Cruciate Ligament Transection Research Articles

Linear ubiquitination of LKB1 activates AMPK pathway to inhibit NLRP3 inflammasome response and reduce chondrocyte pyroptosis in osteoarthritis

Osteoarthritis (OA) is the most common chronic disease. It is characterized by high levels of clinical heterogeneity and low inflammation. Therefore, elucidation of the mechanisms that regulate gene expression is critical for developing effective OA therapies. This study aimed to explore the role of LKB1/AMPK in the progression of OA. Anterior cruciate ligament transection (ACLT) was performed on Sprague Dawley (SD) rats right knee to construct OA model, followed by AICAR [AMP-activated protein kinase (AMPK) activator] treatment. The level changes [AMPK, IL-10, IL-13, IL-1β, TNF-α, IL-6, ASC, Caspase-1, Ki67, and hibit Nod-like receptor protein 3 (NLRP3)] and the degree of tissue injury were assessed by western blot, Immunohistochemical (IHC), Enzyme-linked immunosorbent assay (ELISA), Hematoxylin-eosin staining (HE), Immunofluorescence (IF), Terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay, and Safranin O and Fast Green staining (S-O). Human chondrocytes were induced by LPS to construct a cellular inflammatory model, and then transfected with oe-AMPK or oe-HOIL-1-interacting protein (HOIP). Cell viability/apoptotic and intracellular content of AMPK, HOIP, IL-1β, IL-10, IL-13, TNF-α, IL-6, ASC, NLRP3 and Caspase-1 were measured by western blot, ELISA, CCK-8, IF, flow cytometry and TUNEL assays. After AICAR treatment with OA rats, the expression of p-AMPK, IL-10, IL-13, Ki67 and Bcl-2 increased, the level of NLRP3 inflammasome, TNF-α, IL-6, Bax and Caspase-3 levels were decreased, and tissue damage and apoptosis were significantly alleviated. After transfected with oe-LKB1, chondrocyte activity and LKB1 linear ubiquitination were enhanced, and the level of HOIP, p-AMPK, IL-10 and IL-13 were increased. In contrast, NLRP3 inflammasome (ASC, NLRP3, Caspase-1, IL-1β, and cleaved Caspase-1), TNF-α, and IL-6 levels decreased, apoptosis rate and TUNEL positive rate were attenuated. LKB1/AMPK pathway significantly ameliorated NLRP3 inflammasome response and chondrocyte injury. Activation of AMPK pathway by linear ubiquitination of LKB1 may be a potential target for OA treatment. This study highlights the importance of the LKB1/AMPK pathway in NLRP3 inflammatory body response and chondrocyte injury. Activation of LKB1 by modulating linear ubiquitination may be a potential target for OA treatment.

Instability and excessive mechanical loading mediate subchondral bone changes to induce osteoarthritis.

BackgroundTo assess the diversified effects of mechanical instability, excessive mechanical loading on subchondral bone remodeling. And to investigate the underlying cartilage degeneration and osteoarthritis (OA) progression in ipsilateral and contralateral knees, given that OA progression always affects joints bilaterally.MethodsAnterior cruciate ligament transection (ACLT) of the left knee was used to induce OA in C57/B6 mice for 1, 3 and 6 months. Both left (ipsilateral) and right (contralateral) knees underwent micro-computerized tomography (micro-CT) scan and morphological analysis. The subchondral bone metabolism analysis by immunostaining of tartrate-resistant acid phosphatase (TRAP) and Osterix. Behavioral analyses including von Frey test and CatWalk gait analysis were also performed. Western blot analysis was performed to assess the signaling pathways involved in OA progression.ResultsAnalyses showed that various changes in ipsilateral and contralateral knees lead to OA progression. Articular cartilage was rapidly destroyed on the ipsilateral side but was only gradually destroyed on the contralateral side. Micro-CT data showed a rapid decrease with a subsequent partial recovery of bone volume in the late stage on the ipsilateral side, while a gradual condensation of bone density was seen on the contralateral side. Immunostaining showed increased osteoclastic and osteoblastic activity in the early stage on the ipsilateral side, but only slight osteoblastic changes on the contralateral side. Behavioral analyses including von Frey and gait analysis showed that contralateral knees compensate ipsilateral mechanical loading, but also that this mechanism failed to work in the late stage.ConclusionsDiversified mechanical loading properties lead to OA progression through different mechanisms of subchondral bone remodeling. Acute ACLT led to OA through bone density reduction, while the contralateral side developed OA gradually due to subchondral bone sclerosis.

