OARSI Debate: Are Mechanics Just Another Cytokine?

BARCELONA – It is a long held and substantiated belief that osteoarthritis is a biomechanical disease, but evidence is accumulating to support an inflammatory cause. As testament to the strength of both possible causes of the disease, the vote after the World Congress on Osteoarthritis debate, titled "Is OA a mechanical disease or an inflammatory disease?" resulted in a swing from approximately 70/30 in favor of a biomechanical explanation, to 50/50.

Dr. David T. Felson, professor of medicine and public health, and principal investigator of the NIH-funded Boston University Multipurpose Arthritis and Musculoskeletal Diseases Center, argued in favor of OA as a disease of mechanics.

In opposition, Dr. Francis Berenbaum, head of the department of rheumatology, Saint-Antoine Hospital, Paris, advanced his case for OA as an inflammatory disease.

Dr. Felson went first, noting that "OA is caused by increased physical forces across a local area of a joint. This is either from abnormal anatomy leading to increased stress with normal load, or excess overall load such as with obesity, or a combination of the two."

The animal models of OA almost all have relied on joint injury and major injury to knees such as meniscal tears, which would support a biomechanical origin for OA. "But diseases are often [the result of] the interplay between different causes," he conceded.

Meniscal tears account for 40%-50% of knee OA, Dr. Felson said, adding: "Multiple studies show surgery to remove tears increases focal stress on the cartilage and causes a high rate of subsequent OA."

Dr. Felson’s argument for abnormal stress as being the cause of OA was further supported when he pointed out that congenital dysplasia increases focal load and markedly increases risk of hip OA at a young age. He also listed various occupations and related sites of OA: for example, cotton workers’ fingers; farmers’ hips and knees; and miners’ knees and spines.

The second major tenet of Dr. Felson’s talk centered on the fact that once OA had developed, pathomechanics overwhelmed all other factors. He described the vicious cycle of joint damage caused by a misaligned knee. "Increased focal stress across one area causes cartilage debris and bone damage." Dr. Felson noted that the inflammation seen in OA is caused by absorption of debris by the synovium, which precipitated more cartilage damage and worsened misalignment.

Dr. Felson supported his point about the role of misalignment worsening OA with data from the Multicenter Osteoarthritis Study (MOST) (Ann. Rheum. Dis. 2012 May 1 [doi: 10.1136/annrheumdis-2011-201070]), which found that 82% of knees with OA had misalignment. Furthermore, he said, "I would contend to you that the genetics of OA is probably predominantly related to abnormally shaped joints. Only 5% of OA is associated with systemic genetics."

Finally, conceding that inflammation was a feature of OA but not a primary cause, Dr. Felson explained its role in the disease. "Inflammation in OA is mostly a consequence of pathomechanics, that is meniscal tears and [anterior cruciate ligament] tears that lead to cytokine release in the synovium and induces joint damage."

If the injury was severe or there were multiple injuries then there was no requirement for inflammatory cytokine release because OA could occur without it, Dr. Felson concluded.

During his presentation, Dr. Berenbaum quoted some renowned names in the field of OA research, and linked them to papers on inflammatory causes of OA. He joked that in light of these papers, his job was nearly done; however he then began to build his expert case for OA as an inflammatory disease.

Approaching the first pillar of his argument from a clinical standpoint, Dr. Berenbaum described the existence of flares in OA that sometimes resembled other inflammatory arthritis. "There’s pain at night, morning stiffness, and swelling."

Focusing on both the macroscopic and histological levels, Dr. Berenbaum added that OA showed evidence of synovitis, featuring different levels of inflammation. "It is a patchy synovitis rather than pannus as in [rheumatoid arthritis], but the degree of inflammation has been shown to be correlated to prognosis, which is more severe when a high degree of synovitis is present," he commented.

This synovitis has been well characterized using MRI and ultrasound, according to Dr. Berenbaum. He addressed the evidence on a tissue and cellular level, by saying that inflammatory and immunologic cells have been seen in the OA synovium. "T-cells, B-cells, and macrophages, which play a role in cartilage degradation, have been shown in a murine experimental model. If macrophages are removed from the synovium in collagenase-induced OA, the cartilage is protected from degradation," explained Dr. Berenbaum.

Inflammatory mediators play critical roles in the three most characterized phenotypes, that is, in posttrauma OA, metabolic OA and aging, he continued.

