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Osteoarthritis and type 2 diabetes mellitus: what are the links?

Alice Courties, Jérémie Sellam

PII: S0168-8227(16)30870-1
DOI: http://dx.doi.org/10.1016/j.diabres.2016.10.021
Reference: DIAB 6785

To appear in: Diabetes Research and Clinical Practice

Received Date: 27 October 2016

Please cite this article as: A. Courties, J. Sellam, Osteoarthritis and type 2 diabetes mellitus: what are the links?,
Diabetes Research and Clinical Practice (2016), doi: http://dx.doi.org/10.1016/j.diabres.2016.10.021

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Osteoarthritis and type 2 diabetes mellitus: what are the links?

Alice Courtiesa,b, Jérémie Sellama,b.

a
Rheumatology Department, Saint-Antoine Hospital, Assistance Publique–Hôpitaux de Paris

(AP-HP), DHU i2B, Paris, France

b
Inserm UMR S_938, Sorbonne Universités Univ Paris 06, DHU i2B, Paris, France

Correspondence to :

Prof. Jérémie Sellam

Abstract words: 190

Word count: 3506

Number of pages: 19

Number of Tables/Figures: 3

1
Abstract

Osteoarthritis (OA) is the most frequent joint disorder and one of the leading cause of

disability. During a long time, it was considered as the consequence of aging and mechanical

stress on cartilage. Recent advances in the knowledge of OA have highlighted that it is a

whole joint disease with early modifications of synovium and subchondral bone but also that

it is associated with obesity and metabolic syndrome through systemic mechanisms. In the

past year, type 2 diabetes has been described in two meta-analyzes as an independent risk

factor for OA. In vivo models of diabetes corroborated epidemiological studies. Indeed,

diabetic rodents display a spontaneous and a more severe experimental OA than their non-

diabetic counterparts, which can be partially prevented by diabetes treatment (insulin,

pioglitazone). The negative impact of diabetes on joints could be explain by the induction of

oxidative stress and pro-inflammatory cytokines but also by advanced age products

accumulation in joint tissues exposed to chronic high glucose concentration. Insulin resistance

might also impair joint tissue because of a local insulin resistance of diabetic synovial

membrane but also by the systemic low grade inflammation state related to obesity and

insulin resistant state.

Keywords: osteoarthritis, metabolic syndrome, diabetes mellitus, oxidative stress, glucose

2
 1. Introduction

Osteoarthritis (OA) is the most frequent musculoskeletal disease leading to joint pain,

stiffness and disability. Worldwide estimates are that 9.6% of men and 18.0% of women aged

≥60 years have symptomatic OA. It is expected to be the fourth cause of disability by 2020

and so it represents a public health challenge of the future years [1]. OA is a chronic joint

disease targeting particularly lumbar spine, knee, hand and hip joints. It is characterized by a

loss of cartilage associated with bone hypertrophy and sclerosis and with synovial

inflammation. During a long time, ageing and mechanical stress were considered as the single

risk factors. However, recent advances in the knowledge of OA has highlighted the

involvement of other risk factors such as type 2 diabetes or dyslipidemia, currently included

in the so-called metabolic syndrome (MetS), defining thus a new phenotype called metabolic

OA, wider than obesity-related OA [2]. For some, obesity and metabolic syndrome increased

the risk of knee and hip OA because of the related mechanical impact of overweight on those

weight-bearing joints[3–5]. But, surprisingly, obesity or metabolic syndrome also increased

the risk of hand OA [6–8] and, occurrence of metabolic disturbances associated with obesity

aggravates the association between obesity and OA. Such new data opened to the idea that

metabolic diseases could have a systemic influence on joint tissues, similarly to what happens

for atherosclerosis. In this context, two recent meta-analyzes reported that type 2 diabetes was

an OA risk factor, whatever the localization[9,10]. Moreover, during these last years, several

in vitro and in vivo studies were published to decipher the influence of hyperglycemia and

insulin resistance on joint tissues. High glucose exposure displays a local toxicity on joint

tissue, increasing locally oxidative stress, cytokines, proteolytic enzymes production and

advanced end glycation products (AGE) accumulation[11–13]. Furthermore, human synovial

tissues from diabetic patients are insulin resistant and so potentially less responsive to the

anti-inflammatory and anti-degradative effect of insulin[14]. Finally, in the field of metabolic