Traumatic osteoarthritis-induced persistent mechanical hyperalgesia in a rat model of anterior cruciate ligament transection plus a medial meniscectomy.

BackgroundOsteoarthritis (OA) is a degenerative joint disease characterized by progressive cartilage degeneration, subchondral bone changes, osteophyte formation, and synovitis. A major symptom is pain that is triggered by peripheral and central changes within the pain pathways. Some surgery-induced joint instability rat models of OA were described to mimic traumatic OA. Several behavioral tests were developed to access OA-induced pain. However, follow-up in most studies usually only occurred for about 4 weeks. Since traumatic OA is a chronic disease which gradually develops after trauma, the pattern of pain might differ between early and late stages after the trauma.PurposeTo observe the time-dependent development of hypersensitivity after traumatic OA and to determine the best timing and methods to investigate traumatic OA-induced pain.MethodsAnterior cruciate ligament transection plus medial meniscectomy was used to induce traumatic OA in Sprague-Dawley rats. Traumatic OA-induced pain was evaluated using four different behavioral tests for 15 weeks.ResultsA significant difference in mechanical hypersensitivity developed throughout the observational period. It was worst in the first 3 weeks after the operation, then became less significant after 5 weeks but persisted. There were no differences in thermal hyperalgesia or motor coordination.ConclusionTraumatic OA induced mechanical hyperalgesia but did not cause thermal hyperalgesia or influence motor coordination. Furthermore, to investigate chronic pain induced by OA, the observational period should be at least 5 weeks after the intervention. These findings may help in further research and improve our understanding of traumatic OA-induced pain mechanisms.

Comparative study on identification of healthy and osteoarthritic articular cartilages by fourier transform infrared imaging and chemometrics methods

Two discriminant methods, partial least squares-discriminant analysis (PLS-DA) and Fisher’s discriminant analysis (FDA), were combined with Fourier transform infrared imaging (FTIRI) to differentiate healthy and osteoarthritic articular cartilage in a canine model. Osteoarthritic cartilage had been developed for up to two years after the anterior cruciate ligament (ACL) transection in one knee. Cartilage specimens were sectioned into 10 [Formula: see text]m thickness for FTIRI. A PLS-DA model was developed after spectral pre-processing. All IR spectra extracted from FTIR images were calculated by PLS-DA with the discriminant accuracy of 90%. Prior to FDA, principal component analysis (PCA) was performed to decompose the IR spectral matrix into informative principal component matrices. Based on the different discriminant mechanism, the discriminant accuracy (96%) of PCA-FDA with high convenience was higher than that of PLS-DA. No healthy cartilage sample was mis-assigned by these two methods. The above mentioned suggested that both integrated technologies of FTIRI-PLS-DA and, especially, FTIRI-PCA-FDA could become a promising tool for the discrimination of healthy and osteoarthritic cartilage specimen as well as the diagnosis of cartilage lesion at microscopic level. The results of the study would be helpful for better understanding the pathology of osteoarthritics.

Zoledronic Acid Effect on Chondrocyte Apoptosis in Degenerative Osteoarthritis Model

