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7 Articles in this Series
Addressing Arthralgia in Children
An ACR/ARHP Preview
Axial Spondylitis: Mimics, Progression, the Need for MRI, and New Management Recommendations
How Rheumatic Diseases Can Hurt Sexual Health
Tanezumab for Hip and Knee OA; Cosentyx for Ankylosing Spondylitis; and Upadacitinib for RA
Treating Chronic Musculoskeletal Pain in Older Adults
Uncovered Inflammatory Pathways of Osteoarthritis Call for New Targets

Uncovered Inflammatory Pathways of Osteoarthritis Call for New Targets

The role of low-grade inflammation, mast cells, the complement system, and more. An ACR/ARHP 2018 Meeting Highlight with William H. Robinson, MD, PhD

William H. Robinson, MD, PhD, professor of immunology and rheumatology at Stanford University School of Medicine, led a session on the “Novel Inflammatory Pathways of Osteoarthritis” at the 2018 annual meeting of the American College of Rheumatology (ACR), held in collaboration this year with the Association of Reproductive Health Professionals (ARHP) in Chicago. He provided an overview of recent studies, including several conducted at his lab at Stanford Medicine, the Robinson Lab, and encouraged the audience to consider that osteoarthritis (OA) has previously been attacked from the wrong angle.

In general, he reminded the audience that OA development derives from predisposing factors, propagating factors, and joint failure. These factors ultimately result in mechanisms that promote synovitis (ie, inflammation of the synovial membrane), which then promotes pain and joint breakdown, leading, in many cases, to arthroplasty.

Dr. Robinson shared a number of studies, which can be accessed in full through his ACR slide deck, including how imaging of knee OA has revealed that synovitis is associated with pain, cartilage loss, and progression toward joint replacement, with approximately two-thirds of those reviewed exhibiting significant synovial enhancement.

Knee osteoarthritis (Source: 123RF)Uncovering the potential pathways of osteoarthritis development may provide for new treatment targets and even prevention.

Potential Pathogeneses of Osteoarthritis

Focusing on proteomic analyses of synovial fluid, he noted that several studies have revealed

molecular pathways involved in OA. The Top 5 pathways, according to Dr. Robinson include:

  • acute phase response
  • tissue injury
  • coagulation system
  • immunologic disorder (eg, cytokines, immune cell receptors)
  • the complement system.

Focusing on the latter of these potential pathways, he discussed how synovial fluid involves upregulation of multiple different cytokines—these cytokines are different from those detected in rheumatoid arthritis (RA) synovial fluid, he clarified. “Research validates that there is dysregulation of cytokines and chemokines in OA,” he said, offering a patient example with a meniscal tear that was associated with synovitis. There have been findings in preclinical state, where there is radiographic evidence of active synovitis even though there may not be active OA yet, he said.

Low-Grade Inflammation

So, is chronic low-grade inflammation driving the pathogenesis of OA, Dr. Robinson asked the audience? He described how his lab team has reviewed 10 years of data to screen approximately mice deficient in different immune molecules to look at dysregulation in OA.  “This bottoms-up functional screen aimed to identify pathways that are truly contributing to OA,” he explained. With regard to cytokines and chemokines, Ctgf-deficient mice produced excessive amounts of TGF-beta, indicating Ctgf as a potential protector of OA. Also uncovered was that CCL2/CCR2 mediate inflammation and cartilage destruction.

There may also be endogenous damage/danger signals – or pattern recognition receptors that arise out of innate immune situations, he explained. These “DAMPs” (damage-associated molecular patterns) are serving as innate immune adjuvants. Joint trauma or overuse may lead to inflammation or induce a vascular leak, for instance.


Other potential pathways are macrophages, he went on, pointing to research by Krause, in  Osteoarthritis and Cartilage, 2016. His study showed that 76% of OA knees had positive signals for activated macrophages. (Macrophage activation is associated with pain and OA severity.) Another study from Sun, in PLoS One, 2017 showed that obesity-associated metabolic syndrome may induce a pro-inflammatory state. In mice, the M1 macrophage in the synovium promoted OA compared to mice with a normal diet.


