in each grade. In the moderate group, in which articular cartilage
degeneration had progressed further, thepresence of IGF-1 and IGF-1 receptor
was noted not only in fibroblastic-likecells, but also in chondrocytes clusteringin a layer deeper than fibroblastic-likecells. In contrast to chondrocytes in theweight-bearing regions, these chondrocytes proved to have a very high mitotic
activity in this study. Therefore, it can bespeculated that chondrocytes presumed
to be differentiated from totipotent
immature mesenchymal cells may haveproduced a cartilage matrix by theautocrine mechanism via IGF-1. A previous report has demonstrated that more
IGF-1 is present in human osteoarthritis
cartilage and synovial fluid than in normal
cartilage and synovial fluid, and suggested
that this IGF-1 originated from the synovial membrane (Schneiderman et al.,1995). However, this study could not demonstrate that IGF-1 secreted by totipotent immature mesenchymal cells directly participated in the differentiation tochondrocytes. Some studies have indicated the close involvement of TGF-beta
1 in experimental osteophyte formation(van Beuningen et al., 1994; van denBerg, 1995), and speculated that TGFbeta 1 has a facilitatory effect on differentiation of totipotent immature mesenchymal cells. Furthermore, other growth
factors are also thought to interact in acomplicated manner (Trippel, 1995).

Acknowledgments: We would like to thankProf. Ryota Teshima, Dept. of Orthopedic
Surgery, Faculty of Medicine, Tottori Univ.,
for advice and supervision. I would also liketo thank other members of the Department
for their advice and help.

AJSTBTCFig. 4. Safranin-O (A) staining discloses the obvious
formation of an osteophyte protruding from the articularmargin in the severe group of 18-month-old animals with
end-stage osteoarthritis. The osteophyte consists of type-I
collagen (B), and hardly any chondrocytes and cartilage
matrix positive for type-II collagen are observed (C).
Fibrous connective tissue (arrows) is noted around theosteophyte, and IGF-1 (F) and IGF-1 receptor (G) areidentified in the fibrous connective tissue. Fibroblasticlike cells in the fibrous connective tissue are positive forboth type-I (B) and -III (D) collagens, and slightly positivefor PCNA (E). JS, joint space; T, tibia. Original magnification: A, × 100; B–G, × 200.
[Figs. 4A–C on p. 138; Figs. 4D–G on p. 139]138

Processes of osteophyte formation

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Received September 4, 2000; accepted October 24, 2000
Corresponding author: Dr. Masanori Ono