Apoptosis refers to cell death without inflammatory process, and is related to degenerative changes in joints. We hypothesized that zoledronic acid (ZA) would have a positive effect on chondrocyte viability and decreases in chondrocyte loss, which are important for the progression of degeneration. This study aimed to reveal the difference in time-dependent apoptotic changes in cartilage tissue in the anterior cruciate ligament (ACL) transection model of osteoarthritis (OA) in rat knees after treatment with zoledronic acid. We randomly divided 48 male Wistar albino rats into 6 groups. The knees of all rats except those in the control group underwent the operation for ACL transection. ZA for half of the rats and saline solution for the others was injected weekly into knees. Animals were killed at 0, 3, and 6 weeks after surgery. Apoptosis of chondrocytes were analyzed using the terminal deoxynucleotidyl transferase dUTP nick end labeling method. Comparison of groups was performed using Kruskal Wallis analysis and the Mann Whitney U test. Significant differences were observed between the groups treated with ZA and saline. ZA treatment significantly decreased the number of apoptotic cells in chondral tissue. ZA prevents time-dependent degenerative changes in chondral tissue by decreasing chondrocyte death. Intra-articular ZA may have the potential to treat and conserve chondral viability. ZA prevents chondrocyte loss and may play a therapeutic role in OA and conserving joint health. Further studies are needed to evaluate the potential of intra-articular ZA for the prevention or treatment of age-related degenerative changes.

Recombinant Progranulin Prevents the Loss of Proteoglycan in Surgically Induced Osteoarthritis Model

Osteoarthritis (OA) is a degenerative joint disease that affects more than 46 million people in the United States alone. Since mechanisms by which OA ensues are largely unknown, there are no therapeutic targets that effectively prevent and treat the disease. However, growth factors, cytokines and matrix-degrading enzymes are strongly implicated in initiating and aggravating OA lesions. Thus, a molecular understanding of these molecules will provide invaluable information toward the search for novel therapeutic targets for OA. Our genome-wide screen for novel, differentially expressed genes in OA led to the isolation of progranulin (PGRN) as a novel OA-associated growth factor [1]. In subsequent global screen for the binding proteins of PGRN, we found that PGRN bound to TNF Receptors (TNFR). In addition, PGRN blocks the binding of TNFα to TNFR and inhibits TNFα-induced ADAMTS cleavage of cartilage oligomeric matrix protein (COMP) [2]. These previous findings led us to determine whether recombinant PGRN prevents cartilage degradation in the progression of OA in vivo. For this purpose, we took advantage of PGRN knockout mice to generate anterior cruciate ligament (ACL) transection induced OA models which develop severe OA due to the deficiency of PGRN. Importantly, intra-articular injection of rPGRN growth factor significantly prevented the degeneration of cartilage in PGRN-deficient OA model. PGRN treated mice retained cartilage integrity and showed little or no degradation of cartilage matrix in comparison to highly degraded cartilage of non-treated mice (Figure).

Pain, motor and gait assessment of murine osteoarthritis in a cruciate ligament transection model

The major complaint of Osteoarthritis (OA) patients is pain. However, due to the nature of clinical studies and the limitation of animal studies, few studies have linked function impairment and behavioral changes in OA animal models to cartilage loss and histopathology. Our objective was to study surrogate markers of functional impairment in relation to cartilage loss and pathological changes in a post-traumatic mouse model of OA. We performed a battery of functional analyses in a mouse model of OA generated by cruciate ligament transection (CLT). The changes in functional analyses were linked to histological changes graded by OARSI standards, histological grading of synovitis, and volumetric changes of the articular cartilage and osteophytes quantified by phase contrast micro-computed tomography (μCT). OA generated by CLT led to decreased time on rotarod, delayed response on hotplate analysis, and altered gait starting from 4 weeks after surgery. Activity in open field analysis did not change at 4, 8, or 12 weeks after CLT. The magnitude of behavioral changes was directly correlated with higher OARSI histological scores of OA, synovitis in the knee joints, cartilage volume loss, and osteophyte formation. Our findings link functional analyses to histological grading, synovitis, comprehensive three-dimensional assessment of cartilage volume and osteophyte formation. This serves as a reference for a mouse model in predicting outcomes of OA treatment.

