Impact orientation can significantly affect the outcome of a blunt impact to the rabbit patellofemoral joint

This laboratory has developed a subfracture, joint trauma model in rabbits. Using a dropped impact mass directed onto a slightly abducted joint, chronic softening of retropatellar cartilage and thickening of underlying subchondral bone are documented in studies to 1 year post-insult. It has been hypothesized that these tissue changes are initiated by stresses developed during impact loading. A previous analytical study by this laboratory suggests that tensile strains in retropatellar cartilage can be significantly lowered, without significantly changing the intensity of stresses in the underlying subchondral bone, by reorientation of patellar impact more centrally on the joint. In the current study comparative experiments were performed on groups of animals after either an impact directed on the slightly abducted limb or a more central impact. One-year post-trauma in animals subjected to the central-oriented impact no degradation of the shear modulus for the retropatellar cartilage was documented, but the thickness of the underlying subchondral bone was significantly increased. In contrast, alterations in cartilage and underlying bone following impact on the slightly abducted limb were consistent with previous studies. The current experimental investigation showed the sensitivity of post-trauma alterations in joint tissues to slight changes in the orientation of impact load on the joint. Interestingly, for this trauma model thickening of the underlying subchondral plate occurred without mechanical degradation of the overlying articular cartilage. This supports the current laboratory hypothesis that alterations in the subchondral bone and overlying cartilage occur independently in this animal model.     

Rate of blunt impact loading affects changes in retropatellar cartilage and underlying bone in the rabbit patella

Our laboratory has developed a small animal model using Giant Flemish rabbits to examine chronic degradative changes in joint tissues following a blunt impact. Historically, we observe surface fissuring and decreases in the elastic modulus of retropatellar cartilage along with thickening of the underlying subchondral bone. Previous studies resulted in load insults that peaked in approximately 5ms, while loads that occur during automotive accidents or heavy exercise can produce longer rise times. The objective of the current study was to examine the influence of blunt impact loading rate using our established model. We hypothesized that the extent of fissuring and softening of retropatellar cartilage following impact would not be significantly different for a high (5ms to peak) versus low (50ms to peak) rate of loading experiment. Eight animals were impacted with a high rate of loading blunt impact, while ten animals were subjected to the same impact load at a low rate of loading. An additional eight animals served as a control population. All animals were sacrificed 12 months post-impact. The study yielded unexpected results for the first hypothesis. The high rate of loading experiments generated more surface fissuring of the retropatellar cartilage than the low rate of loading experiments. However, the degree of softening was similar for the two rates, which supported the second hypothesis. Furthermore, the study documented more thickening of bone underlying retropatellar cartilage following the high versus the low rate of loading experiments. The current study suggested that chronic injury mechanisms may be highly dependent on the rate of impact loading. These data could become extremely relevant in the development of high-velocity "safety" devices, such as knee air bags, that are needed to help position an unbelted occupant in an automobile crash.     

Analysis of acute mechanical insult in an animal model of post-traumatic osteoarthrosis.

Chronic degeneration of articular cartilage and bone in a rabbit model of post-traumatic osteoarthrosis has been hypothesized to occur due to acute stresses that exceed a threshold for injury. In this study, we impacted the rabbit patellofemoral joint at low and high intensities. High-intensity impacts produced degenerative changes in the joint, such as softening of retropatellar cartilage, as measured by indentation, an increase in histopathology of the cartilage, and an increase in thickness of subchondral bone underlying the cartilage. Low-intensity impacts did not cause these progressive changes. These data suggest that low-intensity impacts produced acute tissue stresses below the injury threshold, while high-intensity impacts produced stresses that exceeded the threshold for disease pathogenesis. This study begins to identify "safe" and "unsafe" ranges of acute tissue stress, using the rabbit patella, which may have future utility in the design of injury prevention devices for the human.     

