A musculoskeletal finite element model of rat knee joint for evaluating cartilage biomechanics during gait

Abnormal loading of the knee due to injuries or obesity is thought to contribute to the development of osteoarthritis (OA). Small animal models have been used for studying OA progression mechanisms. However, numerical models to study cartilage responses under dynamic loading in preclinical animal models have not been developed. Here we present a musculoskeletal finite element model of a rat knee joint to evaluate cartilage biomechanical responses during a gait cycle. The rat knee joint geometries were obtained from a 3-D MRI dataset and the boundary conditions regarding loading in the joint were extracted from a musculoskeletal model of the rat hindlimb. The fibril-reinforced poroelastic (FRPE) properties of the rat cartilage were derived from data of mechanical indentation tests. Our numerical results showed the relevance of simulating anatomical and locomotion characteristics in the rat knee joint for estimating tissue responses such as contact pressures, stresses, strains, and fluid pressures. We found that the contact pressure and maximum principal strain were virtually constant in the medial compartment whereas they showed the highest values at the beginning of the gait cycle in the lateral compartment. Furthermore, we found that the maximum principal stress increased during the stance phase of gait, with the greatest values at midstance. We anticipate that our approach serves as a first step towards investigating the effects of gait abnormalities on the adaptation and degeneration of rat knee joint tissues and could be used to evaluate biomechanically-driven mechanisms of the progression of OA as a consequence of joint injury or obesity.     

Perspectives on chondrocyte mechanobiology and osteoarthritis

Osteoarthritis, the clinical syndrome of joint pain and dysfunction due to joint degeneration, is among the most frequent and symptomatic medical problems for middle aged and older people, and it is the most common cause of long term disability in most populations of people over 65. Currently there are no effective methods of preventing or curing osteoarthritis. Post-traumatic OA, the joint degeneration, pain and dysfunction that develop following joint injury, is the form of OA that is most directly related to elevated articular surface contact stress. However, mechanical stress that exceeds the tolerance of the articular surface can cause or accelerate the progression of joint degeneration in all individuals and in all synovial joints. In some patients, decreasing mechanical forces on degenerated joint surfaces stimulates formation of a new biologic articular surface. The advances in understanding of the effects of mechanical forces on chondrocytes and cartilage presented and discussed at the 4th Symposium on Mechanobiology: Cartilage and Chondrocyte will help in the efforts to develop new methods of preventing and treating osteoarthritis.     

Post-traumatic osteoarthritis: the role of stress induced chondrocyte damage

Post-traumatic osteoarthritis is the form of osteoarthritis (OA) that develops following joint injury. Although its end-stage is indistinguishable from idiopathic OA, many patients with post-traumatic OA are younger than those with idiopathic OA, and they have a well-defined precipitating insult. Clinical and experimental studies suggest that excessive acute impact energy or chronic mechanical overload cause the degeneration of the articular surface responsible for post-traumatic OA. Yet, the mechanisms by which excessive mechanical force causes OA remain unknown. For these reasons it has not been possible to develop effective methods of preventing or decreasing the risk of post-traumatic OA. We hypothesized that mechanical loading that exceeds the tolerance of the articular surface causes chondrocyte damage due to oxidative stress. Our in vitro tests of human articular cartilage samples showed that shear stress causes chondrocyte death and that anti-oxidants decrease the shear stress induced cell death. These observations suggest that specific patterns of loading are particularly damaging to articular surfaces and that improved treatments of joint injuries may include mechanical methods of minimizing shear stresses and biologic methods of minimizing oxidative damage.     

Lubricin: a novel potential biotherapeutic approaches for the treatment of osteoarthritis