Quantitative imaging of murine osteoarthritic cartilage by phase contrast micro-computed tomography

Objective—Mouse is an optimal model organism in which gene-environment interactions can be studied for the pathogenesis of osteoarthritis. The gold standard in arthritis research in mice is based on histopathology and immunohistochemistry, which are labor intensive, prone to sampling bias and technical variability, and limited in throughput. This study aims to develop a new technique that assesses mouse cartilage by integrating quantitative volumetric imaging techniques. Methods—A novel mouse model of osteoarthritis was generated by cruciate ligament transection (CLT) and evaluated by histopathology and immunohistochemistry. Knee joint samples were then imaged by a novel technique that combines high resolution μ CT and phase-contrast optics followed by quantitative analyses. A comparative analysis was also performed on a previously established mouse model of osteoarthritis generated by destabilization of medial meniscus (DMM). Results—Phase contrast μ CT achieved cellular resolution of chondrocytes and quantitative assessment of parameters such as articular cartilage volume and surface area. In mouse models of OA generated by either CLT or DMM, we showed that phase contrast μ CT distinguished control and OA cartilage by providing quantitative measures with high reproducibility and minimal variability. Features of OA at the cellular or tissue levels could also be observed in images generated by phase contrast μ CT. Conclusion—We established an imaging technology that comprehensively assessed and quantified the 2 and 3 dimensional changes of articular cartilage. Application of this technology will facilitate the rapid and high throughput assessment of genetic and therapeutic models of OA in mice.

The transient receptor potential vanilloid 4 ion channel regulates the biosynthetic response of chondrocytes to dynamic loading

The transient receptor potential vanilloid 4 ion channel regulates the biosynthetic response of chondrocytes to dynamic loading

Proteoglycan 4 expression protects against the development of osteoarthritis

Osteoarthritis (OA) is a common degenerative condition that afflicts more than 70% of the population between 55 and 77 years of age. Although its prevalence is rising globally with aging of the population, current therapy is limited to symptomatic relief and, in severe cases, joint replacement surgery. We report that intra-articular expression of proteoglycan 4 (Prg4) in mice protects against development of OA. Long-term Prg4 expression under the type II collagen promoter (Col2a1) does not adversely affect skeletal development but protects from developing signs of age-related OA. The protective effect is also shown in a model of posttraumatic OA created by cruciate ligament transection. Moreover, intra-articular injection of helper-dependent adenoviral vector expressing Prg4 protected against the development of posttraumatic OA when administered either before or after injury. Gene expression profiling of mouse articular cartilage and in vitro cell studies show that Prg4 expression inhibits the transcriptional programs that promote cartilage catabolism and hypertrophy through the up-regulation of hypoxia-inducible factor 3α. Analyses of available human OA data sets are consistent with the predictions of this model. Hence, our data provide insight into the mechanisms for OA development and offer a potential chondroprotective approach to its treatment.

Quantitative imaging of murine osteoarthritic cartilage by phase‐contrast micro–computed tomography

The mouse is an optimal model organism in which gene-environment interactions can be used to study the pathogenesis of osteoarthritis (OA). The gold standard for arthritis research in mice is based on histopathology and immunohistochemistry, which are labor-intensive, prone to sampling bias and technical variability, and limited in throughput. The aim of this study was to develop a new technique that assesses mouse cartilage by integrating quantitative volumetric imaging techniques. A novel mouse model of OA was generated by cruciate ligament transection (CLT) and evaluated by histopathology and immunohistochemistry. Knee joint specimens were then imaged using a new technique that combines high-resolution micro-computed tomography (micro-CT) and phase-contrast optics followed by quantitative analyses. A comparative analysis was also performed in a previously established mouse model of OA generated by destabilization of the medial meniscus (DMM). Phase-contrast micro-CT achieved cellular resolution of chondrocytes and quantitative assessment of parameters such as articular cartilage volume and surface area. In mouse models of OA generated by either CLT or DMM, we showed that phase-contrast micro-CT distinguished control and OA cartilage by providing quantitative measures with high reproducibility and minimal variability. Features of OA at the cellular or tissue level could also be observed in images generated by phase-contrast micro-CT. We established an imaging technology that comprehensively assessed and quantified the 2-dimensional and 3-dimensional changes of articular cartilage. Application of this technology will facilitate the rapid and high-throughput assessment of genetic and therapeutic models of OA in mice.

