Mechanobiological Mechanisms of Load-Induced Osteoarthritis in the Mouse Knee.

Osteoarthritis (OA) is a degenerative joint disease that affects millions of people worldwide, yet its disease mechanism is not clearly understood. Animal models have been established to study disease progression by initiating OA through modified joint mechanics or altered biological activity within the joint. However, animal models often do not have the capability to directly relate the mechanical environment to joint damage. This review focuses on a novel in vivo approach based on controlled, cyclic tibial compression to induce OA in the mouse knee. First, we discuss the development of the load-induced OA model, its different loading configurations, and other techniques used by research laboratories around the world. Next, we review the lessons learned regarding the mechanobiological mechanisms of load-induced OA and relate these findings to the current understanding of the disease. Then, we discuss the role of specific genetic and cellular pathways involved in load-induced OA progression and the contribution of altered tissue properties to the joint response to mechanical loading. Finally, we propose using this approach to test the therapeutic efficacy of novel treatment strategies for OA. Ultimately, elucidating the mechanobiological mechanisms of load-induced OA will aid in developing targeted treatments for this disabling disease.

Lateral Meniscal Graft Transplantation: Effect of Fixation Method on Joint Contact Mechanics During Simulated Gait.

BACKGROUND: Controversy exists regarding the optimal bony fixation technique for lateral meniscal allografts. PURPOSE/HYPOTHESIS: The objective was to quantify knee joint contact mechanics across the lateral plateau for keyhole and bone plug meniscal allograft transplant fixation techniques throughout simulated gait. It was hypothesized that both methods of fixation would improve contact mechanics relative to the meniscectomized condition, while keyhole fixation would restore the distribution of contact stress closer to that of the intact knee. STUDY DESIGN: Controlled laboratory study. METHODS: Six human cadaveric knees were mounted on a multidirectional dynamic simulator and subjected to the following conditions: (1) native intact meniscus, (2) keyhole fixation of the native meniscus, (3) bone plug fixation of the native meniscus, and (4) meniscectomy. Contact area, peak contact stress, and the distribution of stress across the tibial plateau were computed at 14% and 45% of the gait cycle, at which axial forces are at their highest. Translation of the weighted center of contact stress throughout simulated gait was computed. RESULTS: Both bony fixation techniques improved contact mechanics relative to the meniscectomized condition. The keyhole technique was not significantly different from the intact condition for the following metrics: contact area, peak contact stress, distribution of force between the meniscal footprint and cartilage-to-cartilage contact, and the position of the weighted center of contact. In contrast, bone plug fixation resulted in a significant decrease of 21% to 28% in contact area at 14% and 45% of the simulated gait cycle, a significant increase in peak contact stresses of 34% at 45% of the gait cycle, and a shift in the weighted center of contact, which increased forces in the cartilage-to-cartilage contact area at 45% of the gait cycle. CONCLUSION: While both keyhole and bone plug fixation methods improved lateral compartment contact mechanics relative to the meniscectomized knee, keyhole fixation restored contact mechanics closer to that of the intact knee. CLINICAL RELEVANCE: Method of meniscal fixation is under the direct control of the surgeon. From a biomechanics perspective, keyhole fixation is advocated for its ability to mimic intact knee joint contact mechanics.

Kinematics of meniscal- and ACL-transected mouse knees during controlled tibial compressive loading captured using roentgen stereophotogrammetry.

Pre-clinical studies of post-traumatic OA have examined the pathways that lead to disease after injury by using surgical models such as the destabilization of the medial meniscus (DMM) and anterior cruciate ligament transection (ACLT). While the morphological, molecular, and genetic pathways leading to OA have been examined extensively; the effects of these injuries on joint kinematics, and thus disease progression, have yet to be fully characterized. To this end, we sought to understand the kinematics in the DMM and ACLT joints compared to intact joints subjected to controlled tibial compressive loading. We hypothesized that the DMM and ACLT models would result in different patterns of joint instability compared to intact joints, thus explaining the different patterns of OA initiation and severity in these models. Cadaver adult C57BL/6 mice were subjected to either a DMM or ACLT in their right knee joints, while the left limbs remained as intact controls. All limbs were labeled with fiducial markers, and the rigid body kinematics of the tibia and femur were examined using roentgen stereophotogrammetry (RSA) with application of compressive loads from 0 to 9 N. DMM and intact joints demonstrated similar kinematics under compressive loading, in contrast to ACLT joints, which dislocated even before load application. These results demonstrate the importance of rigorous kinematic analysis in defining the role of joint instability in animal models of OA and suggest significant differences in DMM and ACLT joint instabilities in the context of controlled mechanical loading. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:353-360, 2017.

Progressive cell-mediated changes in articular cartilage and bone in mice are initiated by a single session of controlled cyclic compressive loading.

We previously showed that repetitive cyclic loading of the mouse knee joint causes changes that recapitulate the features of osteoarthritis (OA) in humans. By applying a single loading session, we characterized the temporal progression of the structural and compositional changes in subchondral bone and articular cartilage. We applied loading during a single 5-minute session to the left tibia of adult (26-week-old) C57Bl/6 male mice at a peak load of 9.0N for 1,200 cycles. Knee joints were collected at times 0, 1, and 2 weeks after loading. The changes in articular cartilage and subchondral bone were analyzed by histology, immunohistochemistry (caspase-3 and cathepsin K), and microcomputed tomography. At time 0, no change was evident in chondrocyte viability or cartilage or subchondral bone integrity. However, cartilage pathology demonstrated by localized thinning and proteoglycan loss occurred at 1 and 2 weeks after the single session of loading. Transient cancellous bone loss was evident at 1 week, associated with increased osteoclast number. Bone loss was reversed to control levels at 2 weeks. We observed formation of fibrous and cartilaginous tissues at the joint margins at 1 and 2 weeks. Our findings demonstrate that a single session of noninvasive loading leads to the development of OA-like morphological and cellular alterations in articular cartilage and subchondral bone. The loss in subchondral trabecular bone mass and thickness returns to control levels at 2 weeks, whereas the cartilage thinning and proteoglycan loss persist. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1941-1949, 2016.

Self-assembled smooth muscle cell tissue rings exhibit greater tensile strength than cell-seeded fibrin or collagen gel rings.

In this study, we created self-assembled smooth muscle cell (SMC) tissue rings (comprised entirely of cells and cell-derived matrix; CDM) and compared their structure and material properties with tissue rings created from SMC-seeded fibrin or collagen gels. All tissue rings were cultured statically for 7 days in supplemented growth medium (with ε-amino caproic acid, ascorbic acid, and insulin-transferrin-selenium), prior to uniaxial tensile testing and histology. Self-assembled CDM rings exhibited ultimate tensile strength and stiffness values that were two-fold higher than fibrin gel and collagen gel rings. Tensile testing of CDM, fibrin gel and collagen gel rings treated with deionized water to lyse cells showed little to no change in mechanical properties relative to untreated ring samples, indicating that the ECM dominates the measured ring mechanics. In addition, CDM rings cultured in supplemented growth medium were significantly stronger than CDM rings cultured in standard, unsupplemented growth medium. These results illustrate the potential utility of self-assembled cell rings as model CDM constructs for tissue engineering and biomechanical analysis of ECM material properties.