Osteoarthritis (OA) is a multi-factor disorder of sinovial joints, which characterized by escalated degeneration and loss of articular cartilage. Treatment of OA is a critical unmet need in medicine for regeneration of damaged articular cartilage in elderly. On the other hand, lubricin, a glycoprotein specifically synthesized by chondrocytes located at the surface of articular cartilage, has been shown to provide boundary lubrication of congruent articular surfaces under conditions of high contact pressure and near zero sliding speed. Lubrication of these surfaces is critical to normal joint function, while different gene expressions of lubricin had been found in the synovium of rheumatoid arthritis (RA) and OA. Moreover, mutations or lacking of lubricin gene have been shown to link to the joint disease such as camptodactyly-arthropathy-coxa vara-pericarditis syndrome (CACP), synovial hyperplasia and failure of joint function, suggesting an important role of lubricin in the pathogenesis of these joint disease. Recent studies demonstrate that administration with recombinant lubricin in the joint cavity would be effective in the prevention of cartilage degeneration in animal OA models. Therefore, a treatment with lubricin which would protect cartilage in vivo would be desirable. This article reviews recent findings with regard to the possible role of lubricin in the progression of OA, and further discusses lubricin as a novel potential biotherapeutic approaches for the treatment of OA.     

Bone and cartilage in osteoarthritis: is what's best for one good or bad for the other?

The interest in the relationship between articular cartilage and the structural and functional properties of peri-articular bone relates to the intimate contact that exists between these tissues in joints that are susceptible to the development of osteoarthritis (OA). The demonstration in several animal models that osteoporosis and decreased bone tissue modulus leads to an increased propensity for the development of post-traumatic OA is paradoxical in light of the extensive epidemiological literature indicating that individuals with high systemic bone mass, assessed by bone mineral density, are at increased risk for OA. These observations underscore the need for further studies to define the pathophysiological mechanisms involved in the interaction between subchondral bone and articular cartilage and for applying this information to the development of therapeutic interventions to improve the outcomes in patients with OA.     

Structural and functional changes of the articular surface in a post-traumatic model of early osteoarthritis measured by atomic force microscopy

The functional integrity of the articulating cartilage surface is a critical determinant of joint health. Although a variety of techniques exist to characterize the structural changes in the tissue with osteoarthritis (OA), some with extremely high resolution, most lack the ability to detect and monitor the functional changes that accompany the structural deterioration of this essential bearing surface. Atomic force microscopy (AFM) enables the acquisition of both structural and mechanical properties of the articular cartilage surface, with up to nanoscale resolution, making it particularly useful for evaluating the functional behavior of the macromolecular network forming the cartilage surface, which disintegrates in OA.In the present study, AFM was applied to the articular cartilage surfaces from six pairs of canine knee joints with post-traumatic OA. Microstructure (RMS roughness) and micromechanics (dynamic indentation modulus, E^?) of medial femoral condyle cartilages were compared between contralateral controls and cruciate-transected knee joints, which develop early signs of OA by three months after surgery.Results reveal a significant increase in RMS roughness and a significant four-fold decrease in E^? in cartilages from cruciate-transected joints versus contralateral controls. Compared to previous reports of changes in bulk mechanics, AFM was considerably more sensitive at detecting early cartilage changes due to cruciate-deficiency. The use of AFM in this study provides important new information on early changes in the natural history of OA because of its ability to sensitively detect and measure local structural and functional changes of the articular cartilage surface, the presumptive site of osteoarthritic initiation.     

Synovial mesenchymal progenitor derived aggrecan regulates cartilage homeostasis and endogenous repair capacity

Aggrecan is a critical component of the extracellular matrix of all cartilages. One of the early hallmarks of osteoarthritis (OA) is the loss of aggrecan from articular cartilage followed by degeneration of the tissue. Mesenchymal progenitor cell (MPC) populations in joints, including those in the synovium, have been hypothesized to play a role in the maintenance and/or repair of cartilage, however, the mechanism by which this may occur is unknown. In the current study, we have uncovered that aggrecan is secreted by synovial MPCs from healthy joints yet accumulates inside synovial MPCs within OA joints. Using human synovial biopsies and a rat model of OA, we established that this observation in aggrecan metabolism also occurs in vivo. Moreover, the loss of the “anti-proteinase” molecule alpha-2 macroglobulin (A2M) inhibits aggrecan secretion in OA synovial MPCs, whereas overexpressing A2M rescues the normal secretion of aggrecan. Using mice models of OA and cartilage repair, we have demonstrated that intra-articular injection of aggrecan into OA joints inhibits cartilage degeneration and stimulates cartilage repair respectively. Furthermore, when synovial MPCs overexpressing aggrecan were transplanted into injured joints, increased cartilage regeneration was observed vs. wild-type MPCs or MPCs with diminished aggrecan expression. Overall, these results suggest that aggrecan secreted from joint-associated MPCs may play a role in tissue homeostasis and repair of synovial joints.Subject terms: Mesenchymal stem cells, Cartilage, Experimental models of disease     

