Search Results (7)

Osteoarthritis involves complex interactions between articular joint tissues and the immune system, which is implicated in molecular trafficking via barrier-function modulating cytokines. The current study aims to test effects of an acute spike in TNF-α or TGF-β on vascular barrier function at multiple length scales, from the heart to tissue compartments of the knee, and cellular inhabitants of those respective compartments, in a spontaneous guinea pig model of osteoarthritis. First we quantified the intensity of a fluorescent-tagged 70 kDa tracer, similar in size to albumin, the most prevalent transporter protein in the blood, in tissue compartments of bone (periosteum, marrow space, compact bone, and epiphyseal bone) and cartilage (superficial cartilage, calcified cartilage, and the interface between, i.e., the epiphyseal line), as well as at sites of tendon attachment to bone (entheses). We then examined tracer presence and intensity in the respective pericellular and extracellular matrix zones of bone and cartilage. Acute exposure to TGF-β reduced barrier function (increased permeability) at nearest vascular interfaces in four of eight tissue compartments studied, compared to TNF-α where one of eight tissue compartments showed significant diminishment in barrier function. The increase in permeability associated with reduced barrier function was observed at both tissue compartment and cellular length scales. The observation of pericellular transport of the albumin-sized molecules to osteocytes contrasts with previous observations of barrier function in healthy, untreated animals and is indicative of increased molecular transport in pericellular regions of musculoskeletal tissues in cytokine-treated animals. Understanding age- and disease-related changes in molecular transport within musculoskeletal structures, such as the knee joint, is crucial for elucidating the etiology and pathogenesis of osteoarthritis. Full article

The calcified tissues of vertebrates are essentially represented by bone, cartilage, dentin and calcified tendons. In all these tissues a major hallmark of mineralization is the deposition of the inorganic phase on a pre-existing collagen template, but evident differences exist among these materials and the molecular details of the process are still incompletely understood. In this study, the ultrastructural aspects of the mineral phase of these tissues were investigated by means of high-resolution scanning electron microscopy (HR-SEM) after low-temperature thermal deproteination, a technique allowing a direct, unrestricted visualization of the mineral component. Each tissue showed distinctive features. In most cases, calcification proceeds in a discontinuous way through the formation of clumps or clusters of mineralized tissue; in all cases, except cartilage, the mineral phase shows an evident relationship with the layout and/or the D-period of the collagen fibrils. Our results highlight the peculiar aspect of the mineralization process in the cartilage with respect to the other tissues, all of them containing collagen type I instead of type II, and suggest that a different molecular mechanism may be at work. It is still unclear whether and how this may be related to the content, exclusive of cartilage, of collagen type II. The identification of the tissue-specific features exhibited by cartilage versus those shared by all the other three tissues, although from different species, requires further research on physiological calcification. Full article

Background: This systematic review examines the clinical presentations and prevalence of scapulohumeral periarthritis (SP) by synthesizing the relevant literature from open-access articles from international databases (Medline, Pedro, and EBSCO). Methods: Keywords guiding the review included ‘scapulohumeral periarthritis’, ‘clinical forms’, ‘incidence’, ‘impingement syndrome, ‘calcifying tendinitis’, ‘bicipital tendonitis’, ‘shoulder bursitis’, ‘adhesive capsulitis or frozen shoulder’, ‘rotator cuff tears’, ‘functional assessment’, and ‘clinical trials’. Eligible studies included randomized controlled trials, nonrandomized controlled trials, cross-sectional studies, and review articles published between 1972 and 2024. Results: Our screening identified 2481 initial articles, of which 621 were further reviewed for eligibility resulting in 107 articles that met the relevance criteria. The findings highlight six distinct clinical forms of SP, such as partial rotator cuff tears and calcific tendinitis, each characterized by specific pathological features and prevalence patterns. Key factors contributing to SP include injuries, scapular instability, acromion deformities, and degenerative rotator cuff changes. Functional assessments, including the Neer, Hawkins, Pain Arc, and Yocum tests, demonstrated diagnostic value in distinguishing SP from other shoulder conditions. Conclusions: By comprehensively analyzing the clinical forms, functional assessment methods, and prevalent lesions of SP, functional testing can improve early diagnosis and guide personalized physiotherapy protocols for optimal rehabilitation in the physiotherapist’s practice. Full article

Unsuccessful tendon healing leads to fibrosis and occasionally calcification. In these metaplastic drifts, the mouse AT preclinical injury model represents a robust experimental setting for studying tendon calcifications. Previously, calcium deposits were found in about 30% of tendons after 28 days post-injury. Although a neuromediated healing process has previously been documented, the expression patterns of NF200, NGF, NPY, GAL, and CGRP in mouse AT and their roles in metaplastic calcific repair remain to be explored. This study included a spatiotemporal analysis of these neuromarkers during the inflammatory phase (7 days p.i.) and the proliferative/early-remodelling phase (28 days p.i.). While the inflammatory phase is characterised by NF200 and CGRP upregulation, in the 28 days p.i., the non-calcified tendons (n = 16/24) showed overall NGF, NPY, GAL, and CGRP upregulation (compared to 7 days post-injury) and a return of NF200 expression to values similar to pre-injury. Presenting a different picture, in calcified tendons (n = 8), NF200 persisted at high levels, while NGF and NPY significantly increased, resulting in a higher NPY/CGRP ratio. Therefore, high levels of NF200 and imbalance between vasoconstrictive (NPY) and vasodilatory (CGRP) neuromarkers may be indicative of calcification. Tendon cells contributed to the synthesis of neuromarkers, suggesting that their neuro-autocrine/paracrine role is exerted by coordinating growth factors, cytokines, and neuropeptides. These findings offer insights into the neurobiological mechanisms of early tendon healing and identify new neuromarker profiles predictive of tendon healing outcomes. Full article