3
syndrome, visceral obesity and insulin resistance are associated with a systemic low-grade

inflammation state, which may also participate to OA development. In this review, we will

develop the available evidence of an association between OA and diabetes, that could thus

delineate sub-phenotype within the metabolic OA: the diabetes-induced OA.

2. OA phenotypes classification

Main OA risk factors are age, joint traumatism/injury, family history of OA corresponding to

the genetic component, obesity and metabolic syndrome. They subsequently defined different

phenotypes which are: OA related to ageing, post-traumatic OA, genetic OA and metabolic

OA (Table 1) [2]. This classification is based on the fact that OA affects different population

depending on the risk factors involved which, intuitively, may imply also different pathogenic

pathways and, in the future, specific therapeutic management.

3. Pathophysiology of OA: not only a cartilage disease but a “whole-joint” disease

OA is a complex joint disease, affecting all joint tissues that are articular cartilage,

subchondral bone and synovium. During a long time, it was considered as a “degenerative”

and mechanical disease but OA is associated with a local and systemic low-grade

inflammation state. The different risk factors are responsible for biological and/or mechanical

aggressions, which influence the homeostasis of all tissues and cells.

Articular cartilage is composed of and extracellular matrix that contains a single type of cell:

the chondrocyte - which is responsible for the synthesis of this extracellular matrix

(anabolism). This matrix is mainly composed of water, proteoglycans and type 2 collagen.

There is a low-grade turnover of components of this matrix due to catabolic activity of

chondrocytes. One of the roles of cartilage is to absorb the mechanical stresses between 2

mobile bone surfaces. In OA, a biological or mechanical stress is followed by an increase of

pro-inflammatory mediators production by chondrocytes (i.e., chondrocyte activation) but

inflammatory mediators, cytokines (interleukin-1 β (IL-1β), IL-6, Il-17, Tumor necrosis

factor-α (TNF- α)), radical oxygen species (ROS), advanced glycation end products (AGE)

and bio-active lipids (prostaglandine E2 (PGE2)) are the most represented. This local

inflammation induces an increase production of the proteolytic enzymes (metalloproteinase

(MMP) and aggrecanases) by all 3 cells (i.e., chondrocytes, synoviocytes and osteoblasts) that

will digest the cartilage matrix. In addition, chondrocytes dedifferentiate and die by apoptosis,

leading to a synthesis of an altered matrix (type 10 instead of type 2 collagen) and to a loss of

matrix synthesis respectively. While physiologically cartilage is non-vascularized, neo-

angiogenesis is promoted in the deep layer of cartilage facilitating the passage of soluble

mediators between subchondral bone and cartilage by specific pro-angiogenic mediators and

leads to the development of vascular channel. In addition to cartilage disruption, subchondral

bone undergoes remodeling with condensation and overgrowth (osteophytes) under the

influence of growth factors such as insulin-growth factor and transforming growth factor.

Finally, synovium inflammation occurs in adjacent area of cartilage degradation due to

cartilage debris. Infiltration of inflammatory cells such as lymphocytes and macrophages are

responsible for overproduction of cytokines, oxidative stress and proteolytic enzymes which

in turn aggravate cartilage degradation creating a vicious circle [15].