Functional tissue engineering of chondral and osteochondral constructs

Due to the prevalence of osteoarthritis (OA) and damage to articular cartilage, coupled with the poor intrinsic healing capacity of this avascular connective tissue, there is a great demand for an articular cartilage substitute. As the bearing material of diarthrodial joints, articular cartilage has remarkable functional properties that have been difficult to reproduce in tissue-engineered constructs. We have previously demonstrated that by using a functional tissue engineering approach that incorporates mechanical loading into the long-term culture environment, one can enhance the development of mechanical properties in chondrocyte-seeded agarose constructs. As these gel constructs begin to achieve material properties similar to that of the native tissue, however, new challenges arise, including integration of the construct with the underlying native bone. To address this issue, we have developed a technique for producing gel constructs integrated into an underlying bony substrate. These osteochondral constructs develop cartilage-like extracellular matrix and material properties over time in free swelling culture. In this study, as a preliminary to loading such osteochondral constructs, finite element modeling (FEM) was used to predict the spatial and temporal stress, strain, and fluid flow fields within constructs subjected to dynamic deformational loading. The results of these models suggest that while chondral ("gel alone") constructs see a largely homogenous field of mechanical signals, osteochondral ("gel bone") constructs see a largely inhomogeneous distribution of mechanical signals. Such inhomogeneity in the mechanical environment may aid in the development of inhomogeneity in the engineered osteochondral constructs. Together with experimental observations, we anticipate that such modeling efforts will provide direction for our efforts aimed at the optimization of applied physical forces for the functional tissue engineering of an osteochondral articular cartilage substitute.     

Histochemistry as a Unique Approach for Investigating Normal and Osteoarthritic Cartilage

In this review article, we describe benefits and disadvantages of the established histochemical methods for studying articular cartilage tissue under normal, pathological and experimental conditions. We illustrate the current knowledge on cartilage tissue based on histological and immunohistochemical aspects, and in conclusion we provide a short overview on the degeneration of cartilage, such as osteoarthritis. Adult articular cartilage has low capacity to repair itself, and thus even minor injuries may lead to progressive damage and osteoarthritic joint degeneration, resulting in significant pain and disability. Numerous efforts have been made to implement the knowledge in the study of cartilage in the last years, and histochemistry proved to be an especially powerful tool to this aim.     

Effect of eldecalcitol on articular cartilage through the regulation of transcription factor Erg in a murine model of knee osteoarthritis

Clinical studies have reported an association between low blood levels of 25-hydroxyvitamin D and the progression of osteoarthritis (OA), but the mechanism and effects of vitamin D signaling on articular chondrocytes and cartilage remains unclear. The purpose of this study was to investigate the effects of vitamin D on articular cartilage degeneration using eldecalcitol (ED-71), which is an active vitamin D₃ analog. Eight-week old male C57BL/6NCrSlc mice were subjected to experimental surgery to induce OA and local treatments with 10 μL ED-71 (0.5 μg/mL) were administered weekly. Four and 12 weeks after surgery, joints were evaluated using histological scoring systems. In addition, gene expression was analyzed in chondrocytes that were isolated from wildtype neonatal mice, cultured, and treated with ED-71 (10^?8 M). Joints treated with ED-71 demonstrated slowed progression of OA at 4 weeks after surgery, but few effects were observed at 12 weeks after surgery. Ets-related gene (Erg) expression was upregulated in OA articular cartilage, and further increased by ED-71 treatment. In primary chondrocytes cultured with ED-71, the gene expression of Erg and lubricin/proteoglycan 4 significantly increased, as compared to that of cells cultured without ED-71. Local treatment with ED-71 reduced degenerative changes to the articular cartilage during the early phase of experimental OA. Regulation of Erg by ED-71 in articular cartilage could confer resistance to early osteoarthritic changes.     

