Oxidative Stress and Cellular Senescence in the Progression of Osteoarthritis

Osteoarthritis is a common age-related degenerative joint condition in which cartilage and bone are lost, though in the earlier stages of the condition, changes in cartilage are more subtle and complicated in their effects. While not traditionally seen as an inflammatory condition, as there is no evident, visible joint inflammation as occurs in other forms of arthritis, there is nonetheless a strong case for considering osteoarthritis to be driven by localized inflammation. Recently, the increased number of senescent cells in aged joint tissue has been shown to contribute directly to the development of osteoarthritis. Indeed, osteoarthritis will be near the top of the list of conditions that Unity Biotechnology plans to treat with senolytic drugs capable of selectively destroy senescent cells. These unwanted cells generate inflammation through the signaling molecules they create, and thus a role in osteoarthritis makes a lot of sense in hindsight.

Today's open access paper on the relationship between age and osteoarthritis focuses more on oxidative stress than on inflammation, however. Oxidative stress is the excessive generation of oxidative molecules by cells, which can cause damage or even cell death, but perhaps just as importantly it can alter cellular behavior in quite sweeping ways. Oxidative stress and inflammation often go hand in hand, and there is plenty of evidence to suggest that one is capable of causing the other, with the arrow of causation pointing in either direction. So one might take this paper as a different view of the same overall set of mechanisms, a different emphasis on investigation and intervention.

Nonetheless, if you read through the observations, it is clear that a sizable number of those thought most relevant to the development of osteoarthritis point towards the activities of senescent cells in one way or another. This perhaps even includes the oxidative stress given the lines that can be drawn between cellular senescence and mitochondrial dysfunction, and between inflammation and oxidative stress, though clearly the age-related cross-linking found in cartilage has its own independent and significantly detrimental effects. This isn't just senescent cells at work, even if it turns out to be mostly senescent cells at work. Fortunately the advent of senolytics will enable researchers to make inroads into disentangling these various causes and their consequences: removing one of the causes is the fastest and most effective way to determine the size of its contribution and its relationship with other mechanisms.

The Role of Aging in the Development of Osteoarthritis

Osteoarthritis (OA) is one of the most common causes of pain and disability in adults. There are a host of risk factors for the development of OA that include joint injury, obesity, genetic predisposition, and abnormal joint shape and alignment. However, the factor that has the greatest influence on the incidence and prevalence of OA is age. A major limitation in the management of patients with OA is the lack of any therapy that can slow the progression of the disease. The lack of any intervention that targets the disease process has resulted in a substantial increase in joint replacement surgery. Clearly, a safe, effective and less-expensive treatment that can alter the course of the disease will have a major impact on both quality of life and future health-care expenditures. The obvious billion dollar question is how do we slow or stop the progression of joint damage and improve symptoms in individuals with OA.

OA is a slowly progressive disease of synovial joints characterized pathologically by focal destruction of the articular cartilage, a hypertrophic response in neighboring bone that results in osteophyte formation and subchondral sclerosis, variable degrees of synovial inflammation, a thickening of the joint capsule, and damage to soft tissue structures including ligaments and, in the knee, the meniscus. The destruction and loss of the articular cartilage is central to the development of OA and most of the research to date on aging mechanisms relevant to OA has focused on changes in the cartilage. It is important to note that joint aging and OA are not one and the same but rather aging changes can make the development of OA more likely to occur. With normal aging the cartilage appears slightly brown due to an accumulation of advanced glycation end-products and is thinner than in young adults but is otherwise smooth and intact. The accumulation of advanced glycation end-products has been found to alter the biomechanical properties of cartilage making it more "brittle" and susceptible to degeneration. In contrast, in joints affected by OA there is marked destruction and loss of the cartilage accompanied by osteophytes and subchondral bone thickening.

The destruction and loss of the articular cartilage in OA is driven by an imbalance in the production and activity of pro-inflammatory and catabolic mediators. The imbalance in catabolic and anabolic signaling results in overproduction of matrix degrading enzymes including the matrix metalloproteinases (MMPs) and aggrecanases. MMP-13 is important because of its ability to degrade type II collagen, the major structural protein in cartilage which provides the tissue's tensile strength, whereas the aggrecanases are notable for their ability to degrade aggrecan, the large proteoglycan that is responsible for the resiliency of cartilage.

