Research Proposal: Nursing Interventions to Decrease complications of Diabetes

The adverse effects of diabetes on osteoarthritis: update on clinical evidence and molecular mechanisms

K.B. King†,‡,1 and A.K. Rosenthal§,‖,*

†Department of Orthopaedics, University of Colorado School of Medicine, Aurora, CO, USA

‡Surgical Service, Orthopaedic Service, Eastern Colorado Health Care System, Veterans Affairs, Denver, CO, USA

§Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA

‖Medicine Service, Rheumatology Service, The Clement J. Zablocki Medical Center, Veterans Affairs, Milwaukee, WI, USA

SUMMARY

Projected increases in the prevalence of both diabetes mellitus (DM) and osteoarthritis (OA)

ensure their common co-existence. In an era of increasing attention to personalized medicine,

understanding the influence of common comorbidities such as DM should result in improved care

of patients with OA. In this narrative review, we summarize the literature addressing the

interactions between DM and OA spanning the years from 1962 to 2014. We separated studies

depending on whether they investigated clinical populations, animal models, or cells and tissues.

The clinical literature addressing the influence of DM on OA and its therapeutic outcomes

suggests that DM may augment the development and severity of OA and that DM increases risks

associated with joint replacement surgery. The few high quality studies using animal models also

support an adverse effect of DM on OA. We review strengths and weaknesses of the common

rodent models of DM. The heterogeneous literature derived from studies of articular cells and

tissues also supports the existence of biochemical and biomechanical changes in articular tissues

in DM, and begins to characterize molecular mechanisms activated in diabetic-like environs which

may contribute to OA. Increasing evidence from the clinic and the laboratory supports an adverse

effect of DM on the development, severity, and therapeutic outcomes for OA. To understand the

mechanisms through which DM contributes to OA, further studies are clearly necessary. Future

studies of DM-influenced mechanisms may shed light on general mechanisms of OA pathogenesis

and result in more specific and effective therapies for all OA patients.

*Address correspondence and reprint requests to: A.K. Rosenthal, Zablocki VA Medical Center, 5000 W. National Avenue, Milwaukee, WI 53295-1000, USA. Tel: 1-(414)-955-7027; Fax: 1-(414)-955-6205. 1Department of Orthopaedics, University of Colorado School of Medicine, 12800 E. 19th Avenue, RC1 North, Room 2101, Mail Stop 8343, Aurora, CO 80045, USA. Tel: 1-(303)-724-1596; Fax: 1-(303)-724-0394.

Conflicts of interest No authors have any conflicts of interest related to this work.

Author contributions Both authors contributed substantially to the conception and design of this work, participated actively in writing the manuscript, and approved the final version. Both Dr. King ([email protected]) and Dr. Rosenthal ([email protected]) take full responsibility for the integrity of the work as a whole.

U.S. Department of Veterans Affairs Public Access Author manuscript Osteoarthritis Cartilage. Author manuscript; available in PMC 2017 July 27.

Published in final edited form as: Osteoarthritis Cartilage. 2015 June ; 23(6): 841–850. doi:10.1016/j.joca.2015.03.031.

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Keywords

Osteoarthritis; Diabetes; Hyperglycemia

Introduction

Diabetes mellitus (DM) and osteoarthritis (OA) are common diseases that are predicted to

increase in prevalence in the US and worldwide1,2. Because of the resultant rise in the

coexistence of these two diseases and a burgeoning body of evidence suggesting that DM

may adversely affect articular tissues and exacerbate OA, it seems an opportune time to

review literature in this area and consider ways in which these diseases interact. The ultimate

goal of this field of study is to understand OA in the diabetic patient in order to individualize

therapies and prognosis for patients having both of these common diseases.

DM is defined by metabolic abnormalities resulting from dysfunction in the glucose-

handling machinery of the body. It occurs in two major forms. Type 1 DM (T1DM) is

caused by reduction in quantities of insulin which regulates glucose metabolism. It is the

most common form of DM in children and may have an autoimmune or post-infectious

etiology. Although type 2 DM (T2DM) may occur in children, it comprises the vast majority

of adult-onset DM. T2DM typically involves insulin resistance at the cellular level. The

metabolic abnormalities of DM are shared by all forms of the disease; effective reduction of

insulin activity causes prolonged hyperglycemia which leads to osmotic and oxidative stress

and results in damage to the kidneys, eyes, nerves, and other tissues. By the year 2035, the

number of adults with DM worldwide is estimated to be 592 million1.