Early and stable upregulation of collagen type II,collagen type I and YKL40 expression levels in cartilage during early experimental osteoarthritis occurs independent of joint location and histological grading

While morphologic and biochemical aspects of degenerative joint disease (osteoarthritis [OA]) have been elucidated by numerous studies, the molecular mechanisms underlying the progressive loss of articular cartilage during OA development remain largely unknown. The main focus of the present study was to gain more insight into molecular changes during the very early stages of mechanically induced cartilage degeneration and to relate molecular alterations to histological changes at distinct localizations of the joint. Studies on human articular cartilage are hampered by the difficulty of obtaining normal tissue and early-stage OA tissue, and they allow no progressive follow-up. An experimental OA model in dogs with a slow natural history of OA (Pond–Nuki model) was therefore chosen. Anterior cruciate ligament transection (ACLT) was performed on 24 skeletally mature dogs to induce joint instability resulting in OA. Samples were taken from different joint areas after 6, 12, 24 and 48 weeks, and gene expression levels of common cartilage molecules were quantified in relation to the histological grading (modified Mankin score) of adjacent tissue. Histological changes reflected early progressive degenerative OA. Soon after ACLT, chondrocytes responded to the altered mechanical conditions by significant and stable elevation of collagen type II, collagen type I and YKL40 expression, which persisted throughout the study. In contrast to the mild to moderate histological alterations, these molecular changes were not progressive and were independent of the joint localization (tibia, femur, lateral, medial) and the extent of matrix degeneration. MMP13 remained unaltered until 24 weeks, and aggrecan and tenascinC remained unaltered until 48 weeks after ACLT. These findings indicate that elevated collagen type II, collagen type I and YKL40 mRNA expression levels are early and sensitive measures of ACLT-induced joint instability independent of a certain grade of morphological cartilage degeneration. A second phase of molecular changes in OA may begin around 48 weeks after ACLT with altered expression of further genes, such as MMP13, aggrecan and tenascin. Molecular changes observed in the present study suggest that dog cartilage responds to degenerative conditions by regulating the same genes in a similar direction as that observed for chondrocytes in late human OA.     

Early and stable upregulation of collagen type II, collagen type I and YKL40 expression levels in cartilage during early experimental osteoarthritis occurs independent of joint location and histological grading

While morphologic and biochemical aspects of degenerative joint disease (osteoarthritis [OA]) have been elucidated by numerous studies, the molecular mechanisms underlying the progressive loss of articular cartilage during OA development remain largely unknown. The main focus of the present study was to gain more insight into molecular changes during the very early stages of mechanically induced cartilage degeneration and to relate molecular alterations to histological changes at distinct localizations of the joint. Studies on human articular cartilage are hampered by the difficulty of obtaining normal tissue and early-stage OA tissue, and they allow no progressive follow-up. An experimental OA model in dogs with a slow natural history of OA (Pond-Nuki model) was therefore chosen. Anterior cruciate ligament transection (ACLT) was performed on 24 skeletally mature dogs to induce joint instability resulting in OA. Samples were taken from different joint areas after 6, 12, 24 and 48 weeks, and gene expression levels of common cartilage molecules were quantified in relation to the histological grading (modified Mankin score) of adjacent tissue. Histological changes reflected early progressive degenerative OA. Soon after ACLT, chondrocytes responded to the altered mechanical conditions by significant and stable elevation of collagen type II, collagen type I and YKL40 expression, which persisted throughout the study. In contrast to the mild to moderate histological alterations, these molecular changes were not progressive and were independent of the joint localization (tibia, femur, lateral, medial) and the extent of matrix degeneration. MMP13 remained unaltered until 24 weeks, and aggrecan and tenascinC remained unaltered until 48 weeks after ACLT. These findings indicate that elevated collagen type II, collagen type I and YKL40 mRNA expression levels are early and sensitive measures of ACLT-induced joint instability independent of a certain grade of morphological cartilage degeneration. A second phase of molecular changes in OA may begin around 48 weeks after ACLT with altered expression of further genes, such as MMP13, aggrecan and tenascin. Molecular changes observed in the present study suggest that dog cartilage responds to degenerative conditions by regulating the same genes in a similar direction as that observed for chondrocytes in late human OA.     