All joint tissue including subchondral bone cells, synovial cells, and chondrocytes were able to produce inflammatory cytokines, according to Dr. Berenbaum. "Moreover, nonphysiologic mechanical stress applied on cartilage or subchondral bone induces the release of inflammatory mediators by chondrocytes, or osteoblasts and osteocytes via mechanoreceptors present at the surface of these cells."

"So mechanical stress is a cytokine," he stated.

Findings from experimental models of posttrauma OA provide "...evidence that complement pathways and innate immunity are involved in the OA process."

Adipokines or cytokines produced by the adipose tissue may play a role in OA, he suggested. Hand OA is twice as common in obese patients as in those of normal weight, meaning that systemic mediators may act on joints in obesity, Dr. Berenbaum said.

Courtesy Dr. Francis Berenbaum

To reinforce his point that inflammatory causes rather than mechanical were to blame, Dr. Berenbaum quipped, "I don’t see many obese patients walking on their hands."

Dr. Berenbaum then drew further rationale for his case by describing the features and functions of a particular type of chondrocyte. "The secretory phenotype of a chondrocyte is a well known characteristic of chondrocyte senescence and leads to overexpression of several inflammatory mediators by these cells."

"This means that when exposed to the same level of stress as a younger cell, aging cells produce more cytokines," he explained.

Finally, Dr. Berenbaum described findings supporting the likelihood that there is a systemic effect of low-grade inflammation induced by OA. He discussed a recent paper showing that in a murine model of Alzheimer’s, disease could be accelerated by the presence of OA in multiple joints through the release of the inflammatory mediator interleukin-6 in the blood.

He added that support for this hypothesis was found in publications of studies showing an increase in cytokine production in the blood of patients with OA.

In conclusion, he agreed that in the case of trauma, inflammation was secondary, "but other phenotypes exist which provide signals that inflammation can actually drive OA," he said.

Audience member Dr. Marc Hochberg, professor of medicine, epidemiology, and preventive medicine, and head of the division of rheumatology and clinical immunology, University of Maryland, Baltimore, asked the presenters if their beliefs about biomechanical and inflammatory drivers explained the sex differences seen in OA.

Dr. Felson replied: "I think women’s joints are anatomically smaller and we haven’t seen much study on size of joint relative to size of person and whether stress is greater in relatively smaller joints. But certainly women are weaker than men and weakness is predisposing to disease. They also have greater dynamic laxity in their joints than men which might predispose them to more mechanical injury than men."

An audience member from Copenhagen highlighted the conundrum of treating OA with pain relief when pain relief actually led to increased mechanical loading. "This is one of the reasons why finding treatments in OA has been so difficult," answered Dr. Felson. "If we treat successfully by diminishing pain we face the increased risk of more loading and then more damage and acceleration of the OA. This might be the explanation for the tanezumab story, in that pain is beautifully ablated only to have some patients go on to have rapid joint destruction."

He added that he thought this was an argument in favor of biomechanical therapies that aimed to address the underlying etiology. "This would enable loading that is healthier to the joint and to promote more levels of activity."

The congress was sponsored by Osteoarthritis Research Society International.

BARCELONA – It is a long held and substantiated belief that osteoarthritis is a biomechanical disease, but evidence is accumulating to support an inflammatory cause. As testament to the strength of both possible causes of the disease, the vote after the World Congress on Osteoarthritis debate, titled "Is OA a mechanical disease or an inflammatory disease?" resulted in a swing from approximately 70/30 in favor of a biomechanical explanation, to 50/50.

Dr. David T. Felson, professor of medicine and public health, and principal investigator of the NIH-funded Boston University Multipurpose Arthritis and Musculoskeletal Diseases Center, argued in favor of OA as a disease of mechanics.

In opposition, Dr. Francis Berenbaum, head of the department of rheumatology, Saint-Antoine Hospital, Paris, advanced his case for OA as an inflammatory disease.

Dr. Felson went first, noting that "OA is caused by increased physical forces across a local area of a joint. This is either from abnormal anatomy leading to increased stress with normal load, or excess overall load such as with obesity, or a combination of the two."

The animal models of OA almost all have relied on joint injury and major injury to knees such as meniscal tears, which would support a biomechanical origin for OA. "But diseases are often [the result of] the interplay between different causes," he conceded.

Meniscal tears account for 40%-50% of knee OA, Dr. Felson said, adding: "Multiple studies show surgery to remove tears increases focal stress on the cartilage and causes a high rate of subsequent OA."

