Targeting cartilage EGFR pathway for osteoarthritis treatment

Abstract

Osteoarthritis (OA) is a widespread joint disease for which there are no disease-modifying treatments. Previously, we found that mice with cartilage-specific epidermal growth factor receptor (EGFR) deficiency developed accelerated knee OA. To test whether the EGFR pathway can be targeted as a potential OA therapy, we constructed two cartilage-specific EGFR overactivation models in mice by overexpressing heparin binding EGF-like growth factor (HBEGF), an EGFR ligand. Compared to wild type, Col2-Cre HBEGF-overexpressing mice had persistently enlarged articular cartilage from adolescence, due to an expanded pool of chondroprogenitors with elevated proliferation ability, survival rate, and lubricant production. Adult Col2-Cre HBEGF-overexpressing mice and Aggrecan-CreER HBEGF-overexpressing mice were resistant to cartilage degeneration and other signs of OA after surgical destabilization of the medial meniscus (DMM). Treating mice with gefitinib, an EGFR inhibitor, abolished the protective action against OA in HBEGF-overexpressing mice. Polymeric micellar nanoparticles (NPs) conjugated with transforming growth factor–α (TGFα), a potent EGFR ligand, were stable and nontoxic and had long joint retention, high cartilage uptake, and penetration capabilities. Intra-articular delivery of TGFα-NPs effectively attenuated surgery-induced OA cartilage degeneration, subchondral bone plate sclerosis, and joint pain. Genetic or pharmacologic activation of EGFR revealed no obvious side effects in knee joints and major vital organs in mice. Together, our studies demonstrate the feasibility of using nanotechnology to target EGFR signaling for OA treatment.

Reversing the surface charge of MSC‐derived small extracellular vesicles by εPL‐PEG‐DSPE for enhanced osteoarthritis treatment

“…Reflexive measures of pain using stimulus‐evoked responses, such as hind‐paw withdrawal threshold, are commonly used to assess OA‐related pain (Wei et al., 2021 ). Hind‐paw withdrawal thresholds were measured according to a previous report (Huang et al., 2019 ).…”

Rapamycin microparticles induce autophagy, prevent senescence and are effective in treatment of Osteoarthritis

“…Recent research has shown that micro and nanoparticles can be used to synthesize sustained release systems and can be used to release the disease-modifying drugs and agents to ameliorate OA (70,71).…”

Nanoparticle–Cartilage Interaction: Pathology-Based Intra-articular Drug Delivery for Osteoarthritis Therapy

“…Synovial fluid and serum tend to equilibrate through synovium intercellular gaps in a normal status; in OA, synovial inflammation-associated increased capillary permeability facilitates the elimination of nanoparticles from joint [31]. However, the clearance of nanoparticles in OA joint is impaired compared with the healthy joint, which may be associated with synovial thickening [33,34]. Ageing associated metabolic changes, including less range of joint motion and decreased lubricating fluid, may also impede the clearance of nanoparticles.…”

“…Poly[L-lysine-block-poly(ε-caprolactone)] (PLL)-polycaprolactone (PCL) nanoparticles (25.93 nm) can efficiently bound to the surface of bovine cartilage explants with articular cartilage thickness similar to that of human at day 2 and gradually penetrated inside by at least 1 mm by day 6 (Fig. 3d) [34]. Given the space between the side chains of the proteoglycan network is about 20 nm, small (≤ 15 nm) nanoparticles can easily enter the cartilage matrix by binding and penetrating anionic cartilage tissue [37,38].…”

“…4a). For example, cationic globular proteins and dendrimers can target to the anionic cartilage matrix via electrostatic attraction [34,40,44]. With both approaches, electrostatic interactions between positively charged nanoparticles and the negative fixed charge of cartilage ECM can be optimized to augment the transport, uptake and intra-tissue binding of such nanoparticles.…”