Compressive properties of mouse articular cartilage determined in a novel micro-indentation test method and biphasic finite element model

The mechanical properties of articular cartilage serve as important measures of tissue function or degeneration, and are known to change significantly with osteoarthritis. Interest in small animal and mouse models of osteoarthritis has increased as studies reveal the importance of genetic background in determining predisposition to osteoarthritis. While indentation testing provides a method of determining cartilage mechanical properties in situ, it has been of limited value in studying mouse joints due to the relatively small size of the joint and thickness of the cartilage layer. In this study, we developed a micro-indentation testing system to determine the compressive and biphasic mechanical properties of cartilage in the small joints of the mouse. A nonlinear optimization program employing a genetic algorithm for parameter estimation, combined with a biphasic finite element model of the micro-indentation test, was developed to obtain the biphasic, compressive material properties of articular cartilage. The creep response and material properties of lateral tibial plateau cartilage were obtained for wild-type mouse knee joints, by the micro-indentation testing and optimization algorithm. The newly developed genetic algorithm was found to be efficient and accurate when used with the finite element simulations for nonlinear optimization to the experimental creep data. The biphasic mechanical properties of mouse cartilage in compression (average values: Young's modulus, 2.0 MPa; Poisson's ratio, 0.20; and hydraulic permeability, 1.1 x 10(-16) m4/N-s) were found to be of similar orders of magnitude as previous findings for other animal cartilages, including human, bovine, rat, and rabbit and demonstrate the utility of the new test methods. This study provides the first available data for biphasic compressive properties in mouse cartilage and suggests a promising method for detecting altered cartilage mechanics in small animal models of osteoarthritis.     

骨关节炎软骨细胞发生内质网应激

目的：研究骨关节炎软骨细胞是否发生内质网应激现象。方法：对关节置换术后的人类骨关节炎软骨标本和正常关节软骨标本切片进行内质网应激标志分子免疫球蛋白重链结合蛋白（BiP）的免疫组织化学检测;对小鼠膝关节进行半月板切断术诱发实验性骨关节炎,在术后1、3和6周取材,对组织切片进行番红花“O”染色、Mankin评分及BiP的免疫组织化学检测。结果：所有人类骨关节炎标本中软骨细胞BiP的表达明显升高。番红花“O”染色结果表明,在小鼠骨关节炎模型中,全部手术侧关节表面发生磨损,且随着术后时间延长关节表面磨损范围逐步扩大,手术侧Mankn分值显著高于对照侧;此外,手术侧的软骨细胞内BiP呈阳性表达,且表达量随术后时间延长而增加。结论：在人类骨关节炎标本和实验性小鼠骨关节炎模型中,关节软骨细胞均发生明显的内质网应激现象。     

Large-scale gene expression profiles, differentially represented in osteoarthritic synovium of the knee joint using cDNA microarray technology

Osteoarthritis (OA) is one of the most common age-related chronic disorders of articular cartilage, joints and bone tissue. Diagnosis of OA commonly depends on clinical and radiographic findings. However, changes in cartilage associated with the early stage of OA cannot be detected using radiographs, because significant cartilage degeneration must occur before radiographic findings show alterations of the appearance of cartilage. To identify new biomarkers of OA, we analysed gene expression profiles of synovium from 43 patients with OA, ten patients with rheumatoid arthritis (RA), and eight non-OA/non-RA patients using a novel cDNA microarray chip. We identified 21 genes with simultaneous significant differences in expression between OA and non-OA/non-RA groups and between OA and RA groups. Linear discriminant analysis showed that the three groups could be well separated using those 21 genes. Statistical analysis also revealed that several of the 21 genes were associated with disease progression and clinical presentation. The graphical modelling method indicated that some of the 21 genes are significantly associated with a particular clinical presentation, suggesting biological relationships among those genes. This is the first report of the use of cDNA microarray technology to create large-scale gene expression profiles differentially expressed in situ in OA synovium of the knee joint.     