Like DM, OA is also rising in prevalence and affects millions2. It is typically defined as a

degenerative articular process characterized by eroded articular cartilage, altered

subchondral and peri-cartilagenous bone, mild to moderate synovial inflammation, and pain.

While cartilage damage is the final common endpoint in OA, primary abnormalities of other

tissues such as tendon, bone, or muscle may contribute to or even cause OA. DM, especially

T2DM, and OA share many epidemiologic features. They are both complex diseases with

considerable clinical heterogeneity and multifactorial etiologies involving interactions of

genetic and environmental factors. They also share common risk factors. Aging is a risk

factor for both T2DM and OA. The prevalence in the US of DM is 3.3/1000 among

individuals aged 18–44, and rises to 15.4/1000 for ages 65–793. Similarly, OA dramatically

increases with age, affecting 13.5% of adults 25 years and older and 33.6% of those over the

age of 654. Another important risk factor for both diseases is obesity. The association of OA

with obesity is well-supported5, and obesity occurs in the majority of people with T2DM6.

OA and DM frequently co-exist simply by chance due to their high prevalence and shared

risk factors. Nearly half (47.3%) of patients with DM have some form of arthritis7. The

presence of co-morbid conditions typically increases the care needs of individual patients,

decreases the effectiveness of care, and escalates health–related costs. In addition,

therapeutic strategies that emphasize personalized medicine and take into account co-morbid

conditions may result in improved outcomes for patients with OA8. The development of OA

may also complicate DM. While not the focus of this review, there is increasing evidence

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that OA adds to the burden of cardiovascular disease, which is higher than average in DM

patients9.

For this narrative review, we have searched the literature using combinations of the

following key words: “osteoarthritis”, “diabetes”, “hyperglycemia”, “articular cartilage”,

“bone”, “tendon” and “ligament”. We critically assess the literature exploring the effects of

DM on both OA and its management strategies. The few clinical studies addressing this

issue strongly support an association between DM and OA. While animal studies are also

quite sparse and suffer from some methodological weaknesses, they also suggest that DM

may accelerate OA progression. Further, current evidence derived from basic science studies

suggests that DM may adversely affect the homeostasis and repair of articular tissues. These

research studies give credibility to the hypothesis that DM has clinically relevant effects on

OA and warrant further study.

Clinical studies

Population-based studies of DM and OA

There are only a handful of studies that directly address the effects of DM on OA. Two

cross-sectional population-based studies using questionnaires found that DM was

significantly more common in an OA cohort than a non–OA cohort10,11. In contrast, another

study found no increase in DM among OA patients; however, the study subjects’ healthier

lifestyle may have influenced the results12. The observation that specific features of OA may

be more common with DM – such as increased enthesophytes or more severe cartilage

degeneration – supports an interaction between these diseases13,14.

Multiple studies have used rates of arthroplasty as a surrogate for OA severity in examining

the role of DM in OA. In a cohort of patients undergoing arthroplasty for OA, no

relationship was found between T2DM and bilateral OA or generalized OA after adjustment

for age, sex, BMI, and other confounders for OA15. However, the study design based on

cohort analysis of arthroplasty patients limits the conclusions. This is due to two issues; 1) a

bias effect since OA severe enough to require arthroplasty eliminates potential study subjects with early stage OA, and 2) a survivor effect since uncontrolled diabetes may have been a cause to deter study subjects from arthroplasty.

To avoid these effects, two more recent studies examine a cohort of DM patients with non-

DM patients as control16,17. The first study used the Veterans Affairs Health Administration

(VHA) national administrative database, and DM was defined as having two DM-related in-

or out-patient visits or being prescribed anti-diabetic medication16. The cohorts included

450,000 with DM and over 3 million without DM. Rates of total joint arthroplasty were

increased in patients with DM. The statistically significant odds ratios ranged from 1.2

(primary total knee) to 3.4 (revision total hip). When these data were stratified by age, the

highest risk ratios for each joint were found in the youngest age group studied (46–55 years

of age). The major advantage of this study was its size, while the major disadvantage was

that data on body mass index (BMI) were not available. Overall, if one uses arthroplasty as a

surrogate for severe OA, this study suggests that DM has a negative effect on OA by either

increasing its prevalence or by increasing the rate of progression16.