4. Type 2 diabetes and OA: epidemiological association

Association between diabetes mellitus and OA was first described in 1961[16]. Since

then, considering all the published literature, the independent association between OA and

type 2 diabetes is quite convincing. The 1st large study with an accurate method exploring this

association was from Schett et al. in 2007[17]. They demonstrated in a large population

based-study that patients with type 2 diabetes had 2 times higher rates of knee or hip

arthroplasty for OA- as a maker of OA severity- than non-diabetics. Beyond the number of

5
subjects included (942 subjects) and the longitudinal follow-up of 20 years, the strength of

this study was the numbers of confounders included such as age, low-grade inflammation (us-

CRP), body mass index (BMI) and other metabolic diseases, physical activity score or prior

joint replacement. They also found that the risk of arthroplasty was correlated with type 2

disease duration and that type 2 diabetic patients had more inflammation of synovium (i.e.,

synovitis) and more pain. Eymard et al. found concordant results since they reported that type

2 diabetes patients had a higher rate of knee OA progression than non-diabetics on a 3 years

follow up[18]. The association between OA and type 2 diabetes is also true for hand,

especially for young patients. Indeed, 55-62 years old patients with type 2 diabetes had a 2

times higher rate of hand OA than non-diabetics and it seems to be associated with pain in

erosive hand OA (i.e., a very destructive hand OA subtype) [6,19].

Some other studies have focused on the glycaemia value and OA. During the 90’s,

Cimmino et al. found that the crude fasting plasma glucose level was higher in OA patients

compared to non OA patients[20] and such a high level could be predictive of OA knee

features using magnetic resonance imagery 10 years later[21]. However, a recent cross-

sectional study failed to find an association between Homeostasis Model Assessment of

insulin resistance (HOMA-IR), HbA1c or insulin levels and OA in patients without glucose-

lowering drugs [22].

All these studies were recently included in two independent meta-analyzes. The first from our

group found a greater risk of OA in type 2 diabetic with an odds ratio (OR) = 1.46 (95%

confidence interval (CI) :1.08 to 1.96) and a higher risk of diabetes in OA population with

OR=1.41 (%95CI: 1.21 to 1.65)[9]. However, studies included did not all adjusted for the

weight, which may be a confounding factor. In the 12 studies adjusting for weight, 7 were

positive meaning that weight could not explain exclusively its association. As well, Williams

6
et al., found that the risk of OA in diabetic patients was higher compared to non-diabetic with

an OR: 1.25 (95% CI: 1.05 to 1.46) including only studies controlling for weight or BMI [10].

Those 2 meta-analyzes has been yet counterbalanced by two recent negative study. The first

study from Nielen et al., explored the risk of total joint replacement (TJR) in a case-control

studies (type 1 and type 2 diabetes versus non diabetic subjects) and found no association

between diabetes and TJR. This may be biased to the fact that practitioners preferred the

conservative treatment in diabetic patients because of their frailty which was illustrated by the

fact that the risk of TJR decreased with increasing HbA1c levels [23]. The 2 nd study from

Frey et al., did not find any association between type 2 diabetes, its duration or severity and

incident hand OA[24]. However, it was based on a UK database with uncertainty of diagnoses

and may have underestimated the number of OA and/or diabetic patients.

Surprisingly, the only data available on the specific association between type 1

diabetes and OA comes from an unpublished data of the 2016 Osteoarthritis research Society

International Congress. This study reported no difference of radiographic hand OA

prevalence between type 1 diabetes and age and sex-matched controls. However, patient with

less controlled type 1 diabetes displayed higher hand pain[25]. The study of the specific

association between type 1 diabetes and OA is of interest because it could evaluate the

influence of diabetes in a population with hyperglycemia but without insulin resistance. Such

a result needs to be further confirmed in other studies.

5. Type 2 diabetes and OA: pathological association

Type 2 diabetes has pathogenic effect through 2 major pathways. First, as for other organs,

chronic hyperglycemia induces oxidative stress, overproduction of pro-inflammatory

cytokines and AGEs in joint tissues but it also reduced the stem cells potential of
7
differentiation. Second, the insulin resistance could play a role locally but also through the

systemic low-grade inflammation state. We will discuss the effect of diabetes and glucose on

the joint tissues and cells.

