E. A. Thorndike and A. S. Turner

Department of Clinical Sciences, Colorado State University, Ft.Collins ,CO 80523

Received 9/25/97 Accepted 4/10/98

6. OSTEOARTHRITIS (OA)

Osteoarthritis is defined as "transient and progressive structural changes in joint tissue, principally in articular cartilage, subchondral bone , synovium, and synovial fluid" and is characterized by mild cartilage degeneration with chondromalacia and death of chondrocytes (3). When this disease progresses to extremes, it can result in complete loss of articular surface as well as exposure of subchondral cartilage (2). Consequently, OA has a major impact on the functioning of the elderly and costs of care (40).

6.1 The Relationship Between Estrogen and OA

There is increasing evidence that sex hormones play a role in the development of OA in women. Specifically, the prevalence of OA increases in women following menopause and rises faster with age in women than men. Some women experience rapidly progressing OA in the hand at the time of menopause (40,41). The cross-sectional association of postmenopausal ERT with prevalence of radiographic findings of OA of the hip in a large cohort of elderly white women showed that women who used oral estrogen had a significantly reduced risk of OA in the hip (42). Furthermore, epidemiological studies have implicated estrogen deficiency as a risk factor for OA (43).

Ex vivo studies of cell and organ cultures have provided insight into the biochemical events within cartilage, bone, and synovial fluid (3). Unfortunately, these studies provide little information about the structural changes in the joint. It is difficult to study OA in humans because of genetic variation, numerous nutritional and biochemical variables, and difficulty in clearly identifying the early stages of this disease (3). Furthermore, the elucidation of the early events of OA is difficult when using human subjects because patients usually do not seek medical attention until the pathological changes are advanced (end stages of the disease).

There are few reports on the effects of OVX or chronic sex steroid administration on the properties of articular cartilage. Most animal studies have been inconclusive in proving a relationship between OA and estrogens. A high prevalence of OA lesions (subchondral plate thickening, osteophytes , subchondral cysts, articular cartilage fibrillation, and clefts) was observed in the knee joints of relatively young intact monkeys. However, this study failed to detect an effect of chronic sex steroid administration or OVX on severity of OA (44).

There is a need for an estrogen-deficient large animal model of OA to study the complex structural changes in tissues that evolve over time, spontaneously or following experimental injury, and to determine how constitutive, environmental or biomechanical risk factors may initiate, promote or otherwise regulate these changes" (3). Such a model would be useful in investigating novel therapeutic and pharmaceutical strategies (eg. new estrogen-progestin products or selective estrogen receptor modulators such as raloxifene) which could then be used to control progression of this disease in the postmenopausal women.

6.2 The Use of Sheep as a Model for OA

A popular site to study OA is the knee joint of sheep following unilateral medial or lateral meniscus removal combined with exercise (45-47). One advantage of the sheep over smaller animals such as rats, mice, guinea pigs and rabbits, is the increased amount of tissue available for biochemical, histological and biomechanical studies. Sheep have also been used to assess the effects of therapeutic agents on joint tissues (48). Because sheep have a longer lifespan than rodents, long term changes induced by OA can be studied with non-invasive methods like magnetic resonance imaging (MRI) (3).

In a recent study, sheep were exercised on hard concrete surfaces while a control group of sheep were exercised on soft wood chips. The stress to the joints from the concrete induced degenerative changes in the articular cartilage and subchondral bone. This study provided some insight into the role of mechanical determinants on chondrocyte metabolism (3).

6.3 The Relationship between Estrogen and OA in Sheep

We investigated the effect of OVX with or without ERT on the intrinsic biomechanical properties of articular cartilage in sheep. Skeletally mature ewes were divided into four groups: Sham treated, OVX, OVX plus an estradiol implant (OVXE), OVX and two estradiol implants (OVX2E). Twelve months after the OVX or sham procedure, sheep were euthanized and the left knee joints were disarticulated and separated from the surrounding soft tissues, leaving the articular tissue intact. Using creep indentation methods (49), biomechanical testing of several properties of the cartilage specimens was performed including aggregate modulus (H_A), Poisson’s ratio (v_s), shear modulus (microns), and permeability (k). In the OVX articular cartilage, H_A and shear modulus were significantly lower than in the other groups (50), suggesting that OVX may have a detrimental effect on intrinsic material properties of the articular cartilage of the knee even though the cartilage of the OVX animals appeared grossly normal. Treatment with estradiol implants prevented these deleterious effects; sham, OVXE and OVX2E were not different from each other. Gross signs of OA in the estrogen-deficient sheep model were not observed. However in another study, 13.5 months following OVX an increase in estrogen receptor binding capacity of the articular cartilage in sheep was observed (51). These observations support those of others (52), suggesting that articular cartilage is indeed a sex-hormone sensitive tissue.