Proteoglycan 4, widely known as lubricin, is a protein that performs various functions throughout the body. It is a mucinous glycoprotein, meaning it has both protein and sugar components, which contribute to its unique properties. This protein plays a significant role in maintaining the smooth operation and protection of biological surfaces.
Understanding PRG4 and Its Locations
PRG4 is classified as a proteoglycan and possesses a distinctive structure enabling its lubricating abilities. Its protein core features N- and C-termini and a central mucin domain. This central domain is heavily glycosylated, accounting for roughly 50% of the mucin’s weight, and is responsible for its boundary-lubricating function. The central domain is negatively charged, with positively charged termini.
PRG4 is found in various locations throughout the human body. It is a major component of synovial fluid, the lubricating fluid found in joints, and is also present on the surface of articular cartilage. PRG4 is secreted by synovial type B fibroblasts and superficial zone chondrocytes, specialized cells within joints. Beyond joints, PRG4 has been detected in other tissues, including tendons, menisci, lungs, liver, heart, bone, ligaments, muscles, and skin.
Key Biological Functions of PRG4
PRG4’s primary function is to act as a boundary lubricant, forming a protective layer on surfaces that minimizes friction, even at near-zero sliding speeds. This property helps prevent damage caused by mechanical stress and friction between moving tissues. The ability of PRG4 to form this boundary layer is attributed to its negatively charged central domain, which repels opposing surfaces.
Beyond lubrication, PRG4 also exhibits anti-adhesive properties, preventing cells and proteins from sticking to surfaces inappropriately. It contributes to tissue protection by preventing chondrocyte apoptosis, the programmed death of cartilage cells. PRG4 possesses anti-inflammatory effects by interacting with Toll-like receptors on synovial cells, modulating inflammatory responses within the joint. It can suppress pro-inflammatory signaling pathways and downregulate the expression of inflammatory factors like IL-1β and IL-6.
PRG4’s Role in Joint Health
PRG4 plays a significant role in maintaining healthy joints by reducing friction and wear on articular cartilage surfaces. It forms a lubricating boundary layer on the cartilage, which minimizes damage during joint movement and preserves joint function.
When PRG4 is deficient or dysfunctional in joints, it can lead to severe consequences. An inherited disorder called Camptodactyly Arthropathy Coxa Vara Pericarditis (CACP) syndrome is caused by mutations in the PRG4 gene, leading to a lack of lubricin expression and severe early-onset joint damage. PRG4 deficiency also contributes to the development of osteoarthritis (OA), a widespread joint disease characterized by cartilage degeneration, subchondral bone remodeling, and synovial inflammation.
PRG4 in Other Body Systems
While its role in joint health is well-documented, PRG4 is also present in other parts of the body, offering similar protective and lubricating benefits. In the eyes, PRG4, also known as lubricin, is found on the ocular surface, including the cornea and conjunctiva, where it helps maintain the tear film. A deficiency of PRG4 in mice has been linked to increased corneal fluorescein staining and inflammation, indicating significant corneal damage without its presence.
PRG4’s presence has also been identified in salivary glands, contributing to the boundary lubricating properties of human saliva. This suggests a role in enamel-to-enamel lubrication within the mouth.
Emerging Research and Therapeutic Applications
Ongoing research into PRG4 continues to uncover its potential as a therapeutic agent and a biomarker for various conditions. Recombinant human PRG4 (rhPRG4) is a promising biosimilar being investigated for use in joints at risk for osteoarthritis, including those with traumatic injuries or early OA. Preclinical studies in rodents have shown that intra-articular injections of rhPRG4 can preserve cartilage and delay the progression of post-traumatic osteoarthritis.
Beyond joint conditions, PRG4 is being explored for other applications, such as in eye drops for treating dry eye disease. Clinical trials using recombinant lubricin eye drops for dry eye have shown promising results, with improvements in symptoms and objective signs. PRG4’s anti-inflammatory properties also suggest its potential as a therapeutic for diseases with an immunological basis, such as sepsis. PRG4 levels are being investigated as potential biomarkers for inflammatory processes and disease progression in conditions like gout and osteoarthritis.