Researchers led by Stanford Medicine have identified a new potential method for regenerating damaged knee cartilage and preventing osteoarthritis, offering hope for a therapy that might alleviate the need for joint replacement surgery. In aging and injured mice, they showed that inhibiting the age-related enzyme 15-PGDH can regenerate cartilage and prevent osteoarthritis from forming.
The finding is mostly important because adult articular cartilage has been notoriously unable to repair itself naturally. As well as lacking any blood supply, cartilage has been very difficult to regenerate once damaged as it is an anemic tissue and so can be susceptible to degenerative processes such as osteoarthritis that slowly wears away at the articular surface of the bones on either side.
Rather than trying to jet in some additional stem cells into the joint, the Stanford team found that one can simply encourage the cartilage generating cells in the joint to behave like younger, healthier ones. They searched the joint for the enzyme 15-PGDH, which is found in higher levels as you age. They call it a gerozyme – a protein linked with age-related decline in tissue function.
When a small-molecule inhibitor was used to inhibit the enzyme 15-PGDH in old mice, new articular cartilage was produced. The treatment was successful both when given systemically and when injected directly into the knee joint. They succeeded in producing true hyaline or articular cartilage instead of fibrocartilage, which is normally thought unsuitable for the restoration of a normal joint.
The pain treatment also appeared as if it may be useful for prevention of arthritis following major knee injuries. In experiments where damage was inflicted on the knees of mice to simulate a common human injury, destruction of the ACL is known to lead to greater long-term osteoarthritis risk. Animals, which received the 15-PGDH inhibitor after injury were a lot protected from joint destruction and were more mobile and able to carry weight.
What perhaps was most unbelievable about the research was how the regeneration of tissue was carried out. Scientists did not believe it would be the combination of stem or progenitor cells that become new cartilage, but rather multiple lines of evidence implied mature chondrocytes expressed key changes in transcription in response to therapy, to take on a more juvenile phenotype. Treatment decreased populations of cells, which produced decreased levels of genes involved in degradation of cartilage, while increasing cells, which expressed high levels of genes involved in healthy articular cartilage development and maintenance.
The investigators further evaluated the method on human cartilage tissue gathered from knee replacement operations. This tissue, after application of the 15-PGDH inhibitor, resulted in tissue reductions typical of cartilage degradation and showed the emergence of initial indicators of articular cartilage regrowth. While promising, these results do not provide evidence of in vivo cartilage regeneration within the human knee.
This discovery might ultimately result in an entirely different response to osteoarthritis. Existing treatment methods almost entirely revolve around alleviating pain and preserving mobility, eventually progressing to knee or hip replacement when crippling tissue destruction occurs. A treatment, which is able to regenerate the patient’s own cartilage, would go directly to correcting the tissue destruction.