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A similar but smaller study17, analyzed retrospective data from a prospective study with data

collected over 20 years from a regional hospital in Northern Italy. Of the 927 subjects that

began the prospective study, 69 met criteria for T2DM, defined as having a fasting blood

glucose level over 126 mg/dL or a clinical diagnosis with use of anti-DM medication. The

authors found a significant and positive association of DM with arthroplasty; relative risk

was about two and remained significant in models that controlled for age, sex, and BMI.

Using a subset of the same population (347 total, 43 with T2DM), the authors found worse

functional measures in the T2DM group. In particular, the pain variable was significantly

higher in both the KOOS (Knee Injury and Osteoarthritis Outcome Score) and the WOMAC

(Western Ontario and McMaster Universities Osteoarthritis Index) questionnaires. In

addition, knee synovitis was significantly more common in people with DM. The major

advantages of this study were that known risk factors for OA, particularly BMI, were

controlled in the statistical models and that the characteristics of OA (pain, function, and

synovitis) were further probed. The disadvantage of this study was its small population size.

Despite the differences in approach, these two population-based studies both found that DM

doubles the risk for arthroplasty16,17. The VHA database was large enough to determine that

persons with DM have arthroplasty at younger ages16; while the smaller single hospital

study identified that the hazard risk associated with DM remained after adjustment for other

predictors for OA17. Obviously, arthroplasty is not a perfect outcome measure in OA, and

additional clinical studies comparing individual outcome measures such as pain, function, or

structural damage will be necessary in the future.

Other clinical studies of DM and OA

Several recent studies began to approach the role of DM in contributing to important

outcome measures in OA, including OA progression and pain. The effect of DM on OA

progression was recently studied in a cohort of 559 subjects with well-characterized knee

OA18. At baseline, 6.6% of the participants had T2DM. In men with T2DM, annualized joint

space narrowing was statistically significantly higher than in non-diabetic men matched for

BMI, age, hypertension and dyslipidemia. Of all the components of the metabolic syndrome,

only DM was identified as an independent risk factor for knee OA progression. In a study of

530 subjects with radiographic hand OA, primary analysis showed no clear association

between pain and DM19. Subset analysis, however, showed higher pain scores in patients

with DM who had erosive OA defined as radiographic evidence of more than one IP joint

with erosions. The impact of these conclusions is uncertain since the field does not have

standard classification criteria for erosive OA. Certainly, further validation of these findings

in OA is warranted.

Effect of DM on OA clinical care

The impact of DM on clinical care has been studied frequently, with particular attention paid

to the effects of DM on arthroplasty outcomes. Arthroplasty patients with DM sampled from

the Nationwide Inpatient Sample database have increased postsurgical death20,21. In

contrast, older patients in the Medicare database had no increased risk of postsurgical death

with DM22,23. Several studies have identified decreased functional outcomes for arthroplasty

performed on patients with DM24,25. The most commonly reported DM-associated

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complication is the increased rate of infection21,22,25–29. DM may also increase the need for

revision arthroplasty25,30,31. Some arthroplasty outcomes may pertain to metabolic effects

on joint tissues such as defective bone healing, while others reflect general risks of DM

associated with major surgical procedures. All of these effects can add considerable cost to

clinical care20,21,32.

Effect of DM on human articular tissues

Studies of tissues from patients demonstrate that changes capable of promoting OA occur in

articular tissues in patients with DM. For example, ankle cartilage from DM patients was

softer with lower stiffness indices and larger permeability parameters than cartilage from

non-diabetic patients33. Despite the limitations of this study – including the use of frozen

tissues, the focus on a joint infrequently involved in OA, and the significant age difference of

control subjects – the observed changes in biomechanical properties of articular cartilage

might contribute to the development of OA. Advanced glycation endproducts (AGE) may

accumulate prematurely in diabetic tissues and affect biomechanics34–37. A single, small

study using human tissue showed increased levels of the AGE pentosidine in bone from

patients with DM at the time of joint replacement, but no significant changes in pentosidine

levels in cartilage38. Tendon abnormalities may also contribute to OA. DM patients

demonstrate biochemical and biomechanical changes in tendons that include decreased

rupture threshold and disordered collagen fibrils39. There is also mounting evidence that

bone healing is defective in DM patients40–46. Increased rates of non-healing microfractures

in patients with DM may alter bone mechanics and promote OA, and they may also

contribute to poor arthroplasty outcomes. Multiple clinical studies demonstrate increased

fracture risk in post-menopausal women with T2DM which is not simply linked to low bone

mineral density on clinical densitometry41,42. This paradox may be explained by changes in

bone microarchitecture, including increased cortical porosity43, excess mineralization, and

reduced subchondral bone heterogeneity44 with DM. Patients with DM have reduced serum

biomarkers of bone turnover as well as elevated sclerostin levels45,46. Such changes could

lead to increased bone stiffness which could accelerate OA.

