U.S. Department of Veterans Affairs

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.
VA Author Manuscript
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
‡SurgicalService, 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 (Karen.King@UCDenver.edu) and Dr. Rosenthal (arosenthal@mcw.edu) take full
responsibility for the integrity of the work as a whole.
King and Rosenthal Page 2
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

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.

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

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.

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

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.

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.

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.

VA Author Manuscript VA Author Manuscript VA Author Manuscript
Table I
Commonly used rodent models for type 1 and type 2 DM
Model name* (short name) DM type Preferred control Advantages Disadvantages References
C57BL/6-Ins2Akita (Akita) T1DM Same strain background Available on other backgrounds Genetic background modulates DM 50,52–54
phenotype
King and Rosenthal
Streptozotocin (STZ) T1DM Same strain with vehicle treatment Economical Drug toxicity 50,52,55
Can be used in most rodent strains
and other species
Alloxan monohydrate (Alloxan) T1DM Same strain with vehicle treatment Economical Less efficacious than STZ method 49,50,52
Can be used in most rodent strains
and other species
Biobreeding diabetes-prone rat T1DM Biobreeding diabetes-resistant rat (BBDR) Larger size (rat) Will not develop DM in a pathogen-free 58,71
(BBDP) Polygenic environment
80–95% incidence
No sex bias
Diet-induced obesity (DIO) T2DM Same strain with vehicle treatment (low fat Economical Mild or no hyperglycemia 51,64,66
chow) Can model pre-diabetes state
Works well with C56BL/6 and
NON strains
C57BLKS-Leprdb (db/db) T2DM Heterozygous (+/db) littermates One of the most studied models Monogenic 51,59,67
No sex bias Juvenile-onset
Early death
C57BLKS-Lepob (ob/ob) T2DM Heterozygous (+/ob) littermates A well-studied model Monogenic 511,67
No sex bias Mild, short-term hyperglycemia
Zucker diabetic fatty rats (ZDF) T2DM ZDF lean Larger size (rat) Monogenic 51,67
No or mild hyperglycemia
DM in males only
KK.Cg-Ay/J (KKAy) T2DM Homozygous, non-diabetic siblings Polygenic T2DM Females have lower blood glucose levels 68
Maturity onset
NONcNZO10/LtJ (NcZ10) T2DM NON/LtJ, SWR or FVB (Swiss-derived strains) Polygenic T2DM DM in males only 59,60
on low fat diet Maturity onset Requires high fat diet for high penetrance

TALLYHO/JngJ (TH) T2DM NON/LtJ, SWR, or FVB (Swiss-derived Polygenic T2DM DM in males only 59,70,72
strains). Maturity onset
C57Bl/6 strain has also been used. High penetrance
*
Where relevant, the most commonly used background strain is indicated although other backgrounds may be available. DM.
Page 17
Table II
Mechanisms present in diabetes that can damage joint tissues

Potential DM mechanisms Contributing pathways Examples of major Examples of References

mediators molecular
participants
Inflammation AGE/RAGE, innate immune Cytokines, Adipokines, MMPs, TLR 91,92
pathways Reactive oxygen species
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.

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The adverse effects of diabetes on osteoarthritis: update on

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

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

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

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

Other clinical studies of DM and OA

Effect of DM on OA clinical care

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

Effect of DM on human articular tissues

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

Animal models of T1DM

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

Animal models of T2DM

Animal studies investigating a link between DM and OA

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

demonstrating acceleration of joint degeneration in association with metabolic changes

Effects of DM and hyperglycemia on articular cartilage

Effects of DM and hyperglycemia on bone

Effects of DM and hyperglycemia on tendons and ligaments

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

Effects of DM and hyperglycemia on synovium

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

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

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

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

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

Rheumatol. 1996; 23:716–22. [PubMed: 8730133]

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92:929–34. [PubMed: 20595109]

collagen fiber sliding. Matrix Biol. 2013; 32:169–77. [PubMed: 23348249]

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36. [PubMed: 19504240]

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

and diabetic mouse cartilages. J Orthop Res. 2014

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

chondrocytes is regulated by hypoxia and is a physiologically relevant source of ascorbic acid in

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

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

1. Level and consistency of hyperglycemia. Chemically induced models of

cell regeneration. Hyperglycemia drops among some monogenic T2DM

4. Appropriateness of control group. Different background strains may have

5. Comorbid conditions. It may be desirable to have present comorbid

conditions to answer the specific research questions. Scientists should be

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

Commonly used rodent models for type 1 and type 2 DM

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

Mechanisms present in diabetes that can damage joint tissues

Potential DM mechanisms Contributing pathways Examples of major Examples of References

Osmotic stress Polyol pathway Sorbitol p38 MAPK 96,97

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

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