Post-traumatic osteoarthritis: the role of accelerated chondrocyte senescence

Joint injuries frequently lead to progressive joint degeneration that causes the clinical syndrome of post-traumatic osteoarthritis. The pathogenesis of osteoarthritis remains poorly understood, but patient age is a significant risk factor for progressive joint degeneration. We have found that articular cartilage chondrocytes show strong evidence of senescence with increasing age, including synthesis of smaller more irregular aggrecans; increased expression of lysosomal beta-galactosidase and telomere erosion; and decreased proteoglycan synthesis, response to the anabolic cytokine IGF-I, proliferative capacity, and mitochondrial function. These observations help explain the strong association between age and joint degeneration, but they do not explain how joint injury increases the risk of joint degeneration in younger individuals. We hypothesized that excessive loading of articular surfaces due to acute joint trauma or post-traumatic joint instability, incongruity or mal-alignment increases release of reactive oxygen species, and that the increased oxidative stress on chondrocytes accelerates chondrocyte senescence thereby decreasing the ability of the cells to maintain or restore the tissue. To test this hypothesis, we exposed human articular cartilage chondrocytes from young adults to mechanical and oxidative stress. We found that shear stress applied to cartilage explants in a triaxial pressure vessel increased release of reactive oxygen species and oxidative stress induced chondrocyte senescence (as measured by expression of lysosomal beta-galactosidase, nuclear and mitochondrial DNA damage and decreased mitochondrial function). These observations support the hypothesis that joint injury accelerates chondrocyte senescence and that this acceleration plays a role in the joint degeneration responsible for post-traumatic osteoarthritis.     

Large-scale gene expression profiles,differentially represented in osteoarthritic synovium of the knee joint using cDNA microarray technology

Osteoarthritis (OA) is one of the most common age-related chronic disorders of articular cartilage, joints and bone tissue. Diagnosis of OA commonly depends on clinical and radiographic findings. However, changes in cartilage associated with the early stage of OA cannot be detected using radiographs, because significant cartilage degeneration must occur before radiographic findings show alterations of the appearance of cartilage. To identify new biomarkers of OA, we analysed gene expression profiles of synovium from 43 patients with OA, ten patients with rheumatoid arthritis (RA), and eight non-OA/non-RA patients using a novel cDNA microarray chip. We identified 21 genes with simultaneous significant differences in expression between OA and non-OA/non-RA groups and between OA and RA groups. Linear discriminant analysis showed that the three groups could be well separated using those 21 genes. Statistical analysis also revealed that several of the 21 genes were associated with disease progression and clinical presentation. The graphical modelling method indicated that some of the 21 genes are significantly associated with a particular clinical presentation, suggesting biological relationships among those genes. This is the first report of the use of cDNA microarray technology to create large-scale gene expression profiles differentially expressed in situ in OA synovium of the knee joint.     

Three-Dimensional Quantitative Morphometric Analysis (QMA) for In Situ Joint and Tissue Assessment of Osteoarthritis in a Preclinical Rabbit Disease Model

This work utilises advances in multi-tissue imaging, and incorporates new metrics which define in situ joint changes and individual tissue changes in osteoarthritis (OA). The aims are to (1) demonstrate a protocol for processing intact animal joints for microCT to visualise relevant joint, bone and cartilage structures for understanding OA in a preclinical rabbit model, and (2) introduce a comprehensive three-dimensional (3D) quantitative morphometric analysis (QMA), including an assessment of reproducibility. Sixteen rabbit joints with and without transection of the anterior cruciate ligament were scanned with microCT and contrast agents, and processed for histology. Semi-quantitative evaluation was performed on matching two-dimensional (2D) histology and microCT images. Subsequently, 3D QMA was performed; including measures of cartilage, subchondral cortical and epiphyseal bone, and novel tibio-femoral joint metrics. Reproducibility of the QMA was tested on seven additional joints. A significant correlation was observed in cartilage thickness from matching histology-microCT pairs. The lateral compartment of operated joints had larger joint space width, thicker femoral cartilage and reduced bone volume, while osteophytes could be detected quantitatively. Measures between the in situ tibia and femur indicated an altered loading scenario. High measurement reproducibility was observed for all new parameters; with ICC ranging from 0.754 to 0.998. In conclusion, this study provides a novel 3D QMA to quantify macro and micro tissue measures in the joint of a rabbit OA model. New metrics were established consisting of: an angle to quantitatively measure osteophytes (σ), an angle to indicate erosion between the lateral and medial femoral condyles (ρ), a vector defining altered angulation (λ, α, β, γ) and a twist angle (τ) measuring instability and tissue degeneration between the femur and tibia, a length measure of joint space width (JSW), and a slope and intercept (m, Χ) of joint contact to demonstrate altered loading with disease progression, as well as traditional bone and cartilage and histo-morphometry measures. We demonstrate correlation of microCT and histology, sensitive discrimination of OA change and robust reproducibility.     