Animal studies

The presence of multiple comorbidities and other inherent challenges in designing clinical

studies to delineate mechanisms responsible for increased OA in DM patients have logically

led to the use of animal models of these diseases. While primate and rabbit models of DM

have been described47–49, rodents are most commonly used to replicate human DM50,51.

Very few studies directly address the severity or progression of OA in diabetic animals.

Animal models of T1DM

In T1DM, insulin production is absent or significantly impaired52. Genetic models of T1DM

such as the Akita mouse (C57BL/6-Ins2Akita) are available on several background

strains53,54. A non-genetic and very common method of modeling T1DM is to chemically

damage the pancreatic islets with single or multiple dose regimens of streptozotocin

(STZ)55–57. There are a few rat models of T1DM including the LEW.1AR1/-iddm50 and the

BBDP rat58 both of which involve spontaneous autoimmune pancreatic damage.

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Animal models of T2DM

In order to model human T2DM, the animal should have hyperglycemia non-fasting blood

glucose >250 mg/dL50,51,59,60, insulin insensitivity, and preferably additional characteristics

such as polyuria and polydipsia49,50. Further information on protocols for characterizing

DM in rodents can be found in the literature61,62. However, as with models of T1DM, no

mouse model perfectly mirrors human T2DM disease. The relative contributions of obesity

to acceleration of OA in DM are particularly important in T2DM and its models. While

isolating the biomechanical effects of obesity from the effects of DM is itself a challenge, in

addition, obesity has well-known metabolic consequences that add further complexity to the

situation. These include increased production of inflammatory cytokines such as IL-1,

TNFα, and adipokines (e.g., adiponectin, leptin, and resistin)63 that promote inflammation and may accelerate OA. Because obesity and T2DM almost always co-exist in human

T2DM, animal studies may be particularly useful in separating the pathological

contributions derived from these different mechanisms.

A popular model of T2DM is the diet-induced obesity model (DIO) which attempts to

simulate human obesity-induced T2DM but often results in only modestly increased glucose

levels51,64–66. The db/db mouse, ob/ob mouse, and fa/fa rat have monogenetic defects that disrupt leptin signaling resulting in hyperphagia and morbid obesity67. This leptin signaling

defect is rare in human T2DM60,64,67, and T2DM models created using polygenic mutations

are better models of human T2DM. The KK.Cg-Ay/J mouse was developed by crossing a spontaneously diabetic strain (KK) with the yellow obese strain (Ay) resulting in a mature-

onset T2DM phenotype68. Both DM and control normal glycemic siblings are obese69. The

NONcNZO10/LtJ mouse (NcZ10) is a polygenic model of T2DM with onset of DM in

adulthood. The NcZ10 model requires a chow content of 10–11% fat for higher penetrance

(90–100%)59. The TALLYHO/JngJ mouse (TH) has polygenic and maturity-onset diabetes

and has high penetrance in males59,70. A short list of commonly available rodent models of

T1DM and T2DM is presented in Table I. Readers are encouraged to review additional

details in the references provided.

Animal studies investigating a link between DM and OA

There is an unfortunate paucity of quality research studies in animal models of DM relevant

to OA. A recent study using STZ-induced T1DM in mice suggested the presence of cartilage

damage after 8 weeks of hyperglycemia, and showed elevated levels of circulating AGEs73.

Both abnormalities were ameliorated by the use of the DM drug pioglitazone. The authors

concluded that this drug response implicated PPARγ in this effect, but it was unclear whether this was related to improvement of hyperglycemia or PPARγ inhibition. One valuable study applied the DIO model to the C57Bl/6 strain and made careful measures of

physiological data and histological OA outcomes74. This study combined a high fat diet

(60% by calorie) with the meniscal ligament injury model to induce OA. Higher OA scores

(increased joint degeneration) were found in the mouse group receiving both high-fat diet

and ligament injury. However, since hyperglycemia was not established until the last month

of the experiment, it is unclear whether the hyperadiposity75 or the rising hyperglycemia was

the driving factor for greater OA progression. None the less, this is a valuable study

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demonstrating acceleration of joint degeneration in association with metabolic changes

typically seen in DM patients.