Chronic changes in the rabbit tibial plateau following blunt trauma to the tibiofemoral joint

The knee is often a site of injury that can often lead to a chronic disease known as osteoarthritis (OA). The disease may be initiated, in part, by acute injuries to joint cartilage and its cells. In a recent study by this laboratory, using Flemish Giant rabbits, an impact compressive load on the tibial femoral joint was shown to cause significant levels of acute damage to chondrocytes in cartilage of the medial and lateral tibial plateaus. In the current study, using the same model, histological and mechanical data from the plateaus were documented at 6 and 12 months post impact, and compared to the unimpacted control limbs and a limb from unimpacted, control animals. The mechanical properties of cartilage were measured with indentation relaxation tests on the medial and lateral plateaus in regions covered and uncovered by the meniscus. The histological studies on impacted limbs showed surface lesions on both plateaus, thickening of the underlying subchondral bone at 12 months and numerous occult microcracks at the calcified cartilage–subchondral bone interface at 6 and 12 months, without significant changes in cartilage thickness or its mechanical properties versus controls. Yet, there was an increase in both the matrix and fiber moduli and a decrease in the permeability of uncovered, medial plateau cartilage in both limbs of impacted animals between 6 and 12 months post impact that was not documented in control animals.     

Gene expression analyses of subchondral bone in early experimental osteoarthritis by microarray

Osteoarthritis (OA) is a degenerative joint disease that affects both cartilage and bone. A better understanding of the early molecular changes in subchondral bone may help elucidate the pathogenesis of OA. We used microarray technology to investigate the time course of molecular changes in the subchondral bone in the early stages of experimental osteoarthritis in a rat model. We identified 2,234 differentially expressed (DE) genes at 1 week, 1,944 at 2 weeks and 1,517 at 4 weeks post-surgery. Further analyses of the dysregulated genes indicated that the events underlying subchondral bone remodeling occurred sequentially and in a time-dependent manner at the gene expression level. Some of the identified dysregulated genes that were identified have suspected roles in bone development or remodeling; these genes include Alp, Igf1, Tgf β1, Postn, Mmp3, Tnfsf11, Acp5, Bmp5, Aspn and Ihh. The differences in the expression of these genes were confirmed by real-time PCR, and the results indicated that our microarray data accurately reflected gene expression patterns characteristic of early OA. To validate the results of our microarray analysis at the protein level, immunohistochemistry staining was used to investigate the expression of Mmp3 and Aspn protein in tissue sections. These analyses indicate that Mmp3 protein expression completely matched the results of both the microarray and real-time PCR analyses; however, Aspn protein expression was not observed to differ at any time. In summary, our study demonstrated a simple method of separation of subchondral bone sample from the knee joint of rat, which can effectively avoid bone RNA degradation. These findings also revealed the gene expression profiles of subchondral bone in the rat OA model at multiple time points post-surgery and identified important DE genes with known or suspected roles in bone development or remodeling. These genes may be novel diagnostic markers or therapeutic targets for OA.     

Adaptation of subchondral bone in osteoarthritis

Osteoarthritis is a chronic joint disease with pathological changes in the articulating cartilage and all other tissues that occupy the joint. Radin and coworkers have suggested the involvement of subchondral bone in the disease process. However, evidence for an essential role in the etiology has never been proven. Recent studies showing reduced chemical and mechanical properties of subchondral bone in various stages of the disease have invigorated interest in the role of subchondral bone in the development and progression of the disease. The current study showed that the concept of bone adaptation might explain subchondral stiffening, a process where subchondral bone becomes typically sclerotic in osteoarthritis. In addition, we report reduced mechanical matrix tissue properties as well as an increase in denatured collagen content. In conclusion, although osteoarthritic bone tissue contains increased denatured collagen and has reduced matrix mechanical properties, the widely accepted concept of subchondral stiffening is compatible with the process of normal bone adaptation.     

An approach for the stress analysis of transversely isotropic biphasic cartilage under impact load.

Stress analysis of contact models for isotropic articular cartilage under impacting loads shows high shear stresses at the interface with the subchondral bone and normal compressive stresses near the surface of the cartilage. These stress distributions are not consistent, with lesions observed on the cartilage surface of rabbit patellae from blunt impact, for example, to the patello-femoral joint. The purpose of the present study was to analyze, using the elastic capabilities of a finite element code, the stress distribution in more morphologically realistic transversely isotropic biphasic contact models of cartilage. The elastic properties of an incompressible material, equivalent to those of the transversely isotropic biphasic material at time zero, were derived algebraically using stress-strain relations. Results of the stress analysis showed the highest shear stresses on the surface of the solid skeleton of the cartilage and tensile stresses in the zone of contact. These results can help explain the mechanisms responsible for surface injuries observed during blunt insult experiments.     

