Objectives In the last decade, increasing evidence suggests a key role of adenosine in Parkinson's disease (PD) and A_2A adenosine receptors (A_2AARs) as an important pharmacological target in PD. An overexpression of A_2AARs has been found in putamen and in peripheral blood cells of PD patients. The primary aim of this study was to verify whether the alterations in A_2AARs in lymphocytes of PD subjects correlate with disease severity. Material and methods A consecutive sample of PD patients was enrolled. A clinical examination and a face‐to‐face interview were carried out. A_2AARs were investigated to verify the affinity and receptor density in lymphocyte membranes. The data were compared with those found in healthy controls. Moreover, the correlation between A_2AAR density and affinity and clinical variables was evaluated in PD patients. Results In human lymphocyte membranes from PD patients, an increase in A_2AAR density and a decrease in A_2AAR affinity were found if compared with healthy subjects. A statistically significant correlation between the A_2AAR density or affinity and specific clinical parameters as motor and cognitive impairment was detected. Patients with higher A_2AAR density and lower affinity were more likely to exhibit motor complications. Conclusions Parkinson's disease patients show an A_2AAR upregulation in lymphocyte membranes if compared with healthy subjects. The correlation found between A_2AAR density or affinity and clinical parameters highlights the central role of A_2AAR modulation in the pharmacological treatment for PD and could suggest the putative role of A_2AAR as a candidate biomarker of PD severity.

Estrogens are important regulators of body physiology and have major effects on metabolism, bone, the immune- and central nervous systems. The specific mechanisms underlying the effects of estrogens on various cells, tissues and organs are unclear and mouse models constitute a powerful experimental tool to define the physiological and pathological properties of estrogens. Menopause can be mimicked in animal models by surgical removal of the ovaries and replacement therapy with 17β-estradiol in ovariectomized (OVX) mice is a common technique used to determine specific effects of the hormone. However, these studies are complicated by the non-monotonic dose-response of estradiol, when given as therapy. Increased knowledge of how to distribute estradiol in terms of solvent, dose, and administration frequency, is required in order to accurately mimic physiological conditions in studies where estradiol treatment is performed. In this study, mice were OVX and treated with physiological doses of 17β-estradiol-3-benzoate (E2) dissolved in miglyol or PBS. Subcutaneous injections were performed every 4 days to resemble the estrus cycle in mice. Results show that OVX induces an osteoporotic phenotype, fat accumulation and impairment of the locomotor ability, as expected. Pulsed administration of physiological doses of E2 dissolved in miglyol rescues the phenotypes induced by OVX. However, when E2 is dissolved in PBS the effects are less pronounced, possibly due to rapid wash out of the steroid.

Among patients with knee osteoarthritis (OA), postmenopausal women are over-represented. The purpose of this study was to determine whether deficiency of female sex steroids affects OA progression and to evaluate the protective effect of treatment with a physiological dose of 17β-estradiol (E2) on OA progression using a murine model. Ovariectomy (OVX) of female mice was used to mimic a postmenopausal state. OVX or sham-operated mice underwent surgery for destabilization of the medial meniscus (DMM) to induce OA. E2 was administered in a pulsed manner for 2 and 8 weeks. OVX of OA mice did not influence the cartilage phenotype or synovial thickness, while both cortical and trabecular subchondral bone mineral density (BMD) decreased after OVX compared with sham-operated mice at 8 weeks post-DMM surgery. Additionally, OVX mice displayed decreased motor activity, reduced threshold of pain sensitivity, and increased number of T cells in the inguinal lymph nodes compared to sham-operated mice 2 weeks after OA induction. Eight weeks of treatment with E2 prevented cartilage damage and thickening of the synovium in OVX OA mice. The motor activity was improved after E2 replacement at the 2 weeks time point, which was also associated with lower pain sensitivity in the OA paw. E2 treatment protected against OVX-induced loss of subchondral trabecular bone. The number of T cells in the inguinal lymph nodes was reduced by E2 treatment after 8 weeks. This study demonstrates that treatment with a physiological dose of E2 exerts a protective role by reducing OA symptoms.

Defects of articular joints are becoming an increasing societal burden due to a persistent increase in obesity and aging. For some patients suffering from cartilage erosion, joint replacement is the final option to regain proper motion and limit pain. Extensive research has been undertaken to identify novel strategies enabling earlier intervention to promote regeneration and cartilage healing. With the introduction of decellularized extracellular matrix (dECM), researchers have tapped into the potential for increased tissue regeneration by designing biomaterials with inherent biochemical and immunomodulatory signals. Compared to conventional and synthetic materials, dECM‐based materials invoke a reduced foreign body response. It is therefore highly beneficial to understand the interplay of how these native tissue‐based materials initiate a favorable remodeling process by the immune system. Yet, such an understanding also demands increasing considerations of the pathological environment and remodeling processes, especially for materials designed for early disease intervention. This knowledge will avoid rejection and help predict complications in conditions with inflammatory components such as arthritides. This review outlines general issues facing biomaterial integration and emphasizes the importance of tissue‐derived macromolecular components in regulating essential homeostatic, immunological, and pathological processes to increase biomaterial integration for patients suffering from joint degenerative diseases.

Septic arthritis, the most severe joint disease, is frequently caused by Staphylococcus aureus ( S . aureus ). A substantial proportion of patients with septic arthritis experience poor joint outcomes, often necessitating joint replacement surgery. Here, we show that monocyte depletion confers full protection against bone erosion in a septic arthritis mouse model. In the infected synovium, Ly6C ^hi monocytes exhibited increased expression of osteoclastogenesis-related molecules, including CCR2, c-Fms, and RANK. S . aureus lipoproteins induced elevated levels of RANKL, MCSF, and CCL2 in joints, with synovial fibroblasts identified as the major RANKL producer. Anti-RANKL treatment prevented bone destruction in both local and hematogenous septic arthritis murine models. Importantly, combining anti-RANKL treatment with antibiotics provided robust protection against joint damage. Our results indicate that the infiltration and transformation of monocytes into bone-destructive, osteoclast-like cells are key mechanisms in septic arthritis. Combining anti-RANKL and antibiotic therapy represents a promising therapy against this devastating disease.