The impact of forced joint exercise on lubricin biosynthesis from articular cartilage following ACL transection and intra-articular lubricin's effect in exercised joints following ACL transection

To evaluate the impact of forced joint exercise following acute knee injury on lubricin metabolism and its relationship to cartilage degeneration and to assess chondroprotection of a single-dose purified human lubricin injection in exercised injured joints. Anterior cruciate ligament transection (ACLT) was performed in rats with six experimental groups; 3-week post-ACLT, 3-week post-ACLT + exercise, 5-week post-ACLT, 5-week post-ACLT + exercise, and 5-week post-ACLT + exercise treated with intra-articular phosphate buffered saline (PBS) or lubricin. Joint exercise was achieved using a rotating cylinder at a speed of 6 rpm for 30 min daily, 5 days a week starting 1 week following surgery. Cartilage lubricin expression in injured joints was determined. Histological analyses included Safranin O/Fast Green, activated caspase-3, and lubricin mRNA in-situ hybridization. Assessment of cartilage damage was performed by osteoarthritis research society international (OARSI) modified Mankin scoring and urinary CTXII (uCTXII) levels. At 3 weeks, lubricin expression in exercised ACLT joints was significantly (P < 0.001) lower compared to ACLT joints. The OARSI scores were significantly (P < 0.001) higher in the ACLT + exercise animals compared to ACLT animals at 5 weeks. Compared to 3-week ACLT, 3-week ACLT + exercise cartilage showed increased caspase-3 staining. Compared to ACLT + exercise and PBS-treated ACLT + exercise, lubricin intra-articular treatment resulted in a significant increase (P < 0.001) in cartilage lubricin gene expression and a reduction (P < 0.05) in uCTXII levels. Joint exercise resulted in decreased lubricin cartilage expression, increased cartilage degeneration and reduced superficial zone chondrocyte viability in the ACLT joint. Intra-articular lubricin administration ameliorated cartilage damage due to exercise and preserved superficial zone chondrocytes' viability.

The effects of glucosamine hydrochloride on subchondral bone changes in an animal model of osteoarthritis

To quantify periarticular subchondral bone changes in a rabbit model of experimental osteoarthritis (OA), and to determine the effects of continuous administration of a clinically relevant dose of glucosamine HCl on subchondral bone changes in this model. Anterior cruciate ligament transection (ACLT) was performed on the left femorotibial joints of 16 rabbits to induce OA. Ten rabbits that did not undergo ACLT served as unoperated controls. Eight rabbits that underwent ACLT and 6 control rabbits were treated with 100 mg of glucosamine daily, and the others were given a placebo. The articular cartilage was evaluated macroscopically and graded at the time of necropsy, 8 weeks after ACLT. Bone mineral density (BMD) was measured using dual-energy x-ray absorptiometry on the dissected distal femur and proximal tibia. Subchondral trabecular bone turnover, architecture, and connectivity, as well as subchondral plate thickness and mineralization were studied on the undecalcified tibia sections from each animal. Eight weeks after ACLT, most of the operated joints had various degrees of cartilage damage and fibrillation. Compared with the control group, the ACLT group had significantly increased subchondral bone turnover and lower BMD, bone volume, connectivity, and bone mineralization. The high bone turnover was significantly reduced in glucosamine-treated animals that underwent ACLT. In fact, there were no significant differences between the ACLT/glucosamine group and the control/glucosamine group in most of the bone parameters studied. This study shows that subchondral bone turnover, structure, and mineralization are significantly altered in the early stages of experimental OA, and that these changes are attenuated by glucosamine treatment.

Getting the Dog Moving After Surgery

Getting the Dog Moving After Surgery

Plasma and synovial concentrations of carprofen in dogs with chronic osteoarthritis