Chondrocyte damage and contact pressures following impact on the rabbit tibiofemoral joint

Epidemiological studies show that tibial plateau fractures comprise about 10% of all below-knee injuries in car crashes. Studies from this laboratory document that impacts to the tibiofemoral (TF) joint at 50% of the energy producing gross fracture can generate cartilage damage and microcracks at the interface between calcified cartilage and underlying subchondral bone in the tibial plateau. These injuries are suggestive of the initiation for a long term chronic disease, such as osteoarthritis. The disease process may be further encouraged by acute damage to chondrocytes in the cartilage overlying areas of occult microcracking. The hypothesis of the current study was that significant damage to chondrocytes in tibial plateau cartilage could be generated in areas of high contact pressure by a single impact delivered to the rabbit TF joint, without a gross fracture of bone. Three rabbits received a single, 13 J of energy blunt insult to the TF joint, while another three animals were used as controls. Cell viability analyses compared chondrocyte damage in impacted versus control cartilage. Two additional rabbits were impacted to document contact pressures generated in the TF joint. The study showed high contact pressures in uncovered areas of the plateau, with a trend for higher pressures in the lateral versus medial facets. A significantly higher percentage of damaged chondrocytes existed in impacted versus the opposite, nonimpacted limbs. Additionally, more chondrocyte damage was documented in the superficial zone (top 20% of cartilage thickness) of the cartilage compared to middle (middle 50% of thickness) and deep (bottom 30% of thickness) zones. This study showed that a single blunt insult to the in situ rabbit TF joint, generating large areas of contact pressure exceeding 20 MPa, produces significant chondrocyte damage in the tibial articular cartilage, especially in the superficial zone, without gross fracture of bone. Future studies will be needed to investigate the long term, chronic outcome of this blunt force joint trauma.     

Normal contact of elastic spheres with two elastic layers as a model of joint articulation.

An analytical model of two elastic spheres with two elastic layers in normal, frictionless contact is developed which simulates contact of articulating joints, and allows for the calculation of stresses and displacements in the layered region of contact. Using various layer/layer/substrate combinations, the effects of variations in layer and substrate properties are determined in relation to the occurrence of tensile and shear stresses as the source of crack initiation in joint cartilage and bone. Vertical cracking at the cartilage surface and horizontal splitting at the tidemark have been observed in joints with primary osteoarthritis. Deep vertical cracks in the calcified cartilage and underlying bone have been observed in blunt trauma experiments. The current model shows that cartilage stresses for a particular system are a function of the ratio of contact radius to total layer thickness (a/h). Surface tension, which is observed for a/h small, is alleviated as a/h is increased due to increased load, softening and/or thinning of the cartilage layer. Decreases in a/h due to cartilage stiffening lead to increased global compressive stresses and increased incidence of surface tension, consistent with impact-induced surface cracks. Cartilage stresses are not significantly affected by variations in stiffness of the underlying material. Tensile radial strains in the cartilage layer approach one-third of the normal compressive strains, and increase significantly with cartilage softening. For cases where the middle layer stiffness exceeds that of the underlying substrate, tensile stresses occur at the base of the middle layer, consistent with impact induced cracks in the zone of calcified cartilage and subchondral bone. The presence of the superficial tangential zone appears to have little effect on underlying cartilage stresses.     

Subchondral bone in osteoarthritis: insight into risk factors and microstructural changes

Osteoarthritis (OA) is a major cause of disability in the adult population. As a progressive degenerative joint disorder, OA is characterized by cartilage damage, changes in the subchondral bone, osteophyte formation, muscle weakness, and inflammation of the synovium tissue and tendon. Although OA has long been viewed as a primary disorder of articular cartilage, subchondral bone is attracting increasing attention. It is commonly reported to play a vital role in the pathogenesis of OA. Subchondral bone sclerosis, together with progressive cartilage degradation, is widely considered as a hallmark of OA. Despite the increase in bone volume fraction, subchondral bone is hypomineralized, due to abnormal bone remodeling. Some histopathological changes in the subchondral bone have also been detected, including microdamage, bone marrow edema-like lesions and bone cysts. This review summarizes basic features of the osteochondral junction, which comprises subchondral bone and articular cartilage. Importantly, we discuss risk factors influencing subchondral bone integrity. We also focus on the microarchitectural and histopathological changes of subchondral bone in OA, and provide an overview of their potential contribution to the progression of OA. A hypothetical model for the pathogenesis of OA is proposed.     