5.1 Diabetes and cartilage :

The major advances in the knowledge of the role of high glucose concentration on joint

tissues involve mainly chondrocytes and cartilage. Cartilage is a non-vascularized and non-

innervated tissue and receives nutrients from its connection with subchondral bone and

synovial fluid through joint cavity. However, chondrocytes are glycolytic cells and express

glucose transporters (GLUT), especially GLUT-1, GLUT-3 and GLUT-9[26] and are able to

sense the glucose concentration in the media and to adapt the GLUT expression and

membrane incorporation. Under glucose deprivation, normal chondrocytes increased GLUT-1

expression and membrane incorporation whereas they decreased under high glucose

condition. This capacity of normal chondrocytes to adapt themselves to the local glucose level

is lost during OA: this is responsible for a high glucose uptake and potential glucose toxicity

[27]. Furthermore, GLUT expression is under the control of a number factors. Their

expressions raised under pro-inflammatory stimuli as TNF-alpha and IL-1β through

phosphokinase C, but also under metabolic and hypoxic factors [28] which are involved and

increased during OA.

The 1st negative impact of local high glucose concentration is the reduction of the

chondrogenic differentiation of mesenchymal [29] , muscle [30] and adipose-derived stem

[31] cells which may further decrease the potential of regeneration of cartilage that is already

decreased in OA. As well, adipose derived stem cells from diabetic patient had a spontaneous

less chondrogenic differentiation potential than non-diabetic adipose stem cells.

8
Furthermore, chronic high glucose environment has a noxious effect on chondrocytes

metabolism. Human diabetic cartilages produce more IL-6 and PGE2 under IL1-beta

stimulation than non-diabetic cartilage and displayed reduce autophagy and heme oxygenase

expression, 2 anti-oxidant pathways[11,32,33]. As well, high glucose concentration sensitizes

murine chondrocytes to IL-1 beta inducing a higher production of IL-6 and PGE2 through

oxidative stress compare to IL-1 beta in a normal glucose concentration. Aldose reductase and

the polyol pathway seem also involved in this higher responsiveness. High glucose exposure

also increases MMP production especially in human OA chondrocytes and decreases the

production of collagen II. The pro-inflammatory and pro-degradative effect of high glucose

on chondrocyte is partially inhibited by PPAR (peroxisome proliferator-activated receptors)

gamma agonists[13,34] (Figure 2).

Advanced end glycation products (AGEs) may also participate to diabetes-induced

OA. They are known to accumulate in cells and tissues under high glucose concentration. In

vitro, AGEs induced a pro-inflammatory and pro-catabolic phenotype of chondrocytes via

RAGE (receptor of AGE) and toll-like receptor. The activation of these receptors in

chondrocytes induced a decrease of PPAR-gamma and an activation of Nf-kappa B and MAP

kinase pathways [35–38]. AGEs accumulate with age in OA cartilage modifying its

mechanical properties. However, only one in vivo studies showed that AGE accumulate in

cartilage of diabetic streptozotocin (STZ) rats compared to non-diabetic rats [34] and further

studies are needed to demonstrate the implication of AGE in diabetes-induced OA(Figure 2).

Several in vivo models have explored the role of diabetes on OA using type 1 (STZ models)

or type 2 (high fat diet) diabetes models. In type 1 diabetic rats induced by STZ injection,

Atayde et al. reported first that diabetes induces a spontaneous loss of proteoglycan in OA

cartilage compare to non-diabetic rats despite a lower weight in diabetic group[39]. This was

confirmed and reinforced by El Karib et al. study in which 8 weeks after STZ-diabetes

9
induction, not only a loss of proteoglycan but a significant and spontaneous cartilage damage

appeared compared to non-diabetic rat. This diabetes-induced OA could be prevented by

insulin or by a mimicking agent called vanadium in type 1 diabetic rats [40]. As well, PPAR-

gamma agonist (pioglitazone) has been shown to reduce the diabetes-induced OA in STZ

diabetic mice leading also to a decrease of systemic inflammation (IL-6 and AGE)[34].

