Pathologic and metabolic responses of experimental osteoarthritis to estradiol and an estradiol antagonist.

Tamoxifen, an estradiol antagonist, and estradiol were separately evaluated in a rabbit experimental osteoarthritis. Cartilage from anatomically defined regions of individual rabbit knees was assayed for sulfate and thymidine incorporation. Tamoxifen reduced erosive osteoarthritic pathology, while estradiol worsened it. There was no effect on the incidence of osteophytes. Metabolic studies in organ culture showed no changes relating to treatment. The results suggest that specific medical therapy for osteoarthritis is within the realm of possibility.

Biosynthesis of proteoglycan in vitro by cartilage from human osteochondrophytic spurs.

Proteoglycan biosynthesis by human osteochondrophytic spurs (osteophytes) obtained from osteoarthritic femoral heads at the time of surgical joint replacement was studied under defined culture conditions in vitro. Osteophytes were primarily present in two anatomic locations, marginal and epi-articular. Minced tissue slices were incubated in the presence of [(35)S]sulphate or [(14)C]glucosamine. Osteophytes incorporated both labelled precursors into proteoglycan, which was subsequently characterized by CsCl-isopycnic-density-gradient ultracentrifugation and chromatography on Sepharose CL-2B. The material extracted with 0.5m-guanidinium chloride showed 78.1% of [(35)S]sulphate in the A1 fraction after centrifugation. Only 23.0% of the [(35)S]sulphate in this A1 fraction was eluted in the void volume of Sepharose CL-2B under associative conditions. About 60-80% of the [(35)S]sulphate in the tissue 4m-guanidinium chloride extract was associated with monomeric proteoglycan (fraction D1). The average partition coefficient (K(av.)) of the proteoglycan monomer on Sepharose CL-2B was 0.28-0.33. Approx. 12.4% of this monomer formed stable aggregates with high-molecular-weight hyaluronic acid in vitro. Sepharose CL-2B chromatography of fractions with lower buoyant densities (fractions D2-D4) demonstrated elution profiles on Sepharose CL-2B substantially different than that of fraction D1, indicative of the polydisperse nature of the newly synthesized proteoglycan. Analysis of the composition and chain size of the glycosaminoglycans showed the following: (1) preferential elution of both [(35)S]sulphate and [(14)C]glucosamine in the 0.5m-LiCl fraction on DEAE-cellulose; (2) the predominant sulphated glycosaminoglycan was chondroitin 6-sulphate (60-70%), with 9-11% keratan sulphate in the monomer proteoglycan; (3) K(av.) values of 0.38 on Sephadex G-200 and 0.48 on Sepharose CL-6B were obtained with papain-digested and NaBH(4)-treated D1 monomer respectively. A comparison of the synthetic with endogenous glycosaminoglycans indicated similar types. These studies indicated that human osteophytes synthesized in vitro sulphated proteoglycans with some characteristics similar to those of mature human articular cartilage, notably in the size of their proteoglycan monomer and predominance of chondroitin 6-sulphate. They differed from articular cartilage primarily in the lack of substantial quantities of keratan sulphate and aggregation properties associated with monomer interaction with hyaluronic acid.

A histopathologic differentiation of tissue types in human osteoarthritic cartilage.

A histopathologic system of classifying minced human hip and knee osteoarthritic cartilage often used in organ cultures was developed. The tissue types characterizing the cartilage fragments were correlated with characteristics noted in full thickness cartilage specimens from young normal, aged and osteoarthritic cartilage. In the minced tissue specimens 3 distinct tissue types (A, B, and C) were discerned. Tissue types A and B were seen in nonfibrillated discolored as well as fibrillated osteoarthritic cartilage. Type C tissue was derived principally from chondroosteophytic spurs. Each tissue type differed in the number and organization of chondrocytes and orthochromatic and metachromatic staining of the perilacunar region and interterritorial matrix. No A, B or C tissue types were seen in normal cartilage samples derived from patients below the age of 50. Cartilage from patients above this age contained elements of all 3 tissue types.

A trial of intraarticular orgotein, a superoxide dismutase, in experimentally-induced osteoarthritis.

Intraarticular injections of orgotein, a metalloprotein with superoxide dismutase activity, did not ameliorate experimentally-induced osteoarthritis in the rabbit. Reduction of sulfate incorporation by cartilage of operated osteoarthritic knees with injection of saline-sucrose placebo and orgotein in saline-sucrose vehicle was observed. Repeated intraarticular injections of both orgotein in a sucrose-saline vehicle, and sucrose-saline placebo administered separately induced a severe synovitis in both osteoarthritic and normal knees.

Effects of estrogen on cartilage and experimentally induced osteoarthritis.

Estradiol valerate did not ameliorate experimentally induced osteoarthritis in the rabbit. Both normal and osteoarthritic cartilage were susceptible to estradiol suppression of proteoglycan synthesis. Protoeglycan concentration was not diminished with estradiol, suggesting estradiol suppression of proteoglycan catabolism. The severity of osteoarthritis was unchanged despite markedly decreased proteoglycan catabolism. The severity of osteoarthritis was unchanged despite markedly decreased protoeglycan synthesis in the estrogen treated animals. Osteophyte proteoglycan metabolism differed from other osteoarthritic lesions. Differences in the metabolism of femoral and tibial articular cartilage were observed.