ER Stress in ERp57 Knockout Knee Joint Chondrocytes Induces Osteoarthritic Cartilage Degradation and Osteophyte Formation

Ageing or obesity are risk factors for protein aggregation in the endoplasmic reticulum (ER) of chondrocytes. This condition is called ER stress and leads to induction of the unfolded protein response (UPR), which, depending on the stress level, restores normal cell function or initiates apoptotic cell death. Here the role of ER stress in knee osteoarthritis (OA) was evaluated. It was first tested in vitro and in vivo whether a knockout (KO) of the protein disulfide isomerase ERp57 in chondrocytes induces sufficient ER stress for such analyses. ER stress in ERp57 KO chondrocytes was confirmed by immunofluorescence, immunohistochemistry, and transmission electron microscopy. Knee joints of wildtype (WT) and cartilage-specific ERp57 KO mice (ERp57 cKO) were analyzed by indentation-type atomic force microscopy (IT-AFM), toluidine blue, and immunofluorescence/-histochemical staining. Apoptotic cell death was investigated by a TUNEL assay. Additionally, OA was induced via forced exercise on a treadmill. ER stress in chondrocytes resulted in a reduced compressive stiffness of knee cartilage. With ER stress, 18-month-old mice developed osteoarthritic cartilage degeneration with osteophyte formation in knee joints. These degenerative changes were preceded by apoptotic death in articular chondrocytes. Young mice were not susceptible to OA, even when subjected to forced exercise. This study demonstrates that ER stress induces the development of age-related knee osteoarthritis owing to a decreased protective function of the UPR in chondrocytes with increasing age, while apoptosis increases. Therefore, inhibition of ER stress appears to be an attractive therapeutic target for OA.

The Impact of Trace Elements on Osteoarthritis

Osteoarthritis (OA) is a progressive degenerative disease characterized by cartilage degradation, synovial inflammation, subchondral sclerosis and osteophyte formation. It has a multifactorial etiology with potential contributions from heredity, endocrine function, abnormal mechanical load and nutrition. Of particular considerations are trace element status. Several trace elements, such as boron and magnesium are essential for normal development of the bone and joint in human. While cadmium correlates with the severity of OA. The present review focuses on the roles of trace elements (boron, cadmium, copper, iron, magnesium, manganese, selenium, zinc) in OA and explores the mechanisms by which they act.

Have the Radiographic Characteristics of Total Knee Arthroplasty Recipients in Rheumatoid Arthritis Changed After the Induction of Biologic Disease Modifying Anti-Rheumatic Drugs?

Objectives Whether the characteristics of patients with rheumatoid arthritis (RA) undergoing total knee arthroplasty (TKA) have changed in the era of biologic disease-modifying antirheumatic drugs (bDMARDs) is unclear. We compared the radiographic findings of the knees in TKA recipients with RA before and after the introduction of bDMARDs. Methods Consecutive patients who underwent primary TKA between 1999 and 2002 (115 knees; 79 patients, group A) and between 2013 and 2017 (117 knees; 95 patients, group B) were retrospectively evaluated. Clinical data, including disease duration, medication, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and rheumatoid factor (RF), were collected. The Larsen classification, joint space narrowing (JSN), bone erosion, geode and osteophyte formation were evaluated on preoperative radiographs. Results Osteophyte formation was significantly increased, and bone erosion and geode formation were significantly decreased in group B. In addition, medial-dominant JSN was significantly increased, and bicompartmental JSN was significantly decreased in group B. Medial-dominant JSN was positively, and bone erosion was negatively associated with osteophyte formation. Conclusions Following the introduction of bDMARDs, typical radiographic findings of rheumatoid knees have decreased, and secondary osteoarthritis (OA)-like changes, characterized by osteophyte formation and medial-dominant JSN, have increased in the knees of TKA recipients.

