Implantation of Various Cell-Free Matrixes Does Not Contribute to the Restoration of Hyaline Cartilage within Full-Thickness Focal Defects

Articular cartilage is a highly organized tissue that has a limited ability to heal. Tissue engineering is actively exploited for joint tissue reconstruction in numerous cases of articular cartilage degeneration associated with trauma, arthrosis, rheumatoid arthritis, and osteoarthritis. However, the optimal scaffolds for cartilage repair are not yet identified. Here we have directly compared five various scaffolds, namely collagen-I membrane, collagen-II membrane, decellularized cartilage, a cellulose-based implant, and commercially available Chondro-Gide® (Geistlich Pharma AG, Wolhusen, Switzerland) collagen membrane. The scaffolds were implanted in osteochondral full-thickness defects, formed on adult Wistar rats using a hand-held cutter with a diameter of 2.0 mm and a depth of up to the subchondral bone. The congruence of the articular surface was almost fully restored by decellularized cartilage and collagen type II-based scaffold. The most vivid restoration was observed 4 months after the implantation. The formation of hyaline cartilage was not detected in any of the groups. Despite cellular infiltration into scaffolds being observed in each group except cellulose, neither chondrocytes nor chondro-progenitors were detected. We concluded that for restoration of hyaline cartilage, scaffolds have to be combined either with cellular therapy or morphogens promoting chondrogenic differentiation.

Comparison of intra-articular administration of adenosine, lidocaine and magnesium solution and tranexamic acid for alleviating postoperative inflammation and joint fibrosis in an experimental model of knee arthroplasty

Background Dysregulated inflammatory responses are implicated in the pathogenesis of joint stiffness and arthrofibrosis following total knee arthroplasty (TKA). The purpose of this study was to compare the effects of intra-articular (IA) administration of tranexamic acid (TXA), an anti-fibrinolytic commonly used in TKA, and ALM chondroprotective solution on postoperative inflammation and joint tissue healing in a rat model of knee implant surgery. Methods Male Sprague–Dawley rats (n = 24) were randomly divided into TXA or ALM treatment groups. The right knee of each rat was implanted with titanium (femur) and polyethylene (tibia) implants. An IA bolus (0.1 ml) of TXA or ALM was administered after implantation and capsule closure, and before skin closure. Postoperative coagulopathy, haematology and systemic inflammatory changes were assessed. Inflammatory and fibrotic markers were assessed in joint tissue, 28 days after surgery. Results Haemostasis was comparable in animals treated with TXA or ALM after knee implant surgery. In contrast to ALM-treated animals, systemic inflammatory markers remained elevated at day 5 (IL-6, IL-12, IL-10, platelet count) and day 28 (IL-1β, IL-10) following surgery in TXA-treated animals. At day 28 following surgery, the extension range of motion of operated knees was 1.7-fold higher for ALM-treated animals compared to the TXA group. Key inflammatory mediators (NF-κB, IL-12, IL-2), immune cell infiltration (CD68+ cells) and markers of fibrosis (α-SMA, TGF-β) were also lower in capsular tissue of ALM-treated knees at day 28. Conclusion Data suggest that IA administration of ALM is superior to TXA for reducing postoperative systemic and joint inflammation and promoting restoration of healthy joint tissue architecture in a rat model of TKA. Further studies are warranted to assess the clinical translational potential of ALM IA solution to improve patient outcomes following arthroplasty.

Avascular Necrosis Bone Complication after Active COVID-19 Infection: Preliminary Results

Background and objectives: The course of SARS-CoV-2 (COVID-19) is still under analysis. The majority of complications arising from the infection are related to the respiratory system. The adverse effect of the viral infection on bone and joint tissue has also been observed. Materials and Methods: We present a group of 10 patients with degeneration of large joints and adjacent epiphyses of long bones and the spine, with a background of bone infarctions and avascular necrosis (AVN) immediately after infection with the COVID-19 virus. In MR imaging, changes in the characteristics of AVN were documented. Results: Observation of this group showed a clear correlation among the history of COVID-19 disease in the patients, moderately severe symptoms, high levels of IgG antibodies, and the time of occurrence of joint changes. No other clinically significant complications were observed following COVID-19 infection in the study group. No other risk factors for AVN or autoimmune or degenerative diseases were found in the study group. The group of patients responded well to empirical treatment with steroids, which normalized acute inflammatory symptoms and pain in the joints. Conclusions: During coronavirus (COVID-19) infection, there are complications in the locomotor system, such as microembolism and the formation of AVN; hence, more research is needed.