Dr. Felson’s argument for abnormal stress as being the cause of OA was further supported when he pointed out that congenital dysplasia increases focal load and markedly increases risk of hip OA at a young age. He also listed various occupations and related sites of OA: for example, cotton workers’ fingers; farmers’ hips and knees; and miners’ knees and spines.

The second major tenet of Dr. Felson’s talk centered on the fact that once OA had developed, pathomechanics overwhelmed all other factors. He described the vicious cycle of joint damage caused by a misaligned knee. "Increased focal stress across one area causes cartilage debris and bone damage." Dr. Felson noted that the inflammation seen in OA is caused by absorption of debris by the synovium, which precipitated more cartilage damage and worsened misalignment.

Dr. Felson supported his point about the role of misalignment worsening OA with data from the Multicenter Osteoarthritis Study (MOST) (Ann. Rheum. Dis. 2012 May 1 [doi: 10.1136/annrheumdis-2011-201070]), which found that 82% of knees with OA had misalignment. Furthermore, he said, "I would contend to you that the genetics of OA is probably predominantly related to abnormally shaped joints. Only 5% of OA is associated with systemic genetics."

Finally, conceding that inflammation was a feature of OA but not a primary cause, Dr. Felson explained its role in the disease. "Inflammation in OA is mostly a consequence of pathomechanics, that is meniscal tears and [anterior cruciate ligament] tears that lead to cytokine release in the synovium and induces joint damage."

If the injury was severe or there were multiple injuries then there was no requirement for inflammatory cytokine release because OA could occur without it, Dr. Felson concluded.

During his presentation, Dr. Berenbaum quoted some renowned names in the field of OA research, and linked them to papers on inflammatory causes of OA. He joked that in light of these papers, his job was nearly done; however he then began to build his expert case for OA as an inflammatory disease.

Approaching the first pillar of his argument from a clinical standpoint, Dr. Berenbaum described the existence of flares in OA that sometimes resembled other inflammatory arthritis. "There’s pain at night, morning stiffness, and swelling."

Focusing on both the macroscopic and histological levels, Dr. Berenbaum added that OA showed evidence of synovitis, featuring different levels of inflammation. "It is a patchy synovitis rather than pannus as in [rheumatoid arthritis], but the degree of inflammation has been shown to be correlated to prognosis, which is more severe when a high degree of synovitis is present," he commented.

This synovitis has been well characterized using MRI and ultrasound, according to Dr. Berenbaum. He addressed the evidence on a tissue and cellular level, by saying that inflammatory and immunologic cells have been seen in the OA synovium. "T-cells, B-cells, and macrophages, which play a role in cartilage degradation, have been shown in a murine experimental model. If macrophages are removed from the synovium in collagenase-induced OA, the cartilage is protected from degradation," explained Dr. Berenbaum.

Inflammatory mediators play critical roles in the three most characterized phenotypes, that is, in posttrauma OA, metabolic OA and aging, he continued.

All joint tissue including subchondral bone cells, synovial cells, and chondrocytes were able to produce inflammatory cytokines, according to Dr. Berenbaum. "Moreover, nonphysiologic mechanical stress applied on cartilage or subchondral bone induces the release of inflammatory mediators by chondrocytes, or osteoblasts and osteocytes via mechanoreceptors present at the surface of these cells."

"So mechanical stress is a cytokine," he stated.

Findings from experimental models of posttrauma OA provide "...evidence that complement pathways and innate immunity are involved in the OA process."

Adipokines or cytokines produced by the adipose tissue may play a role in OA, he suggested. Hand OA is twice as common in obese patients as in those of normal weight, meaning that systemic mediators may act on joints in obesity, Dr. Berenbaum said.

Courtesy Dr. Francis Berenbaum

To reinforce his point that inflammatory causes rather than mechanical were to blame, Dr. Berenbaum quipped, "I don’t see many obese patients walking on their hands."

Dr. Berenbaum then drew further rationale for his case by describing the features and functions of a particular type of chondrocyte. "The secretory phenotype of a chondrocyte is a well known characteristic of chondrocyte senescence and leads to overexpression of several inflammatory mediators by these cells."

"This means that when exposed to the same level of stress as a younger cell, aging cells produce more cytokines," he explained.

Finally, Dr. Berenbaum described findings supporting the likelihood that there is a systemic effect of low-grade inflammation induced by OA. He discussed a recent paper showing that in a murine model of Alzheimer’s, disease could be accelerated by the presence of OA in multiple joints through the release of the inflammatory mediator interleukin-6 in the blood.