Quantitative Assessment of Murine Articular Cartilage and Bone Using X-Ray Phase-Contrast Imaging

Murine models for rheumatoid arthritis (RA) research can provide important insights for understanding RA pathogenesis and evaluating the efficacy of novel treatments. However, simultaneously imaging both murine articular cartilage and subchondral bone using conventional techniques is challenging because of low spatial resolution and poor soft tissue contrast. X-ray phase-contrast imaging (XPCI) is a new technique that offers high spatial resolution for the visualisation of cartilage and skeletal tissues. The purpose of this study was to utilise XPCI to observe articular cartilage and subchondral bone in a collagen-induced arthritis (CIA) murine model and quantitatively assess changes in the joint microstructure. XPCI was performed on the two treatment groups (the control group and CIA group, n = 9 per group) to monitor the progression of damage to the femur from the knee joint in a longitudinal study (at 0, 4 and 8 weeks after primary injection). For quantitative assessment, morphologic parameters were measured in three-dimensional (3D) images using appropriate image analysis software. Our results showed that the average femoral cartilage volume, surface area and thickness were significantly decreased (P<0.05) in the CIA group compared to the control group. Meanwhile, these decreases were accompanied by obvious destruction of the surface of subchondral bone and a loss of trabecular bone in the CIA group. This study confirms that XPCI technology has the ability to qualitatively and quantitatively evaluate microstructural changes in mouse joints. This technique has the potential to become a routine analysis method for accurately monitoring joint damage and comprehensively assessing treatment efficacy.     

Impact-induced osteochondral fracture in the tibial plateau

In this study, human tibia plateaus with the meniscus removed were impacted on various regions of the plateau surface via a drop test using a 5mm indenter. Osteochondral blocks containing the failure site were then extracted, chemically fixed, dehydrated, gold-particle coated, and sent for X-ray micro-CT imaging to obtain 3-D image reconstructions of the cartilage and underlying bone. Cartilage failure upon impact appeared to be characteristically brittle in nature. Impacted cartilage from the region not protected by the meniscus showed a relatively large cavernous disruption with microcrack propagation extending radially into the subchondral bone, while impacted cartilage from beneath the meniscus showed less dramatic surface disruption and with no underlying bone failure.     

Role of cartilage collagen fibrils networks in knee joint biomechanics under compression

Collagen fibrils networks in knee cartilage and menisci change in content and structure from a region to another. While resisting tension, they influence global joint response as well as local strains particularly at short-term periods. To investigate the role of fibrils networks in knee joint mechanics and in particular cartilage response, a novel model of the knee joint is developed that incorporates the cartilage and meniscus fibrils networks as well as depth-dependent properties in cartilage. The joint response under up to 2000 N compression is investigated for conditions simulating the absence in cartilage of deep fibrils normal to subchondral bone or superficial fibrils parallel to surface as well as localized split of cartilage at subchondral junction or localized damage to superficial fibrils at loaded areas. Deep vertical fibrils network in cartilage play a crucial role in stiffening (by 10%) global response and protecting cartilage by reducing large strains (from maximum of 102% to 38%), in particular at subchondral junction. Superficial horizontal fibrils protect the tissue mainly from excessive strains at superficial layers (from 27% to 8%). Local cartilage split at base disrupts the normal function of vertical fibrils at the affected areas resulting in higher strains.Deep fibrils, and to a lesser extent superficial fibrils, play dominant mechanical roles in cartilage response under transient compression. Any treatment modality attempting to repair or regenerate cartilage defects involving partial or full thickness osteochondral grafts should account for the crucial role of collagen fibrils networks and the demanding mechanical environment of the tissue.     

