No abstract

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 two and eight weeks. OVX of OA mice did not influence the cartilage phenotype or synovial thickness, while both cortical and trabecular subchondral bone mineral density were decreased after OVX compared with sham-operated mice at eight 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 at two 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 two 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 eight weeks. This study demonstrates that treatment with a physiological dose of E2 exerts a protective role by reducing OA symptoms.

A major obstacle for joint drug delivery is to penetrate the dense, negatively charged cartilage matrix. Previous studies have extensively investigated particle approaches to cartilage tissue uptake but have neglected to address potential interactions between the particles and the synovial fluid. Here, a NP panel with different PEGylation were incubated with synovial fluid from either rheumatoid or osteoarthritic patients, or FCS. Compared to non-protein covered NPs, we observed a prominent impact of the protein coronas on NP uptake into cartilage, chondrocytes, and monocytes. Utilizing a quantitative proteomics approach, we identified abundant proteins on all panel members irrespective of the NP modifications. Nonetheless, NP and protein condition-specific differences were also observed between the groups. Our study, therefore, suggests that the protein abundance dictates NP efficacy, emphasizing the importance of considering the biological milieu for translating drug delivery designs to the clinic.

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.

A major obstacle for joint drug delivery is to penetrate the dense, negatively charged cartilage matrix. Previous studies have extensively investigated particle approaches to increase uptake efficiency into tissues but have neglected to address potential interactions with the synovial fluid. Here, we developed a nanoparticle (NP) panel with varying PEGylation and incubated them with synovial fluid from either osteoarthritic (OA) or rheumatoid arthritis (RA) patients, or fetal calf serum (FCS). Compared to nonprotein- covered NPs, the formed protein coronas majorly impacted NP uptake into cartilage tissue and dictated their uptake in chondrocytes and monocytes - a measure of targeting efficiency and clearance potential. Utilizing a quantitative proteomics approach, we identified certain families of proteins on all panel members irrespective of the NP modifications. Nonetheless, NP-, and protein-specific differences were also observed between the groups, and candidate proteins were identified that could account for the observed differences. This study is the first to demonstrate how protein coronas from different biological origins impact NP uptake into cartilage, emphasizing the importance of considering the several aspects of the biological microenvironment for successful translation of drug delivery vehicles into clinics.