SummaryThe objective of this study was to measure the synovial and plasma concentration of carprofen in normal and osteoarthritic stifle joints throughout a 12-hour period. Eight healthy male mixed breed hound dogs with chronic right stifle osteoarthritis (OA) secondary to right cruciate ligament transection, were used. Each dog was treated with carprofen (2mg/kg every 12 hours) for 14 days at four different time periods. Prior to treatment, each dog had baseline data collected that included two force plate evaluations (seven days apart), synovial fluid, and plasma collections. Plasma samples were collected at three hours post drug administration on days two, four, six, eight, 10, and 12. On days #7 and 14 plasma, serum, bilateral stifle synovial fluid and ground reaction forces (GRFs) were collected at three, six, nine, or 12 hours post-medication, depending upon the test protocol. Vertical and cranio-caudal ground reaction forces were recorded at each time period. Plasma concentrations measured at three hours remained constant over each testing protocol. There were not any differences between the plasma carprofen concentrations at three, nine, or 12 hours between days #7 or 14. A significant difference was not found in the carprofen synovial concentrations between left and right stifles at any time. Significant increases in vertical impulse data were found at six hours post-treatment, for all of the collection periods on days three, seven and 14. During the study, there was not any indication that carprofen had a ‘preference’ for the OA stifle as opposed to the normal stifle. Carprofen administration increased the total force transmitted through the abnormal limb.Carprofen concentrations in the plasma and synovial fluid and ground reaction forces were measured in dogs with single stifle osteoarthritis at three, six, nine and 12 hours following dosing at 2 mg/kg every 12 hours. Carprofen did not have a ‘preference’ for the OA stifle as opposed to the normal stifle. Carprofen administration increased the total force transmitted through the abnormal limb.

Differences in type II collagen degradation between peripheral and central cartilage of rat stifle joints after cranial cruciate ligament transection.

Type II collagen degradation is thought to be the key process in cartilage degradation during the development of osteoarthritis (OA). In this study, we investigated the kinetics of type II collagen degradation during surgically induced OA. Experimental OA was induced in male Wistar rats by transecting the cranial (anterior) cruciate ligament (CCL). Hematoxylin and eosin staining was used to study overall cartilage degradation, while immunostained sections were used to demonstrate denatured type II collagen (Col2-3/4m antibody) and the collagenase cleavage site in type II collagen (Col2-3/ 4Cshort antibody). During the first 3-4 weeks, cartilage destruction, associated with chondrocyte death, proteoglycan depletion, and a marked increase in the collagenase cleavage neoepitope, was mainly located at the margins of the cartilage. From weeks 3-4, the central part of the cartilage showed increased surface fibrillation and apparent chondrocyte death. In these areas, increased denatured type II collagen staining but little cleavage-site staining was present. These results indicate that cartilage degradation after CCL transection in the rat consists of 2 phases. An early phase located at the cartilage margins and a late phase located at the central part of the cartilage. In the early phase, collagenase-dependent cartilage damage occurred. During the late phase, the level of type II collagen denaturation increased.

Diacerhein treatment reduces the severity of osteoarthritis in the canine cruciate-deficiency model of osteoarthritis.

To determine if diacerhein protects against the early stages of joint damage in a canine model of osteoarthritis (OA). OA was induced in 20 adult mongrel dogs by transection of the anterior cruciate ligament of the left knee. Beginning the day after surgery, dogs in the active treatment group were dosed twice a day with capsules of diacerhein, providing a total daily dose of 40 mg/kg, for 32 weeks. Dogs in the control group received placebo capsules on the same schedule. Pathology in the unstable knee was assessed arthroscopically 16 weeks after surgery and by direct observation when the dogs were killed 32 weeks after surgery. The severity of gross joint pathology was recorded, and samples of the medial femoral condyle cartilage and the synovial tissue adjacent to the central portion of the medial meniscus were collected for histologic evaluation. Water content and uronic acid concentration of the articular cartilage from the femoral condyle were determined, and collagenolytic activity in extracts of cartilage pooled from the medial and lateral tibial plateaus was assayed against 14C-labeled collagen fibers. Diacerhein treatment slowed the progression of OA, as measured by grading of gross changes in the unstable knee at arthroscopy 16 weeks after cruciate ligament transection (P = 0.04) and at the time the animals were killed, 32 weeks after surgery (P = 0.05). However, 32 weeks after ACL transection, the mean proteoglycan concentration and water content of the OA cartilage and the level of collagenolytic activity in extracts of the cartilage were not significantly different in the diacerhein treatment group than in the placebo treatment group. Diacerhein treatment significantly reduced the severity of morphologic changes of OA compared with placebo. These findings support the view that diacerhein may be a disease-modifying drug for OA.

Bone density and local growth factors in generalized osteoarthritis.

