There is currently no cure for osteoarthritis, but a group of scientists believe they’ve discovered a method through which a simple knee injection could potentially stop the disease’s effects.
These researchers showed that they could target a specific protein pathway in mice, put it into overdrive and halt cartilage degeneration over time. Building on that finding, they were able to show that treating mice with surgery-induced knee cartilage degeneration through the same pathway via the state of the art of nanomedicine could dramatically reduce the cartilage degeneration and knee pain. These findings were published in Science Translational Medicine.
“Our lab is one of the few in the world studying epidermal growth factor receptor (EGFR) signaling in cartilage and, from the beginning, we have found that EGFR deficiency or inactivation accelerates osteoarthritis progression in mice,” said Ling Qin, Ph.D., an associate professor of Orthopedic Surgery.
“Thus, we proposed that its activation could be used to treat osteoarthritis, and in this study, we’ve proven for the first time that over-activating it inside the knee blocks the progression of osteoarthritis.”
Qin explained that tests from the other labs that do work with EGFR have drawn “confusing and controversial” results. But Qin’s lab has consistently found the ties between osteoarthritis and EGFR deficiencies, which formed the bedrock of their hypothesis.
The researchers compared typical mice with those that had a molecule that bound to EGFR, called a ligand, that was over-overexpressed in chondrocytes, the building blocks of cartilage. This overexpression drives the over-activation of EGFR signaling in knee cartilage.
When examining them, the mice with overexpressed HBEGF (the EGFR ligand) were found to consistently have enlarged cartilage, meaning that it wasn’t wearing away like the mice who had normal EGFR activity.
Moreover, when these mice aged to adulthood, their cartilage was resistant to degeneration and other hallmarks of osteoarthritis, even if their knee’s meniscus was damaged.
To further prove that the over-activated EGFR was the reason for the mice’s resiliency, the researchers found that gefitinib treatments, which are designed to block EFGR function, took away the protection against cartilage degeneration.
With all of this knowledge gained, the researchers turned an eye toward potential clinical treatment solutions. In a new series of tests they created nanotherapeutics by attaching a potent EGFR ligand, transforming growth factor-alpha, onto synthetic nanoparticles, to inject into mice who already had cartilage damage in their knees.
“Free EGFR ligands have a short half-life and cannot be retained inside of a joint capsule due to their small size,” explained Zhiliang Cheng, Ph.D., a research associate professor in Penn Engineering and another of the co-corresponding authors on the paper.
“Nanoparticles help to protect them from degradation, restrict them within the joint, reduce off-target toxicity, and carry them deep inside dense cartilage to reach chondrocytes.”
When mice were injected with these nanotherapeutics, the researchers saw that they slowed cartilage degeneration and bone hardening, as well as eased knee pain. There also were no major side effects seen in the mice who were treated.
“While many of the technical aspects of this application still need to be worked out, the ability to stop or slow the course of osteoarthritis with an injection rather than surgery would dramatically change how we feel and function as we age and after injury,” said one of the study’s co- authors, Jaimo Ahn, MD, Ph.D., a former faculty member at Penn Medicine now chief of orthopedic trauma and associate chair of orthopedic surgery at the University of Michigan.
The treatment is likely some time away for human patients, but the nanoparticles used have already been clinically tested and deemed safe, which makes it easier to quickly translate to clinical use.
“There is a great unmet medical need for a disease-modifying osteoarthritis drug,” Qin said. “In the future, we will optimize the drug design and test it in large animals before proceeding to clinical trials. We hope our research could lead to a novel drug that will improve the health and well-being of the more than 27 million osteoarthritis patients in the United States.”
Osteoarthritis (OA), a chronic degenerative joint disease, is the most common form of arthritis. OA affects 242 million individuals worldwide, but that number will grow due to increasing life expectancies [1].
This statistic is alarming, considering the disability, the loss of quality of life, and the costs to the health system generated by OA. Currently, there are pharmacological treatments available to manage OA symptoms such as pain [2,3,4] as well as surgical joint replacement at the end stage of disease [5, 6].
Unfortunately, however, there is no cure for OA. Progressive understanding of the pathophysiology of OA suggests that the disease is a heterogeneous condition, so further research is needed to direct the clinical approaches to disease management [7].