Forced mobilization accelerates pathogenesis: characterization of a preclinical surgical model of osteoarthritis

Preclinical osteoarthritis (OA) models are often employed in studies investigating disease-modifying OA drugs (DMOADs). In this study we present a comprehensive, longitudinal evaluation of OA pathogenesis in a rat model of OA, including histologic and biochemical analyses of articular cartilage degradation and assessment of subchondral bone sclerosis. Male Sprague-Dawley rats underwent joint destabilization surgery by anterior cruciate ligament transection and partial medial meniscectomy. The contralateral joint was evaluated as a secondary treatment, and sham surgery was performed in a separate group of animals (controls). Furthermore, the effects of walking on a rotating cylinder (to force mobilization of the joint) on OA pathogenesis were assessed. Destabilization-induced OA was investigated at several time points up to 20 weeks after surgery using Osteoarthritis Research Society International histopathology scores, in vivo micro-computed tomography (CT) volumetric bone mineral density analysis, and biochemical analysis of type II collagen breakdown using the CTX II biomarker. Expression of hypertrophic chondrocyte markers was also assessed in articular cartilage. Cartilage degradation, subchondral changes, and subchondral bone loss were observed as early as 2 weeks after surgery, with considerable correlation to that seen in human OA. We found excellent correlation between histologic changes and micro-CT analysis of underlying bone, which reflected properties of human OA, and identified additional molecular changes that enhance our understanding of OA pathogenesis. Interestingly, forced mobilization exercise accelerated OA progression. Minor OA activity was also observed in the contralateral joint, including proteoglycan loss. Finally, we observed increased chondrocyte hypertrophy during pathogenesis. We conclude that forced mobilization accelerates OA damage in the destabilized joint. This surgical model of OA with forced mobilization is suitable for longitudinal preclinical studies, and it is well adapted for investigation of both early and late stages of OA. The time course of OA progression can be modulated through the use of forced mobilization.     

Anti-Osteoarthritic Effects of the Litsea japonica Fruit in a Rat Model of Osteoarthritis Induced by Monosodium Iodoacetate

Osteoarthritis (OA) is a degenerative chronic disease that affects various tissues surrounding the joints, such as the subchondral bone and articular cartilage. The onset of OA is associated with uncontrolled catabolic and anabolic remodeling processes of the joints, including the cartilage and subchondral bone, to adapt to local biological and biochemical signals. In this study, we determined whether 70% ethanolic (EtOH) extract of Litsea japonica fruit (LJFE) had beneficial effects on the articular cartilage, including structural changes in the tibial subchondral bone, matrix degradation, and inflammatory responses, in OA by using a rat model of monosodium iodoacetate-induced OA. Our results showed that administration of LJFE increased the bone volume and cross-section thickness, but the mean number of objects per slice in this group was lower than that in the OA control (OAC) group. In addition, the LJFE decreased the expression of inflammatory cytokines. Compared to the OAC group, the group treated with high doses of LJFE (100 and 200 mg/kg) showed a more than 80% inhibition of the expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases. Our results suggest that LJFE can be used as a potential anti-osteoarthritic agent.     

Osteoarthritis

Osteoarthritis (OA) is characterized by degeneration of articular cartilage, limited intraarticular inflammation with synovitis, and changes in peri-articular and subchondral bone. Multiple factors are involved in the pathogenesis of OA, including mechanical influences, the effects of aging on cartilage matrix composition and structure, and genetic factors. Since the initial stages of OA involve increased cell proliferation and synthesis of matrix proteins, proteinases, growth factors, cytokines, and other inflammatory mediators by chondrocytes, research has focused on the chondrocyte as the cellular mediator of OA pathogenesis. The other cells and tissues of the joint, including the synovium and subchondral bone, also contribute to pathogenesis. The adult articular chondrocyte, which normally maintains the cartilage with a low turnover of matrix constituents, has limited capacity to regenerate the original cartilage matrix architecture. It may attempt to recapitulate phenotypes of early stages of cartilage development, but the precise zonal variations of the original cartilage cannot be replicated. Current pharmacological interventions that address chronic pain are insufficient, and no proven structure-modifying therapy is available. Cartilage tissue engineering with or without gene therapy is the subject of intense investigation. There are multiple animal models of OA, but there is no single model that faithfully replicates the human disease. This review will focus on questions currently under study that may lead to better understanding of mechanisms of OA pathogenesis and elucidation of effective strategies for therapy, with emphasis on mechanisms that affect the function of chondrocytes and interactions with surrounding tissues.     