Do changes in the mechanical properties of articular cartilage promote catabolic destruction of cartilage and osteoarthritis?

Osteoarthritis (OA) is a joint disease characterized by cartilage degeneration, a thickening of subchondral bone, and formation of marginal osteophytes. Previous mechanical characterization of cartilage in our laboratory suggests that energy storage and dissipation is reduced in osteoarthritis as the extent of fibrillation and fissure formation increases. It is not clear whether the loss of energy storage and dissipation characteristics is a result of biochemical and/or biophysical changes that occur to hyaline cartilage in joints. The purpose of this study is to present data, on the strain rate dependence of the elastic and viscous behaviors of cartilage, in order to further characterize changes that occur in the mechanical properties that are associated with OA. We have previously hypothesized that the changes seen in the mechanical properties of cartilage may be due to altered mechanochemical transduction by chondrocytes. Results of incremental tensile stress-strain tests at strain rates between 100%/min and 10,000%/min conducted on OA cartilage indicate that the slope of the elastic stress-strain curve increases with increasing strain rate, unlike the reported behavior of skin and self-assembled collagen fibers. It is suggested that the strain-rate dependence of the elastic stress-strain curve is due to the presence of large quantities of proteoglycans (PGs), which protect articular cartilage by increasing the apparent stiffness. The increased apparent stiffness of articular cartilage at high strain rates may limit the stresses borne and prolong the onset of OA. It is further hypothesized that increased compressive loading of chondrocytes in the intermediate zone of articular cartilage occurs as a result of normal wear to the superficial zone or from excessive impact loading. Once the superficial zone of articular cartilage is worn away, the tension is decreased throughout all cartilage zones leading to increased chondrocyte compressive loading and up-regulation of mechanochemical transduction processes that elaborate catabolic enzymes.     

Evidence that miR‐146a attenuates aging‐ and trauma‐induced osteoarthritis by inhibiting Notch1, IL‐6, and IL‐1 mediated catabolism

Primary osteoarthritis (OA) is associated with aging, while post‐traumatic OA (PTOA) is associated with mechanical injury and inflammation. It is not clear whether the two types of osteoarthritis share common mechanisms. We found that miR‐146a, a microRNA‐associated with inflammation, is activated by cyclic load in the physiological range but suppressed by mechanical overload in human articular chondrocytes. Furthermore, miR‐146a expression is decreased in the OA lesions of human articular cartilage. To understand the role of miR‐146a in osteoarthritis, we systemically characterized mice in which miR‐146a is either deficient in whole body or overexpressed in chondrogenic cells specifically. miR‐146a‐deficient mice develop early onset of OA characterized by cartilage degeneration, synovitis, and osteophytes. Conversely, miR‐146a chondrogenic overexpressing mice are resistant to aging‐associated OA. Loss of miR‐146a exacerbates articular cartilage degeneration during PTOA, while chondrogenic overexpression of miR‐146a inhibits PTOA. Thus, miR‐146a inhibits both OA and PTOA in mice, suggesting a common protective mechanism initiated by miR‐146a. miR‐146a suppresses IL‐1β of catabolic factors, and we provide evidence that miR‐146a directly inhibits Notch1 expression. Therefore, such inhibition of Notch1 may explain suppression of inflammatory mediators by miR‐146a. Chondrogenic overexpression of miR‐146a or intra‐articular administration of a Notch1 inhibitor alleviates IL‐1β‐induced catabolism and rescues joint degeneration in miR‐146a‐deficient mice, suggesting that miR‐146a is sufficient to protect OA pathogenesis by inhibiting Notch signaling in the joint. Thus, miR‐146a may be used to counter both aging‐associated OA and mechanical injury‐/inflammation‐induced PTOA.