He added that support for this hypothesis was found in publications of studies showing an increase in cytokine production in the blood of patients with OA.

In conclusion, he agreed that in the case of trauma, inflammation was secondary, "but other phenotypes exist which provide signals that inflammation can actually drive OA," he said.

Audience member Dr. Marc Hochberg, professor of medicine, epidemiology, and preventive medicine, and head of the division of rheumatology and clinical immunology, University of Maryland, Baltimore, asked the presenters if their beliefs about biomechanical and inflammatory drivers explained the sex differences seen in OA.

Dr. Felson replied: "I think women’s joints are anatomically smaller and we haven’t seen much study on size of joint relative to size of person and whether stress is greater in relatively smaller joints. But certainly women are weaker than men and weakness is predisposing to disease. They also have greater dynamic laxity in their joints than men which might predispose them to more mechanical injury than men."

An audience member from Copenhagen highlighted the conundrum of treating OA with pain relief when pain relief actually led to increased mechanical loading. "This is one of the reasons why finding treatments in OA has been so difficult," answered Dr. Felson. "If we treat successfully by diminishing pain we face the increased risk of more loading and then more damage and acceleration of the OA. This might be the explanation for the tanezumab story, in that pain is beautifully ablated only to have some patients go on to have rapid joint destruction."

He added that he thought this was an argument in favor of biomechanical therapies that aimed to address the underlying etiology. "This would enable loading that is healthier to the joint and to promote more levels of activity."

The congress was sponsored by Osteoarthritis Research Society International.

BARCELONA – It is a long held and substantiated belief that osteoarthritis is a biomechanical disease, but evidence is accumulating to support an inflammatory cause. As testament to the strength of both possible causes of the disease, the vote after the World Congress on Osteoarthritis debate, titled "Is OA a mechanical disease or an inflammatory disease?" resulted in a swing from approximately 70/30 in favor of a biomechanical explanation, to 50/50.

Dr. David T. Felson, professor of medicine and public health, and principal investigator of the NIH-funded Boston University Multipurpose Arthritis and Musculoskeletal Diseases Center, argued in favor of OA as a disease of mechanics.

In opposition, Dr. Francis Berenbaum, head of the department of rheumatology, Saint-Antoine Hospital, Paris, advanced his case for OA as an inflammatory disease.

Dr. Felson went first, noting that "OA is caused by increased physical forces across a local area of a joint. This is either from abnormal anatomy leading to increased stress with normal load, or excess overall load such as with obesity, or a combination of the two."

The animal models of OA almost all have relied on joint injury and major injury to knees such as meniscal tears, which would support a biomechanical origin for OA. "But diseases are often [the result of] the interplay between different causes," he conceded.

Meniscal tears account for 40%-50% of knee OA, Dr. Felson said, adding: "Multiple studies show surgery to remove tears increases focal stress on the cartilage and causes a high rate of subsequent OA."

Dr. Felson’s argument for abnormal stress as being the cause of OA was further supported when he pointed out that congenital dysplasia increases focal load and markedly increases risk of hip OA at a young age. He also listed various occupations and related sites of OA: for example, cotton workers’ fingers; farmers’ hips and knees; and miners’ knees and spines.

The second major tenet of Dr. Felson’s talk centered on the fact that once OA had developed, pathomechanics overwhelmed all other factors. He described the vicious cycle of joint damage caused by a misaligned knee. "Increased focal stress across one area causes cartilage debris and bone damage." Dr. Felson noted that the inflammation seen in OA is caused by absorption of debris by the synovium, which precipitated more cartilage damage and worsened misalignment.

Dr. Felson supported his point about the role of misalignment worsening OA with data from the Multicenter Osteoarthritis Study (MOST) (Ann. Rheum. Dis. 2012 May 1 [doi: 10.1136/annrheumdis-2011-201070]), which found that 82% of knees with OA had misalignment. Furthermore, he said, "I would contend to you that the genetics of OA is probably predominantly related to abnormally shaped joints. Only 5% of OA is associated with systemic genetics."

Finally, conceding that inflammation was a feature of OA but not a primary cause, Dr. Felson explained its role in the disease. "Inflammation in OA is mostly a consequence of pathomechanics, that is meniscal tears and [anterior cruciate ligament] tears that lead to cytokine release in the synovium and induces joint damage."

If the injury was severe or there were multiple injuries then there was no requirement for inflammatory cytokine release because OA could occur without it, Dr. Felson concluded.