The effect of the sagittal ridge angle on cartilage stress in the equine metacarpo-phalangeal (fetlock) joint

Fatigue failure of bones of the metacarpo-phalangeal (fetlock, MCP) joint is common in thoroughbred racehorses. Stresses within the fetlock joint cartilages are affected by the morphology of the third metacarpal bone (MC3) and proximal phalangeal bone, and the steepness of the median sagittal ridge of MC3 is believed to be associated with fracture. This study investigated the influence of the steepness of the sagittal ridge on cartilage stress distribution using a finite element model of the joint. Changes to the steepness of the sagittal ridge were made by applying a parabolic function to the mesh, creating four different models with sagittal ridge angles ranging from 95° to 105°. In the fetlock joint of Thoroughbred racehorses, sagittal ridge angles of >100° were associated with higher Von Mises stresses in cartilage at the palmar aspect of the condylar groove than such stresses in joints with sagittal ridge angles of <100°. Stresses were high in the specific region where fractures are known to originate in MC3. This aspect of morphology of the fetlock joint thus appears to play an important role in the magnitude and distribution of cartilage stresses, which, when acting on the underlying hard tissues of the articular calcified cartilage and subchondral bone may play a role in the initiation of fatigue fracture in the third metacarpal bone.     

If good things come from above,do bad things come from below?

Factors in the synovial fluid that maintain healthy articular cartilage, such as hyaluronic acid and lubricin, come from above. Is it possible that factors which lead to the destruction of cartilage come from below in the subchondral bone? The recent acquisition of tools to probe early events in osteoarthritis is shedding new light on possible contributions from this compartment on the initiation and progression of the disease. Tanamas and co-workers now provide evidence that bone marrow lesions in the subchondral bone are predictive, both of loss of cartilage and of formation of subchondral cysts. These data provoke questions about the nature and role of bone marrow lesions.Finding the factors that initiate, or the mechanisms that lead to progression of, osteoarthritis (OA) has proven frustrating and largely unproductive. Identification of risk factors for the condition - such as prior trauma to the joint, elevated body weight and female sex - may have helped with management of OA but has done little to progress understanding of the underlying factors that drive it. OA research has been more difficult than research for some other diseases of the skeleton, for several important reasons. Early OA, at the level of symptoms, can be episodic, making it difficult to identify the disease and to follow it longitudinally. Since the main early symptom is pain, clinical trials of new therapies have been problematic. Animal experiments have been bedevilled by a lack of models that accurately replicate the human disease. And perhaps, as argued by a minority of workers in the field, disease initiators have been sought in the wrong place; that is, cartilage versus bone.The recent study of Tanamas and colleagues highlights the way in which new-generation imaging holds the promise of shedding new light on this old problem [1]. In particular, high-resolution magnetic resonance imaging (MRI) can now deliver objective, measurable information about all structures of the joint, including the amount and quality of articular cartilage, and is also a powerful tool to investigate the subchondral bone. The holy grail of clinical investigation, namely longitudinal study with quantitative endpoints, is now accessible for OA. What Tanamas and colleagues'' study shows is important because it adds to emerging evidence that processes in the subchondral bone relate strongly to changes in the volumetric amount of articular cartilage. Specifically, bone marrow lesions (BMLs), the mysterious MRI-bright regions in the subchondral bone that occur more commonly in OA, were shown to be predictive of loss of cartilage and of formation of subchondral cysts. In turn, cysts were more likely than BMLs to occur in association with loss of cartilage.These data pose the intriguing question of whether BMLs encode key clues to the aetiology of OA. Longitudinal studies have shown that the presence of BMLs constitutes a potent risk factor for structural deterioration in knee OA [2]. BML enlargement has been strongly associated with increased cartilage loss, and Tanamas and colleagues'' data further suggest that their conversion into cysts is even more predictive of cartilage loss. Significantly, a reduction in the extent of BMLs on MRI has been shown to associate with a decrease in cartilage degradation [3]. Since the origin of BMLs is not known, its investigation needs to be prioritised as an important research topic. Current informed guesses are that BMLs comprise regions of oedema, perhaps secondary to episodes of local ischaemia. Although it is not possible to biopsy BMLs in patients with early OA, several studies have sought to correlate the MRI findings with histology in more severe disease. Regions of BMLs in end-stage OA patients at knee replacement were more likely to exhibit oedema, bone necrosis and trabecular abnormalities than were control sites [4].If BMLs are secondary to local ischaemia in the subchondral bone, there are several possible consequences. Firstly, the supply of nutrients and oxygen from regions of ischaemic subchondral bone, to the overlying articular cartilage, might be reduced. Cartilage nutrition has been considered to derive from the synovial fluid. The work of Imhof and colleagues, however, suggested that more than 50% of the glucose, oxygen and water requirements of cartilage are provided by perfusion from the subchondral vessels [5]. They described the dense subchondral vasculature in close proximity to the cartilage, and the micro-channels that penetrate the subchondral mineralisation zone and permit communication between the bone and the cartilage. More recent work indicates that small molecules can diffuse, in healthy joints, bidirectionally from the synovial compartment into the cartilage and underlying bone and from the subchondral bone into the overlying cartilage [6]. Inspection of the osteochondral junction of long bones reveals that osteocytes and osteocyte canaliculi, which are also probable conduits of nutrients, are intimately associated with the articular cartilage. Experimental interruption of contact between articular cartilage and subchondral bone results in degeneration of the cartilage, and osteoblasts from OA subchondral bone conferred catabolic changes in articular chondrocytes [7].Secondly, osteocyte death in bone is becoming recognised as a signalling event for osteoclastic removal of the nonviable bone and its replacement in a remodelling episode [8]. Although subchondral bone is constantly being remodelled, concentration of this activity in a particular region of the bone could alter its mechanical integrity and its ability to properly support the overlying cartilage.Tanamas and colleagues conclude that cysts (and BMLs) may provide therapeutic targets for the treatment of knee OA [1]. Certainly, the recent acquisition of tools to probe early events in subchondral bone in OA should deliver rapid advances in our understanding of the natural history of this condition.     