Pro-regenerative Dialogue Between Macrophages and Mesenchymal Stem/Stromal Cells in Osteoarthritis

Osteoarthritis (OA), the most common degenerative and inflammatory joint disorder, is multifaceted. Indeed, OA characteristics include cartilage degradation, osteophytes formation, subchondral bone changes, and synovium inflammation. The difficulty in discovering new efficient treatments for OA patients up to now comes from the adoption of monotherapy approaches targeting either joint tissue repair/catabolism or inflammation to address the diverse components of OA. When satisfactory, these approaches only provide short-term beneficial effects, since they only result in the repair and not the full structural and functional reconstitution of the damaged tissues. In the present review, we will briefly discuss the current therapeutic approaches used to repair the damaged OA cartilage. We will highlight the results obtained with cell-based products in clinical trials and demonstrate how the current strategies result in articular cartilage repair showing restricted early-stage clinical improvements. In order to identify novel therapeutic targets and provide to OA patients long-term clinical benefits, herein, we will review the basis of the regenerative process. We will focus on macrophages and their ambivalent roles in OA development and tissue regeneration, and review the therapeutic strategies to target the macrophage response and favor regeneration in OA.

Mitochondria in Injury, Inflammation and Disease of Articular Skeletal Joints

Inflammation is an important biological response to tissue damage caused by injury, with a crucial role in initiating and controlling the healing process. However, dysregulation of the process can also be a major contributor to tissue damage. Related to this, although mitochondria are typically thought of in terms of energy production, it has recently become clear that these important organelles also orchestrate the inflammatory response via multiple mechanisms. Dysregulated inflammation is a well-recognised problem in skeletal joint diseases, such as rheumatoid arthritis. Interestingly osteoarthritis (OA), despite traditionally being known as a ‘non-inflammatory arthritis’, now appears to involve an element of chronic inflammation. OA is considered an umbrella term for a family of diseases stemming from a range of aetiologies (age, obesity etc.), but all with a common presentation. One particular OA sub-set called Post-Traumatic OA (PTOA) results from acute mechanical injury to the joint. Whether the initial mechanical tissue damage, or the subsequent inflammatory response drives disease, is currently unclear. In the former case; mechanobiological properties of cells/tissues in the joint are a crucial consideration. Many such cell-types have been shown to be exquisitely sensitive to their mechanical environment, which can alter their mitochondrial and cellular function. For example, in bone and cartilage cells fluid-flow induced shear stresses can modulate cytoskeletal dynamics and gene expression profiles. More recently, immune cells were shown to be highly sensitive to hydrostatic pressure. In each of these cases mitochondria were central to these responses. In terms of acute inflammation, mitochondria may have a pivotal role in linking joint tissue injury with chronic disease. These processes could involve the immune cells recruited to the joint, native/resident joint cells that have been damaged, or both. Taken together, these observations suggest that mitochondria are likely to play an important role in linking acute joint tissue injury, inflammation, and long-term chronic joint degeneration - and that the process involves mechanobiological factors. In this review, we will explore the links between mechanobiology, mitochondrial function, inflammation/tissue-damage in joint injury and disease. We will also explore some emerging mitochondrial therapeutics and their potential for application in PTOA.

Pathogenesis, Pathology and Genetics of Osteoarthritis

Osteoarthritis (OA) is a condition with high prevalence worldwide. OA affects not only the articular cartilage, but the entire joint, including the subchondral bone, ligaments, capsule, synovial membrane and the periarticular muscles. Despite the fact that the risks associated with OA increase with age, it is not a part of the natural aging process. It typically involves the knee, hip, spine, hand and foot joints. Several factors play an important role in the pathogenesis of OA, including biomechanical factors, proinflammatory mediators and proteases. On the other hand, it was mostly the results of the studies conducted on the genetic, genomic and epigenetic aspects of OA, from among many of its underlying etiological factors, which shed light on the molecular processes involved in the etiopathogenesis of OA. As the mechanisms that cause joint tissue damage in OA come to light, the treatment of OA will go beyond just providing symptomatic relief. Consequentially, new treatments will emerge that will either slow or completely stop the progression of OA.

Integrated Single Cell and Spatial Transcriptomics Reveal Autoreactive Differentiated B Cells in Joints of Early Rheumatoid Arthritis

Rheumatoid Arthritis (RA) is a prevalent autoimmune disease characterized by inflammation of peripheral joints. Patients can be subdivided by the presence or absence of Rheumatoid Factor and anti-citrullinated protein antibodies (ACPA) in their circulation. Inflammation of the joint tissue is associated with infiltration of leukocytes from the blood, which can result in generation of lymphoid structures composed of B and T cells. Previous studies have shown that both memory B cells and antibody-secreting plasma cells populate the rheumatic joint tissue when captured from established and often long-standing disease. However, it has remained unclear, whether these cells are autoreactive and whether the associated lymphoid structures are present at the site of inflammation already at the time of diagnosis. Here, we used an integrated single cell and spatial transcriptomic approach to study B and plasma cells in synovial tissue of ACPA- and ACPA+ RA patients at this early time point. We found evidence for T cell help to B cells and presence of memory B and plasma cell pools in ACPA- as well as in ACPA+ RA. Our results demonstrated common supportive microenvironments in both patient subgroups, clonal relationships between the memory B and plasma cell pools and autoreactivity within the plasma cell compartment. These findings challenge our understanding of the dynamics of local adaptive immune responses in the RA joint of ACPA- and ACPA+ patients at the time of diagnosis, with direct implications for B and T cell targeting therapies for both patient subgroups.