During his presentation, Dr. Berenbaum quoted some renowned names in the field of OA research, and linked them to papers on inflammatory causes of OA. He joked that in light of these papers, his job was nearly done; however he then began to build his expert case for OA as an inflammatory disease.

Approaching the first pillar of his argument from a clinical standpoint, Dr. Berenbaum described the existence of flares in OA that sometimes resembled other inflammatory arthritis. "There’s pain at night, morning stiffness, and swelling."

Focusing on both the macroscopic and histological levels, Dr. Berenbaum added that OA showed evidence of synovitis, featuring different levels of inflammation. "It is a patchy synovitis rather than pannus as in [rheumatoid arthritis], but the degree of inflammation has been shown to be correlated to prognosis, which is more severe when a high degree of synovitis is present," he commented.

This synovitis has been well characterized using MRI and ultrasound, according to Dr. Berenbaum. He addressed the evidence on a tissue and cellular level, by saying that inflammatory and immunologic cells have been seen in the OA synovium. "T-cells, B-cells, and macrophages, which play a role in cartilage degradation, have been shown in a murine experimental model. If macrophages are removed from the synovium in collagenase-induced OA, the cartilage is protected from degradation," explained Dr. Berenbaum.

Inflammatory mediators play critical roles in the three most characterized phenotypes, that is, in posttrauma OA, metabolic OA and aging, he continued.

All joint tissue including subchondral bone cells, synovial cells, and chondrocytes were able to produce inflammatory cytokines, according to Dr. Berenbaum. "Moreover, nonphysiologic mechanical stress applied on cartilage or subchondral bone induces the release of inflammatory mediators by chondrocytes, or osteoblasts and osteocytes via mechanoreceptors present at the surface of these cells."

"So mechanical stress is a cytokine," he stated.

Findings from experimental models of posttrauma OA provide "...evidence that complement pathways and innate immunity are involved in the OA process."

Adipokines or cytokines produced by the adipose tissue may play a role in OA, he suggested. Hand OA is twice as common in obese patients as in those of normal weight, meaning that systemic mediators may act on joints in obesity, Dr. Berenbaum said.

Courtesy Dr. Francis Berenbaum

To reinforce his point that inflammatory causes rather than mechanical were to blame, Dr. Berenbaum quipped, "I don’t see many obese patients walking on their hands."

Dr. Berenbaum then drew further rationale for his case by describing the features and functions of a particular type of chondrocyte. "The secretory phenotype of a chondrocyte is a well known characteristic of chondrocyte senescence and leads to overexpression of several inflammatory mediators by these cells."

"This means that when exposed to the same level of stress as a younger cell, aging cells produce more cytokines," he explained.

Finally, Dr. Berenbaum described findings supporting the likelihood that there is a systemic effect of low-grade inflammation induced by OA. He discussed a recent paper showing that in a murine model of Alzheimer’s, disease could be accelerated by the presence of OA in multiple joints through the release of the inflammatory mediator interleukin-6 in the blood.

He added that support for this hypothesis was found in publications of studies showing an increase in cytokine production in the blood of patients with OA.

In conclusion, he agreed that in the case of trauma, inflammation was secondary, "but other phenotypes exist which provide signals that inflammation can actually drive OA," he said.

Audience member Dr. Marc Hochberg, professor of medicine, epidemiology, and preventive medicine, and head of the division of rheumatology and clinical immunology, University of Maryland, Baltimore, asked the presenters if their beliefs about biomechanical and inflammatory drivers explained the sex differences seen in OA.

Dr. Felson replied: "I think women’s joints are anatomically smaller and we haven’t seen much study on size of joint relative to size of person and whether stress is greater in relatively smaller joints. But certainly women are weaker than men and weakness is predisposing to disease. They also have greater dynamic laxity in their joints than men which might predispose them to more mechanical injury than men."

An audience member from Copenhagen highlighted the conundrum of treating OA with pain relief when pain relief actually led to increased mechanical loading. "This is one of the reasons why finding treatments in OA has been so difficult," answered Dr. Felson. "If we treat successfully by diminishing pain we face the increased risk of more loading and then more damage and acceleration of the OA. This might be the explanation for the tanezumab story, in that pain is beautifully ablated only to have some patients go on to have rapid joint destruction."

He added that he thought this was an argument in favor of biomechanical therapies that aimed to address the underlying etiology. "This would enable loading that is healthier to the joint and to promote more levels of activity."

The congress was sponsored by Osteoarthritis Research Society International.