7-Tesla MRI Evaluation of the Knee, 25 Years after Cartilage Repair Surgery: The Influence of Intralesional Osteophytes on Biochemical Quality of Cartilage

Objective To evaluate the morphological and biochemical quality of cartilage transplants and surrounding articular cartilage of patients 25 years after perichondrium transplantation (PT) and autologous chondrocyte transplantation (ACT) as measured by ultra-high-field 7-Tesla (7T) magnetic resonance imaging (MRI) and to present these findings next to clinical outcome. Design Seven PT patients and 5 ACT patients who underwent surgery on the femoral condyle between 1986 and 1996 were included. Patient-reported outcome measures (PROMs) were assessed by the clinical questionnaires: Knee injury and Osteoarthritis Outcome Score (KOOS), International Knee Documentation Committee (IKDC), and Visual Analogue Scale (VAS) for knee pain. The morphological (MOCART score) and biochemical quality (glycosaminoglycans [GAGs] content and collagen integrity) of cartilage transplants and surrounding articular cartilage were analyzed by 7T MRI. The results of the PT and ACT patients were compared. Finally, a detailed morphological analysis of the grafts alone was performed. Results No statistically significant difference was found for the PROMs and MOCART scores of PT and ACT patients. Evaluation of the graft alone showed poor repair tissue quality and high prevalence of intralesional osteophyte formation in both the PT and ACT patients. Penetration of the graft surface by the intralesional osteophyte was related to biochemically damaged opposing tibial cartilage; GAG content was significantly lower in patients with an osteophyte penetrating the graft surface. Conclusions Both PT and ACT patients have a high incidence of intralesional osteophyte formation 25 years after surgery. The resulting biochemical damage to the opposing tibial cartilage might be dependent on osteophyte morphology.

The Incidence of Post-Traumatic Osteoarthritis on Clinical Radiographs at 10 Years after Anterior Cruciate Ligament Reconstruction: Data from the MOON Nested Cohort (168)

Objectives: 1) To prospectively determine the incidence of post-traumatic osteoarthritis (PTOA) at 10 years after anterior cruciate ligament reconstruction (ACLR) in young athletic patients on clinical radiographs: and 2) to determine the average difference in clinical radiographic osteoarthritis changes (joint space narrowing [JSN] and osteophyte formation) between the ACLR and contralateral ACL-intact knees. Methods: The first 146 patients in an ongoing prospective nested cohort study within the Multicenter Orthopaedic Outcomes Network (MOON) cohort returned onsite for minimum 10-year follow-up. Inclusion criteria were that patients had a sports-related ACL injury, no prior history of knee surgery, no contralateral ACL injury, and were less than 33 years of age at the time of their ACLR. Bilateral knee standing metatarsophalangeal (MTP) view radiographs were obtained and graded by International Knee Documentation Committee (IKDC), Osteoarthritis Research Society International (OARSI), and modified Kellgren-Lawrence (KL) criteria by two blinded reviewers. Inter-rater reliability was determined for all clinical radiographic OA grading criteria. The incidence and severity of ipsilateral and contralateral knee osteoarthritis were determined among patients without a contralateral ACL injury before 10-year follow-up (n=133). Results: Inter-rater reliability was substantial for IKDC (Gwet’s AC1 = 0.71), moderate for KL (0.48) and almost perfect for OARSI (0.84) grading systems. The 10-year incidence of PTOA on clinical radiographs in the ACLR knee was 43% as defined by osteophytes and 27% as defined by JSN (Table 1). In the contralateral ACL-intact knee, the incidence of osteophyte-defined OA was 10% and JSN-defined OA was 5%. The maximum side-to side difference in medial or lateral compartment OARSI osteophyte grade was 0 in 65% of patients, 1 in 20%, and 2+ in 15% (Figure 1) (Table 2). The maximum difference in OARSI JSN grade was 0 in 77% of patients, 1 in 19%, and 2+ in 4% (Figure 2) (Table 2). Conclusions: In young active patients, the 10-year incidence on clinical radiographs of osteophyte-defined PTOA after ACLR is 43% and JSN-defined PTOA is 27%. The average difference in degree of osteophyte formation (≤1 grade in 85%) and JSN (≤1 grade in 96%) between the ACLR knee and contralateral ACL-intact knee is small.