Osteoarthritis is usually considered to be a primary disorder of chondrocyte function with secondary changes in bones. However, a defect in the subchondral bone resulting in loss of its shock absorbing capacity could transfer the stress of loading directly to the articular cartilage with secondary changes in the cartilage. Review of histomorphometric and bone densitometric studies at sites of osteoarthritis at the hip or knee revealed that cartilage fibrillation could not be dissociated from bony changes even in the earliest stages of osteoarthritis and that subchondral trabeculae are thickened and more spaced in osteoarthritis. Microfractures of subchondral trabecular bone were less frequently seen in osteoarthritis compared to controls. Changes of the tidemark were found to be multiform and metabolically active in the osteoarthritic process. Endochondral ossification depletes the calcified cartilage at the cartilage/bone interface and the tidemark has been thought of as a calcification front advancing in the direction of non-calcified cartilage. Duplication of the tidemark is cited as evidence of this advancement. In the few experimental animal studies of subchondral bone in osteoarthritis, thicker trabeculae which were closer together were found in guinea pigs already when only mild cartilage changes were present. In the dog, with cruciate ligament transection, changes in bone were later than in the cartilage, but the changes in bone could still contribute to the progression of osteoarthritis. To study if bone changes may precede injury to the cartilage and if metabolic and systemic influences can also alter the subchondral bone, rendering it less able to withstand normal mechanical stresses, bone at different sites in the body has been studied extensively by the authors. Epidemiological and case control studies have revealed that osteoarthritis cases have more bone at all sites than expected and that bone in cases with generalized osteoarthritis shows both quantitative and qualitative differences, including increased contents of growth factors and hypermineralization. These findings suggest that a more generalized bone alteration may be the basis of the pathogenesis of osteoarthritis.

The weight-bearing knee after anterior cruciate ligament rupture

Unilateral weight bearing was simulated on 12 cadaver knees to quantitate anterior tibial translation (ATT) after anterior cruciate ligament (ACL) transection and to asses the role of the posteromedial structure and the hamstrings in controlling laxity. With the ACL intact, ATT was 3.5 +/- 2.8 mm in extension and 4.3 +/- 3.6 mm at 60 degrees flexion. After sectioning the ACL, ATT was 6.5 +/- 4.7 mm in extension and 17.5 +/- 10 mm at 60 degrees flexion (P = 0.001). Applying a force in the hamstrings was unable to correct the pathological ATT observed after ACL section. Partial medial meniscectomy did not increase ATT after the ACL section. Disinsertion of the posterior horn of the medial meniscus and total medial meniscectomy increased ATT significantly compared to isolated ACL section. After ACL transection, sectioning the meniscotibial fibers or posteromedial capsule significantly increased ATT (6.5 +/- 0.5 mm in extension). Section of the postero-oblique ligament or popliteus tendon had no effect on ATT.

Sensory nerves only temporarily protect the unstable canine knee joint from osteoarthritis. Evidence that sensory nerves reprogram the central nervous system after cruciate ligament transection.

The slow rate at which articular cartilage degrades in dogs after transection of the anterior cruciate ligament (ACLT) has been attributed to capsular thickening and buttressing by osteophytes. We investigated the roles of the peripheral and central nervous systems in protecting knee joints with chronic ACL deficiency from breakdown. Five groups of dogs were studied; all were killed 72 weeks after left knee surgery. Group A had ACLT, group B had ACLT followed 52 weeks later by ipsilateral L4-S1 dorsal root ganglionectomy (DRG), group C had DRG followed 2 weeks later by ACLT, group D had sham DRG followed 2 weeks later by ACLT, and group E had DRG followed 2 weeks later by sham ACTL. Group E dogs did not develop knee pathology. All cruciate-deficient knees were lax at the end of the study. The osteoarthritis (OA) that developed in groups A, B, and D was comparable (P > 0.05), and was significantly greater than that in group E (P < 0.05). Group C developed much more severe OA than any of the other groups (P < 0.05). Ipsilateral sensory input is temporarily important in protecting the unstable joint from rapid breakdown. Over time, the central nervous system apparently acquires the ability to protect the unstable joint without continued ipsilateral sensory input.