Osteoarthritis is a disease of aging and is directly related to the stresses of weight bearing, mechanical overuse or injury to the joint. Both joint space cartilage and the subchondral bone are implicated in the disease process. The role of the bone in initiating and/or propagating this process is not clearly understood. More than thirty years ago, it was proposed that changes in bone might be the predisposing event leading to the development of osteoarthritis. Today, although it is recognized that bony changes are a prominent feature of OA, we remain uncertain of causal relationship to this disease. In osteoarthritis, it is believed that the bone immediately below the articular cartilage (the subchondral bone) is prone to stress injury, which leads to microcracks in the bone. These microcracks may lead to the death of bone cells, and the initiation of the bone remodeling process. This bone remodeling results in the formation of bony over-growth in the form of mineralized callus at the bone injury site. These calluses increase the bone volume and stiffness, when compared to normal tissue.? ? We have undertaken three projects to gain insight into the pathogenesis of osteoarthritis. In the first project, we utilized an animal model of osteogenesis imperfecta. Osteogenesis imperfecta (OI) comprises a variety of genetic lesions that result in brittle bones. In many cases, the disease is due mutations of the gene encoding type I collagen. We have employed a knock-in murine model for OI that carries a typical OI mutation in type I collagen under the control of the endogenous promoter. This mouse is termed the Brittle (Brtl) mouse, which bears a gly349cys substitution in one col1a1 alleles. We assessed the development of osteoarthritis in these mice and determined that there is increased rate of development of osteoarthritis in these mice. We used a combination of standard histological assessments as well as more sophisticated imaging techniques. The results indicate that abnormalities in subchondral bone appear to promote the development of osteoarthritis. ? ? In the second project, we investigated the role of Osteopontin (OPN) in the pathogenesis of osteoarthritis. OPN a specialized protein (phosphorylated and sulphated glycoprotein). It can be found in a variety of tissues; e.g., bone forming cells, primitive cells from the uterus, placenta, kidney, and nervous system. It has also been found in activated macrophage and lymphocytes. OPN plays an important role in bone formation. It is believed that OPN in bone send signals to the cells in response to mechanical stimuli. In the embryonic tissue, OPN is detected in the bone-forming and cartilage cells. It is usually absent in normal healthy adult cartilage. However, in osteoarthritis, OPN is present in the cartilage and its presence increases with the severity of the disease. It can also be found in the bone forming cells (osteoblasts) of the subchondral bone. OPN production by the bone remodeling cells plays an important role in new bone formation. OPN's role may be to facilitate cell attachment to the mineral component of the bone.It also interacts with other bone forming components like type I collagen, osteocalcin, and fibronectin. Mechanical forces stimulate OPN production by acting on the cell to produce shear stress at its adhesion site. This stress transmits a signal to the cell, resulting in OPN production. The final result is a change in the shape of the cell and how it responds to (or interacts with) its environment.? We used OPN knockout mouse model to examine the role of cartilage and bone forming cells in modulating the development of exercise-induced OA. We hypothesized that the OPN-deficient (OPN -/-) mouse may be an ideal model to study chondrocyte viability in articular cartilage, and the role of the subchondral bone alterations in knee osteoarthritis. This study is still underway. ? ? Cartilage is a very specialized tissue containing only one cell type, the chondrocyte. Chondrocyte metabolism and function are influenced by the composition of the extracellular environment (Oxygen tension, pH, ionic concentration), the extracellular matrix composition, the matrix-cell interactions and the physical signals (stress and stain) transmitted across the articular surfaces of the joint. The failure of cartilage to regenerate itself is believed to be one of the fundamental pathways in the pathophysiology of degenerative osteoarthritis. The goals of this project are to determine the utility of non-invasive imaging techniques for early detection and longitudinal progression of age-related degenerative joint disease in a non-human primate model for spontaneous osteoarthritis; and to examine the reparative potential of chondrocytes taken from aging non-human primates at various stages of joint degeneration. Non-human primate knees have been collected from the NIH tissue bank and the specimens have been imaged by micro-CT and micro-MRI. These results indicate that micro-MRI and micro-CT can be used to detect early degenerative changes in nonhuman primate knee articular cartilage and subchondral bone respectively. These imaging modalities are also valuable in the long-term studies of the rate of disease progression, to quantify joint destruction, osteophyte formation and changes in bone mineral density in the non-human primate model for spontaneous OA. During the past year, we have concentrated our efforts towards determining the volume of knee articular cartilage in the aging nonhuman primate knee, and to correlate these findings with the respective subchondral bone mineral density. Our future goal is to complete the evaluation of the above studies, and to correlate our findings with quantitative measurements of serum biomarkers. These studies are also underway.
