Of mice and men: converging on a common molecular understanding of osteoarthritis

Abstract

Despite an increasing burden of osteoarthritis in developed societies, target discovery has been slow and there are currently no approved disease-modifying osteoarthritis drugs. This lack of progress is due in part to a series of misconceptions over the years: that osteoarthritis is an inevitable consequence of ageing, that damaged articular cartilage cannot heal itself, and that osteoarthritis is driven by synovial inflammation similar to that seen in rheumatoid arthritis. Molecular interrogation of disease through ex-vivo tissue analysis, in-vitro studies, and preclinical models have radically reshaped the knowledge landscape. Inflammation in osteoarthritis appears to be distinct from that seen in rheumatoid arthritis. Recent randomised controlled trials, using treatments repurposed from rheumatoid arthritis, have largely been unsuccessful. Genome-wide studies point to defects in repair pathways, which accords well with recent promise using growth factor therapies or Wnt pathway antagonism. Nerve growth factor has emerged as a robust target in osteoarthritis pain in phase 2–3 trials. These studies, both positive and negative, align well with those in preclinical surgical models of osteoarthritis, indicating that pathogenic mechanisms identified in mice can lead researchers to valid human targets. Several novel candidate pathways are emerging from preclinical studies that offer hope of future translational impact. Enhancing trust between industry, basic, and clinical scientists will optimise our collective chance of success.

How close are disease‐modifying drugs for osteoarthritis?

“…Again, the pathways are complex. However, nerve growth factor (NGF), which sensitises pain fibres and directs the growth of new nerves, is attracting considerable attention 5 . Antibodies against NGF produce promising analgesia in hip and knee osteoarthritis 4,5 .…”

“…However, nerve growth factor (NGF), which sensitises pain fibres and directs the growth of new nerves, is attracting considerable attention 5 . Antibodies against NGF produce promising analgesia in hip and knee osteoarthritis 4,5 . “Antibodies against NGF are extremely effective analgesics, but there is no evidence they are DMDs,” says Professor Vincent, who recently authored an insightful review on DMDs for osteoarthritis 5 .…”

“…About 90% of people have radiographic osteoarthritis somewhere in their body by the time they are 75 years old 1 . Over time, the cumulative and dynamic interplay between mechanical, inflammatory and metabolic factors change the composition of cartilage, resulting in a loss of integrity that increases the joint's vulnerability to physical forces and, in turn, induces the mechano‐inflammatory pathways that seem to drive osteoarthritis 4,5 …”

“…Mechanical stress can activate Wnt‐signalling pathways that trigger pathogenic hallmarks of osteoarthritis, such as changes to chondrocytes, alter bone remodelling and induce catabolic enzymes seen in osteoarthritis. Wnt signalling seems to be a disease‐modifying pathway in mouse models of osteoarthritis 5 . “It's still early days, but modifying Wnt signalling seems promising,” she says.…”

“…Professor Vincent's research highlights the importance of ‘mechanoflammation’ in driving osteoarthritis. In other words, mechanical injury directly stimulates inflammatory signalling and expression of genes encoding inflammatory proteins in the articular cartilage, synovium and other joint tissues that ultimately ends in osteoarthritis 5 …”