Mechanoregulated bone adaptation in osteoarthritis

Abstract

Osteoarthritis (OA) is the most common joint disease and a leading cause of long-term disability. For many years, pharmaceutical therapies for OA have been focused on the degenerating cartilage. However, there is increasing evidence that changes in the bone play an important role in OA as well. The structural and material properties of the subchondral bone are modified, cartilage is replaced with bone tissue via endochondral ossification, and bone cysts and osteophytes may develop. The cause of these bone changes is subject of debate, and a better understanding of the mechanisms involved may help in the development of bone-targeting OA therapies. Normally, bone architecture is maintained through tightly regulated cellular processes, in response to mechanical loading. Since there is no evidence that these processes are disturbed in OA patients, we postulated that the bone architectural changes result from mechanoregulated adaptation in response to adverse circumstances in the joint. To evaluate this hypothesis, we used an established mathematical bone adaptation model to predict the bone response under various conditions that occur in OA. In the model, osteocytes respond to the local mechanical tissue load by promoting osteoblastic bone formation, while osteoclasts resorb bone near randomly occurring microcracks. To investigate whether the predicted bone architectural changes represented an OA phenotype, we compared our simulation results to experimental data. We found that high loading conditions and decreased bone material properties could both induce an adaptation response resulting in bone microarchitectural changes that are in concurrence with OA clinical and animal studies from the literature. Subsequent quantitative comparison of simulation results to data that we obtained from human OA tibia plateaus indicated that the decrease in bone mineralization could explain only part of the increase in bone volume fraction. Therefore, we concluded that decreased mineralization may contribute to the alterations in subchondral bone architecture, but cannot be the main cause. In addition to adaptation of the existing trabecular structure, we considered the replacement of mineralized cartilage with bone tissue as the cause of the subchondral bone structural changes in OA. We simulated the replacement of mineralized cartilage with bone tissue under both normal and high loading conditions and compared the results to experimental data from human OA tibia plateaus. According to our simulations, endochondral ossification may explain different experimental observations that could not be explained by adaptation of the existing trabecular structure to altered loading circumstances, such as the high trabecular number underneath areas of severe cartilage degeneration, and the presence of a second subchondral plate. However, endochondral ossification under normal loading conditions could not explain the subchondral sclerosis, in contrast with bone adaptation and endochondral ossification under high loading conditions. These data thus indicated that while both high joint loading and the replacement of mineralized cartilage with bone tissue may have contributed to the bone architectural changes that we determined experimentally, neither was solely responsible for these changes. As the alterations in bone microarchitecture are not the only bone changes characteristic for OA, we also studied the development of subchondral bone cysts. In the literature, the entrance of pressurized synovial fluid into the bone has been suggested as the underlying cause for the development of cysts. The pressurized fluid was hypothesized to induce cyst growth through either overloading of the bone tissue or through osteocyte death. With the mathematical model, we showed that bone adaptation in response to both altered loading conditions resulting from the presence of pressurized fluid, and the presence of dead osteocytes may lead to the development of subchondral bone cysts. To summarize, we could explain how mechanoregulated remodeling of bone and mineralized cartilage under various conditions associated with OA may result in bone microarchitectural changes similar to those observed in OA, and we showed that bone adaptation in response to fluid pressure or osteocyte death may explain cyst growth. These results support our hypothesis that mechanoregulated adaptation is the mechanism responsible for the alterations in bone structure in OA.