Effects of DM and hyperglycemia on articular cartilage

Biomechanical properties of cartilage are highly influenced by the composition of the

extracellular matrix (ECM), and there is some evidence that metabolic abnormalities

associated with DM alter cartilage ECM. Early studies in animal models of DM have shown

that decreased collagen production76 and increased proteoglycan catabolism77 occurs in DM

cartilage. Increased proteoglycan catabolism in DM animals has also been observed in non-

articular connective tissues78.

Effects of DM and hyperglycemia on bone

Studies showing delayed fracture healing in animals with DM support the ample clinical

data associating DM with bone abnormalities. The STZ mouse model demonstrates that poor

diabetic fracture healing is related to premature resorption of cartilage at the fracture

callus79, and that this was due to high levels of the inflammatory cytokine TNFα in mice with DM80.

Effects of DM and hyperglycemia on tendons and ligaments

Animal models of DM fairly consistently show histologic and biochemical abnormalities in

tendons and ligaments, as well as less well-characterized biomechanical changes, such as

lower Young’s modulus and increased intra-substance failure81–83. Further, several studies

identify delayed tendon healing after injury in the presence of DM84–87. These types of

tendon and ligament abnormalities are known to promote OA88.

Effects of DM and hyperglycemia on synovium

The synovium of T1DM rats is abnormal and contains fibrotic tissue with higher amounts of

type I collagen and lower quantities of types III and V collagen89. Synovial pathology is a

significant contributing factor to OA; early inflammatory changes in the synovium may

cause damage that then creates long-term production of catabolic mediators90.

Potential mechanisms

Basic science studies have also identified some potential mechanisms linked to DM-

influenced end-organ joint damage. Mediators such as hyperglycemia, AGEs, sorbitol,

adipokines, and cytokines act through oxidative, osmotic, and inflammatory mechanisms to

produce tissue damage (Table II). Further complexity is added by the participation of similar

molecular participants in multiple catabolic pathways and the contributions of similar

metabolic derangements in obesity.

An increasing recognition of a key role for inflammation in both OA98 and DM provides an

important mechanistic link between these two conditions. Significant synovitis occurs in OA

and may be exacerbated by the increased levels of inflammatory cytokines, adipokines, and

prostaglandins seen in DM tissues63. Signaling through pathways of innate immunity, such

as toll-like receptors, also may produce inflammation in both DM92 and OA99.

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In a hyperglycemic environment, there is increased production of reactive oxygen species

contributing to tissue damage. Cellular transport of glucose becomes critical and may

contribute to excess oxidative stress. One group found that human OA chondrocytes from

donors aged ≥66 years cultured in high glucose are unable to decrease GLUT1 protein or

reduce glucose transport activity in comparison with normal chondrocytes from young

donors (age 28–35 years)94,100. They also found that high glucose conditions favored

production of oxidants and promoted matrix catabolism which would accelerate OA.

However, age and media osmolarity were not controlled in those experiments101. The effects

of high glucose may be associated with impaired function of ATP-sensitive K+ channels

which couple GLUT to intracellular ATP/ADP levels and membrane potential102,103.

The AGE/RAGE system also plays a role in DM end-organ damage through induction of

inflammation and/or increased oxidative stress. Collagen has an extraordinary low turnover

in many connective tissues and as such is prone to modification by AGEs. The formation of

AGEs is accelerated by high tissue levels of glucose38. AGEs signal through RAGE

(receptor for AGEs) and other receptors to produce various deleterious effects on

chondrocytes including inflammation and cytokine-mediated catabolism104–106 and have

been postulated to play a role in end-organ damage in DM38. Further, AGE mediated cross-

linking of collagen can alter a tissue’s biomechanical properties as shown for cartilage and

tendon35–37. Cross-linking by AGEs may also inhibit ECM turnover by restricting access to

proteolytic sites106. On the other hand, a recent study in dogs suggests that an artificial

increase in AGE levels alone using repeated ribose injections did not accelerate OA in a mild

injury model107, but we know little about the effect of AGEs in the context of the diabetic

milieu. Thus, whether or how AGE’s play a significant role in OA remains unclear.