Research Progress on the Antiosteoarthritic Mechanism of Action of Natural Products

Background. Osteoarthritis (OA) is a clinical joint degenerative disease, the pathogenic factors of which include age, obesity, and mechanical injury. Its main pathological features include cartilage loss, narrowing of joint space, and osteophyte formation. At present, there are a variety of treatment methods for OA. Natural products, which are gradually being applied in the treatment of OA, are advantageous as they present with low toxicity and low costs and act on multiple targets. Methods. The terms “natural products,” “osteoarthritis,” and “chondrocytes” were searched in PubMed to screen the related literature in the recent 10 years. Results. We comprehensively introduced 62 published papers on 48 natural products involving 6, 3, 5, 12, 4, and 5 kinds of terpenoids, polysaccharides, polyphenols, flavonoids, alkaloids, and saponins, respectively (and others). Conclusion. The mechanisms of their anti-OA action mainly involve reducing the production of inflammatory factors, reducing oxidative stress, regulating the metabolism of chondrocytes, promoting the proliferation of chondrocytes, or inhibiting chondrocyte apoptosis. This article summarizes the anti-OA activity of natural products in the last 10 years and provides candidate monomers for further study for use in OA treatment.

Cartilage Repair Activity during Joint-Preserving Treatment May Be Accompanied by Osteophyte Formation

Knee joint distraction (KJD) treatment has shown cartilage repair and clinical improvement in patients with osteoarthritis, as has high tibial osteotomy (HTO). Following KJD, TGFβ-1 and IL-6 were increased in synovial fluid (SF), factors related to cartilage regeneration, but also to osteophyte formation. As such, osteophyte formation after both joint-preserving treatments was studied. Radiographic osteophyte size was measured before, one year, and two years after treatment. Changes were compared with natural progression in patients from the CHECK cohort before undergoing total knee arthroplasty. An additional KJD cohort underwent SF aspiration, and one-year Altman osteophyte score changes were compared to SF-marker changes during treatment. After two years, both KJD (n = 58) and HTO (n = 38) patients showed an increase in osteophyte size (+6.2 mm2 and +7.0 mm2 resp.; both p < 0.004), with no significant differences between treatments (p = 0.592). Untreated CHECK patients (n = 44) did not show significant two-year changes (+2.1 mm2; p = 0.207) and showed significant differences with KJD and HTO (both p < 0.044). In SF aspiration patients (n = 17), there were significant differences in TGFβ-1 changes (p = 0.044), but not IL-6 (p = 0.898), between patients with a decrease, no change, or increase in osteophyte Altman score. Since KJD and HTO showed joint space widening and clinical improvement accompanied by osteophyte formation, increased osteophytosis after joint-preserving treatments may be a bystander effect of cartilage repair activity related to intra-articular factors like TGFβ-1 and raises questions regarding osteophyte formation as solely characteristic of the joint degenerative process.

Reduction of knee joint load suppresses cartilage degeneration, osteophyte formation, and synovitis in early-stage osteoarthritis using a post-traumatic rat model

The purpose of this study was to clarify the histological effect of reducing the loading to knee on cartilage degeneration, osteophyte formation, and synovitis in early-stage osteoarthritis (OA) using a post-traumatic rat model. Ten male rats were randomly allocated into two experimental groups: OA induction by surgical destabilization of medial meniscus (DMM, OA group) and hindlimb suspension after OA induction by DMM (OAHS group). The articular cartilage, osteophyte formation, and synovial membrane in the medial tibiofemoral joint were analyzed histologically and histomorphometrically at 2 and 4 weeks after surgery. The histological scores and changes in articular cartilage and osteophyte formation were significantly milder and slower in the OAHS group than in the OA group. At 2 and 4 weeks, there were no significant differences in cartilage thickness and matrix staining intensity between both the groups, but chondrocytes density was significantly lower in the OA group. Synovitis was milder in OAHS group than in OA group at 2 weeks. Reducing knee joint loading inhibited histological OA changes in articular cartilage, osteophyte formation, and synovial inflammation. This result supports the latest clinical guidelines for OA treatment. Further studies using biochemical and mechanical analyses are necessary to elucidate the mechanism underlying delayed OA progression caused by joint-load reduction.

Efficacy of the use of unsaponifiable fractions of avocado and soybean oil in osteoarthritis

Osteoarthritis, which affects approximately 18% of women and 10% of men after the age of 60, is undoubtedly a serious public problem. The main pathological changes in osteoarthritis include the degeneration and loss of articular cartilage, changes in the subchondral bone and osteophyte formation in the bone epiphyses. Pain accompanying degenerative modifications significantly reduces the quality of life of patients. The purpose of this article is to discuss the use of unsaponifiable fractions of avocado and soybean oil to control the symptoms of osteoarthritis of the knee on a case-by-case basis.