Repair and regeneration of osteochondral defects in the articular joints

People suffering from pain due to osteoarthritic or rheumatoidal changes in the joints are still waiting for a better treatment. Although some studies have achieved success in repairing small cartilage defects, there is no widely accepted method for complete repair of osteochondral defects. Also joint replacements have not yet succeeded in replacing of natural cartilage without complications. Therefore, there is room for a new medical approach, which outperforms currently used methods. The aim of this study is to show potential of using a tissue engineering approach for regeneration of osteochondral defects. The critical review of currently used methods for treatment of osteochondral defects is also provided. In this study, two kinds of hybrid scaffolds developed in Hutmacher's group have been analysed. The first biphasic scaffold consists of fibrin and PCL. The fibrin serves as a cartilage phase while the porous PCL scaffold acts as the subchondral phase. The second system comprises of PCL and PCL-TCP. The scaffolds were fabricated via fused deposition modeling which is a rapid prototyping system. Bone marrow-derived mesenchymal cells were isolated from New Zealand White rabbits, cultured in vitro and seeded into the scaffolds. Bone regenerations of the subchondral phases were quantified via micro CT analysis and the results demonstrated the potential of the porous PCL and PCL-TCP scaffolds in promoting bone healing. Fibrin was found to be lacking in this aspect as it degrades rapidly. On the other hand, the porous PCL scaffold degrades slowly hence it provides an effective mechanical support. This study shows that in the field of cartilage repair or replacement, tissue engineering may have big impact in the future. In vivo bone and cartilage engineering via combining a novel composite, biphasic scaffold technology with a MSC has been shown a high potential in the knee defect regeneration in the animal models. However, the clinical application of tissue engineering requires the future research work due to several problems, such as scaffold design, cellular delivery and implantation strategies.