Recent studies have shown that OA is a multifactorial disease of the whole joint; however, its pathogenesis remains still poorly understood [8]. Genetic, environmental, and biomechanical factors can accelerate the onset of OA [9].
The articular cartilage is a highly specialized tissue that forms the smooth gliding surface of synovial joints, with chondrocytes as the only cellular component of the cartilage [10]. The homeostasis of the cartilage extracellular matrix (ECM) involves a dynamic equilibrium between anabolic and catabolic pathways controlled by chondrocytes [11].
The progression of OA is associated with dramatic alteration in the integrity of the cartilage ECM network formed by a large number of proteoglycans (mostly aggrecan), collagen II, and other non-collagenous matrix proteins [12]. In addition, ECM synthesis is regulated by a number of transcriptional regulators involved in chondrogenesis, specifically sex-determining- region-Y box 9 (SOX9), L-SOX 5, and SOX6 that regulate type II collagen (Col2a1) and aggrecan (Acan) gene expression [13].
On the other hand, catabolic events are dominant in OA, and cells are exposed to degenerative enzymes such as aggrecanases (e.g., ADAMTS-4, ADAMTS-5) [12, 14], collagenases (e.g., MMP-1, MMP-3, MMP-8, MMP-13) [15], and gelatinases (e.g.,MMP-2 and MMP-9), all of which have implications in articular cartilage degeneration [16].
A number of growth factors [17] play a role in OA pathology, such as transforming growth factor-β [18], BMP-2 [19], insulin growth factor 1 (IGF-1) [20], and fibroblast growth factor (FGF), but the exact regulation of chondrocyte physiology is still not completely understood.
Recent studies in our laboratory [21, 22] have identified the epidermal growth factor receptor (EGFR) and its ligand transforming growth factor alpha (TGFα) as possible mediators of cartilage degeneration [23,24,25]. The human TGFA gene locus was also strongly linked to hip OA and cartilage thickness in genome-wide association studies [26, 27].
TGFα stimulates EGFR signaling and activates various cell-signaling pathways in chondrocytes, including extracellular signal-regulated kinase 1 and 2 (ERK1/2) and phosphoinositide 3-kinase (P13K) [28]. EGFR signaling plays important roles in endochondral ossification [29, 30], growth plate development [29], and cartilage maintenance and homeostasis [31,32,33], but many aspects of its action in the cartilage are still not well understood. However, both protective and catabolic effects of EGFR signaling in OA have been reported, suggesting context-specific roles of this pathway [34].
Mitogen-inducible gene 6 (Mig-6) is also known as Gene 33, ErbB receptor feedback inhibitor 1 (ERRFI1), or RALT and is found in the cytosol [35]. Mig-6 protein binds to and inhibits EGFR signaling through a two-tiered mechanism: suppression of EGFR catalytic activity and receptor downregulation [36].
Interestingly, various studies have reported that loss of Mig-6 induces the onset of OA-like symptoms in mice [35, 37,38,39]. Cartilage-specific (Col2-Cre) knockout of Mig-6 mice results in the formation of chondro-osseous nodules in the knee, but also increased thickness of the articular cartilage in the knee, ankle, and elbow [40]. Prx1-Cre-mediated knockout of Mig-6 in the limb mesenchyme results in a similar phenotype as that observed in cartilage-specific knockout mice [32].
These phenotypes appeared to be caused by an increase in chondrocyte proliferation in articular cartilage, supported by the increased expression of Sox9 and EGFR activation in the cartilage [32]. Since our studies suggest dosage- and/or context-specific roles of EGFR signaling in the process of cartilage degeneration in OA, in this study, we used a cartilage-specific (Col2-Cre) to examine effects of Mig-6 overexpression specifically in articular cartilage. We hypothesized that overexpression of Mig-6/EGFR accelerates cartilage degeneration during aging.
reference link: https://arthritis-research.biomedcentral.com/articles/10.1186/s13075-020-02213-z
More information: Yulong Wei et al, Targeting cartilage EGFR pathway for osteoarthritis treatment, Science Translational Medicine (2021). DOI: 10.1126/scitranslmed.abb3946