Aging processes that promote an imbalance in chondrocyte signaling resulting in increased production of MMPs and aggrecanases would be central to the development and progression of OA. A focus of our research efforts, and others in the field, has been on gaining a better understanding of the basic molecular mechanisms driving this imbalance in signaling. This could be due to cellular senescence and the development of what has been termed the senescence-associated secretory phenotype. The senescence-associated secretory phenotype is characterized by increased production of many of the same cytokines, chemokines, and MMPs found in OA cartilage, suggesting that OA chondrocytes assume a senescent phenotype. More studies are needed to define the underlying mechanisms of chondrocyte senescence and to determine if removal of senescent cells using compounds that have been called "senolytics" would slow the progression of OA and be disease and/or symptom modifying.

Hallmarks of aging have been proposed, such as cellular senescence and telomere attrition, that are believed to represent key mechanisms by which aging contributes to the development of age-related conditions. One of the hallmarks is mitochondrial dysfunction which can promote age-related disorders in part through increased levels of reactive oxygen species (ROS). Age-related mitochondrial dysfunction has been suggested as a contributing factor in the development of OA. To obtain in vivo support for the hypothesis that mitochondrial dysfunction promotes the development of OA through increased levels of ROS, we evaluated the severity of naturally occurring OA in transgenic mice engineered to express human catalase targeted to the mitochondria. These mice have been shown to have reduced markers of oxidative stress with aging, accompanied by a reduction in age-related pathology and increased lifespan. Compared to age-matched wild-type controls, we found that the 18- to 33-month-old male MCAT mice had a modest but significant reduction in the severity of OA changes in knee articular cartilage.

It is thought that elevated levels of ROS, found in oxidative stress conditions, could promote age-related conditions through the disruption of physiologic signaling. In a series of studies, we have shown that oxidative stress occurs with aging in articular cartilage and this promotes an imbalance in catabolic and anabolic signaling that could play a key role in the development of OA. IGF-1 and OP-1 are key cartilage growth factors and we showed a reduced response of human articular chondrocytes to IGF-1 or the combination of IGF-1 and OP-1, resulting in reduced matrix gene expression and matrix protein synthesis. The reduced response to these growth factors appears to be due to altered cell signaling mediated by oxidative stress.

In summary, there are likely multiple factors related to aging that promote the development of age-related conditions such as OA. A central feature of OA is the imbalance in catabolic and anabolic signaling in cartilage that results in progressive matrix destruction. Our studies are providing evidence that age-related oxidative stress plays a key role in this catabolic-anabolic imbalance. Studies on the molecular mechanism are revealing excessive oxidation of key anti-oxidant systems in chondrocytes. Oxidative inactivation of anti-oxidant systems allows for rising levels of intracellular ROS that cause disruption of physiologic signaling. The failure of simple anti-oxidants to impact aging and age-related disease may be related to their inability to specifically target this disrupted signaling. Future interventions that can restore proper redox signaling in aging chondrocytes hold promise for the treatment of OA.

Comments

this research paper provides a theoretical justification for DMSO - which is a potent antioxidant used to great effect in the horse racing community to repair injuries and support joint health in horses for instance. Placebos don't work on horses.

Posted by: David Gobel at August 16th, 2017 11:44 AM

I believe the effect you are alluding to is the belief in HUMANS that the treatment they are giving to animals is helping the animal. So, once again, placebos work in creatures that are capable of beliefs based on the ability to simulate potential future outcomes. Not horses. See: "clever Hans"...

Unfortunately I do not have access to the reference you supplied. I am always open to having new facts influence and change my thinking. I welcome such. So if you have the full paper, I'd like to see it.

Posted by: David Gobel at August 17th, 2017 1:07 PM

No, it's not.

The pdf can be easily found using Google. I don't know if I can post the link here, but it's the second or third result in Google writing the title and author.

As for animal beliefs about future outcomes, see for example: https://en.wikipedia.org/wiki/B._F._Skinner#Superstition_in_the_pigeon

Posted by: Antonio at August 17th, 2017 4:43 PM

Post a comment; thoughtful, considered opinions are valued. Comments incorporating ad hominem attacks, advertising, and other forms of inappropriate behavior are likely to be deleted.

Note that there is a comment feed for those who like to keep up with conversations.