Integrins may also play a role in OA pathogenesis, said Dr. Robinson. RGD-containing integrins are involved in cartilage homeostasis and regular cellular trafficking and function. The CD47 protein and coreceptor alphaVbeta3, in particular, activate cytokine production and block phagocytosis. As a result, cartilage debris may not be clearing, paving the way to more inflammation. Based on his lab’s ongoing research, primarily in mice to date, he said he believes their data shows that cartilage breakdown products promote macrophage activation via alphaVbeta3/CD47 to promote OA pathogenesis.

Complement Pathway

Dr. Robinson shared research on the complement pathway using proteomic evidence as well. He pointed to Wang, Robinson, et al, in Nat Med, 2011. There is increased C3a and MAC (ie, membrane attack complex) in OA synovial fluid. Individuals with early OA have significant elevation in the activation of C3A in synovial fluid.  MAC also increased synovial fluid in early OA and late-stage OA, validating their results. MAC is deposited around chondrocytes and synoviocytes in OA joint tissue. Essentially, sublytic MAC stimulates chondrocytes to express genes encoding inflammatory and degradatory mediators. In human OA, MAC co-localizes with activated downstream, signaling molecules and degradative mediators.

Involved in the complement pathways are C5—so genetic and pharmacologic blockade of complement C5 activation may protect against OA—and the cartilage component fibromodulin, which activates the complement system.

Mast Cells

Finally, Dr. Robinson spoke about the potential role of mast cells in OA development. Synovial mast cells are higher in OA than in RA, he explained, and those high numbers have been correlated with increasing synovitis scores in both rheumatic conditions. “Mast cells are full of enzymes and inflammatory mediators…with the right stimuli, they release these,” he said. Mast cells are capable of activating T-cells as well, he noted.

Whether these cells are epiphenomena or involved in the pathogenesis of OA remains to be seen. Dr. Robinson’s lab has started to dig into this inquiry by trying to determine whether mast-cell related genes are overexpressed in OA human synovium compared to normal tissues. While there are a similar number of cells in post-trauma non-OA cells and OA cells, in OA, there is an increased degranulation and Tryptase release of these cells, he explained. To validate this initial finding, his lab looked at active Tryptase, which they found to be much higher in OA synovial fluids compared to non-OA synovial fluids. Further findings showed that KitW-sh/W-sh mast-cell deficient mice are protected against OA. The same appears to be true for Cpa3-Cre; Mcl-1fl/fl mast cell deficient mice. Overall, mast-cell derived Tryptase beta catabolizes cartilage, induces chrondrocyte apoptosis in vitro; and induce pro-inflammatory responses in synovial fibroblasts. As a result, the inhibition of Tryptase activity may protect against OA.

As mast cells and mast-cell tryptases clearly seem to play a key role the in pathogenesis of OA, joint trauma or joint overuse end up leading to a chronic cycle of inflammation, tissue damage and remodeling. But, if the healthcare community can target these mast cells pharmacologically to inhibit their development or function, they may be able to prevent OA, he proposed.


New Pathways Need New Targets

Overall, Dr. Robinson concluded that all the data shared in his presentation fit into the field of degenerative diseases and their implications. Similar to classic degenerative diseases, such as Alzheimer’s and macular generation, inflammation plays a critical role in osteoarthritis. Current therapies for OA to date have not worked great, he said. NSAIDs are not the answer, he added, but rather, specific targets for the innate pathways defined herein are needed. “We need a different type of fire extinguisher for this inflammatory condition. We need next-generation molecular diagnostics and new therapeutic approaches to target OA.”

There may also be a way to prevent the continued degradation with early identification.

During the Q&A session, audience members asked about patients with hypoglycemia, thyroid issues, and EDS and whether those underlying conditions may be leading to OA via mast-cell activation. Dr. Robinson said that may indeed be possible and recommended that researchers look at these subpopulations and then expand them out larger OA studies, which may show just how these mechanisms relate.

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