Pathologic calcification (PC) is a painful and disabling condition whereby calcium-containing crystals deposit in tissues that do not physiologically calcify: cartilage, tendons, muscle, vessels and skin. In cartilage, compression and inflammation triggered by PC leads to cartilage degradation typical of osteoarthritis (OA). The PC process is poorly understood and treatments able to target the underlying mechanisms of the disease are lacking. Here we show a crucial role of the gasotransmitter hydrogen sulfide (H₂S) and, in particular, of the H₂S-producing enzyme cystathionine γ-lyase (CSE), in regulating PC in cartilage. Cse deficiency (Cse KO mice) exacerbated calcification in both surgically-induced (menisectomy) and spontaneous (aging) murine models of cartilage PC, and augmented PC was closely associated with cartilage degradation (OA). On the contrary, Cse overexpression (Cse tg mice) protected from these features. In vitro, Cse KO chondrocytes showed increased calcification, potentially via enhanced alkaline phosphatase (Alpl) expression and activity and increased IL-6 production. The opposite results were obtained in Cse tg chondrocytes. In cartilage samples from patients with OA, CSE expression inversely correlated with the degree of tissue calcification and disease severity. Increased cartilage degradation in murine and human tissues lacking or expressing low CSE levels may be accounted for by dysregulated catabolism. We found higher levels of matrix-degrading metalloproteases Mmp-3 and -13 in Cse KO chondrocytes, whereas the opposite results were obtained in Cse tg cells. Finally, by high-throughput screening, we identified a novel small molecule CSE positive allosteric modulator (PAM), and demonstrated that it was able to increase cellular H₂S production, and decrease murine and human chondrocyte calcification and IL-6 secretion. Together, these data implicate impaired CSE-dependent H₂S production by chondrocytes in the etiology of cartilage PC and worsening of secondary outcomes (OA). In this context, enhancing CSE expression and/or activity in chondrocytes could represent a potential strategy to inhibit PC. Full article

This review describes the first studies on successful conversion of porcine soft-tissue bioprostheses into viable permanently functional tissue in humans. This process includes gradual degradation of the porcine tissue, with concomitant neo-vascularization and reconstruction of the implanted bioprosthesis with human cells and extracellular matrix. Such a reconstruction process is referred to in this review as “humanization”. Humanization was achieved with porcine bone-patellar-tendon-bone (BTB), replacing torn anterior-cruciate-ligament (ACL) in patients. In addition to its possible use in orthopedic surgery, it is suggested that this humanization method should be studied as a possible mechanism for converting implanted porcine bioprosthetic heart-valves (BHV) into viable tissue valves in young patients. Presently, these patients are only implanted with mechanical heart-valves, which require constant anticoagulation therapy. The processing of porcine bioprostheses, which enables humanization, includes elimination of α-gal epitopes and partial (incomplete) crosslinking with glutaraldehyde. Studies on implantation of porcine BTB bioprostheses indicated that enzymatic elimination of α-gal epitopes prevents subsequent accelerated destruction of implanted tissues by the natural anti-Gal antibody, whereas the partial crosslinking by glutaraldehyde molecules results in their function as “speed bumps” that slow the infiltration of macrophages. Anti-non gal antibodies produced against porcine antigens in implanted bioprostheses recruit macrophages, which infiltrate at a pace that enables slow degradation of the porcine tissue, neo-vascularization, and infiltration of fibroblasts. These fibroblasts align with the porcine collagen-fibers scaffold, secrete their collagen-fibers and other extracellular-matrix (ECM) components, and gradually replace porcine tissues degraded by macrophages with autologous functional viable tissue. Porcine BTB implanted in patients completes humanization into autologous ACL within ~2 years. The similarities in cells and ECM comprising heart-valves and tendons, raises the possibility that porcine BHV undergoing a similar processing, may also undergo humanization, resulting in formation of an autologous, viable, permanently functional, non-calcifying heart-valves. Full article

Calcific tendonitis is a frequent cause of chronic shoulder pain. Its cause is currently poorly known. The objectives of this study were to better characterize the cells and mechanisms involved in depositing apatite crystals in human tendons. Histologic sections of cadaveric calcified tendons were analyzed, and human calcific deposits from patients undergoing lavage of their calcification were obtained to perform infrared spectroscopy and mass spectrometry-based proteomic characterizations. In vitro, the mineralization ability of human rotator cuff cells from osteoarthritis donors was assessed by alizarin red or Von Kossa staining. Calcifications were amorphous areas surrounded by a fibrocartilaginous metaplasia containing hypertrophic chondrocyte-like cells that expressed tissue non-specific alkaline phosphatase (TNAP) and ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), which are two key enzymes of the mineralization process. Calcific deposits were composed of apatite crystals associated with proteins involved in bone and cartilage development and endochondral bone growth. In vitro, tenocyte-like cells extracted from the rotator cuff were able to mineralize in osteogenic cultures, and expressed TNAP, type X COLLAGEN, and MMP13, which are hypertrophic chondrocytes markers. The use of a TNAP inhibitor significantly prevented mineral deposits. We provide evidence that tenocytes have a propensity to differentiate into hypertrophic chondrocyte-like cells to produce TNAP-dependent calcium deposits. We believe that these results may pave the way to identifying regulating factors that might represent valuable targets in calcific tendonitis. Full article