In the polyol pathway, aldose reductase converts glucose to sorbitol and galactose to

galactitol. This mechanism is activated in DM with excess polyols leading to cellular

osmotic stress108. Although not yet directly linked to OA, there is some evidence that this

pathway is activated in DM in intervertebral disc cartilage and enhances matrix catabolism

via p38 MAPK activation109.

Although not covered in detail in this review, additional DM-relevant pathways have been

proposed. For example, there is considerable evidence that adipokines may induce

inflammation and have adverse effects on cartilage75,110 and tissue healing111. Because

altered adipokine levels are seen in obesity in both the absence and presence of diabetes112,

the contribution of adipokines to OA in obese patients with DM will require further study.

Alteration in angiogenesis, autophagy, and apoptosis are also associated with end-organ

damage in OA58,113–116. Insulin receptors are present on chondrocytes100, and thus, excess

insulin as seen in T2DM patients may also damage cartilage. In one study, PPARγ downregulation was shown to occur in articular chondrocytes exposed to high glucose

media, but methodologic challenges warrant confirmation of this finding73. Whether one or

more pathways are involved, which pathway is most relevant, and how molecular mediators

intersect multiple pathways will require additional study.

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Conclusions

In summary, increasing evidence from the clinic and the laboratory supports an adverse

effect of DM on the development, severity, and therapeutic outcomes for OA. The etiology

and clinical manifestations of OA are complex, and currently we know little about how the

multiple mechanisms altered in DM may affect OA that originates from different causes.

Further, the clinical impact of DM on OA may be underestimated by the high prevalence of

undiagnosed diabetes3. A deeper understanding of OA in the setting of DM could result in

significant improvements in clinical care. For example, reducing OA-related joint pain may

allow DM patients to perform the exercise necessary for cardiovascular health. A full

appreciation of these disease interactions may also reduce the increased medical costs

associated with arthroplasty and other surgeries in patients with comorbid DM20,21,32. To

understand the mechanisms through which DM contributes to OA, further work is clearly

necessary. Future studies of DM-influenced mechanisms may shed light on the general

mechanisms of OA pathogenesis and result in more specific and effective therapies for all

OA patients.

Acknowledgments

We would like to thank the VA Research Service for research space and support (AKR, 101BX000812), an OREF/ Goldberg Arthritis Research Grant (Bucknell and King), and Dr Frank Beier for his thoughtful comments and suggestions on this review.

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As there is no perfect animal model that entirely recapitulates either T1DM or T2DM,

compromises are likely to be required with any one model. Ideally the selected model(s)

should be well characterized in terms of the following:

1. Level and consistency of hyperglycemia. Chemically induced models of T1DM have been known to lose their hyperglycemic state over time due to β- cell regeneration. Hyperglycemia drops among some monogenic T2DM

models.

2. Age at onset of diabetes. T2DM and OA are more common amongst older humans, therefore the use of older animals in these research studies should be

considered and the lifespan of the model should be sufficient to allow

development of OA.

3. Sex differences. There is a gender bias in diabetes severity and age of onset In many rodent models of diabetes.

4. Appropriateness of control group. Different background strains may have greatly different susceptibility to obesity and change in blood glucose.

5. Comorbid conditions. It may be desirable to have present comorbid conditions to answer the specific research questions. Scientists should be

aware that not all DM models have been fully characterized for comorbid

conditions.

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King and Rosenthal Page 17

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Osteoarthritis Cartilage. Author manuscript; available in PMC 2017 July 27.

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King and Rosenthal Page 18

Table II

Mechanisms present in diabetes that can damage joint tissues

Potential DM mechanisms Contributing pathways Examples of major mediators

Examples of molecular participants

References

Inflammation AGE/RAGE, innate immune pathways

Cytokines, Adipokines, Reactive oxygen species

MMPs, TLR 91,92

Oxidative stress Glucose transporters AGE/RAGE Reactive oxygen species GLUT, ATP, ADP 93–95

Osmotic stress Polyol pathway Sorbitol p38 MAPK 96,97

AGE = advanced glycation end products, RAGE = receptor for AGE, MMP = matrix metalloproteinase, TLR = toll-like receptors, GLUT = glucose transporter family, ATP = adenosine triphosphate, ADP = adenosine diphosphate, MAPK = mitogen-activated protein kinase.

Osteoarthritis Cartilage. Author manuscript; available in PMC 2017 July 27.