Using type 2 diabetic rat model, Onur et al. found that diabetic rats spontaneously

developed OA[41]. However, in this model, type 2 diabetic rats had significant higher weight

than non-diabetic, which is a bias. These results should be interpreted with caution even if

Mooney et al. previously showed that, whatever the weight gain was, type 2 diabetes and

obese mice had the same OA scores, probably because of the systemic metabolic disturbances

and low-grade inflammation associated[42]. Finally, in an experimental and mechanical

model of OA due to destabilization of medial meniscus in type 2 diabetic mice, rapamycin, a

pharmacological activator of autophagy, prevented the diabetes-accelerated OA[43].

5.2 Diabetes and synovium

Less is known about hyperglycemia and synovium. High glucose concentration increases

pro-angiogenic factors such as vascular endothelial growth factor (VEGF)

expression in human synovial fibroblasts via oxidative stress, PI3K, Akt, c-Jun and AP-1

signaling pathways [44]. Synovial angiogenesis is known to induce pro-inflammatory cells

locally. Some in vivo diabetic models discussed below have shown that diabetes induce more

synovial inflammation especially in type 2 models than non-diabetic [43]. This is in the line

with the clinical observation of more synovitis in knee OA in diabetic than in non-diabetic

patients using ultrasound examination[17]. Such data have been recently corroborated by

Hamada et al. who reported that the spontaneous OA of type 2 diabetes obese mice under

high-fat diet was in part mediated by synovial overproduction of TNF-α in obese diabetic

10
mice. Furthermore, they showed that human OA fibroblast like-synoviocytes (FLS) expressed

insulin receptor and were responsive to insulin which was able to partially counteract the pro-

inflammatory and pro-degradative effect of TNFα. As insulin response was blunted in FLS

from diabetic patients and TNF expression increased compared to non-diabetics, it could be

possible that, because of their insulin resistant state, the FLS of diabetic patients are more

sensitive to overproduce local TNF α a[14].

5.3 Diabetes and subchondral bone

Most of the studies on the relationship between bone and diabetes were published in

the context of osteoporosis because diabetes is known to decrease bone remodeling. Specific

study of subchondral bone and diabetes are rare. Fasting glucose concentration is associated

with bone marrow lesions (BML) in knee joint in women using MRI [21]. These BML are

known to predict OA structural damages[45]. In diabetic and hypertensive patients with

advanced knee OA requiring arthroplasty, the loss of subchondral bone is increased depicted

by a lower bone mineral density and a higher porosity, independently of weight[46]. Finally,

AGE accumulate in subchondral bone of diabetic patients more than in non-diabetic which

may impact the mechanical resistance of subchondral and display pro-inflammatory

effects[47].

5.4 Diabetes and joint tissues: systemic impact

Insulin resistance and type 2 diabetes are most of the time the consequences of chronic

visceral obesity and meta-inflammation that have been deeply explored [48]. Obesity is not

only associated with knee or hip OA but also with hand OA, raising by 2-fold the risk of hand

OA[49]. As there is no mechanical link possible, it opens to the idea of a systemic association

between obesity and OA. Several mechanisms have been developed in this field. First,

visceral fat mass of obese patient is responsible for a higher production of cytokines,

11
adipokines and acute phase reactant which play a major role in insulin resistance-

related[48,50,51]. As well, this chronic low-grade metabolic inflammation (i.e.,

metainflammation) could be one of the links between insulin resistance and OA. As we

discuss below, inflammatory mediators are involved in OA pathophysiology. Griffin et al.

developed mice models of obesity and insulin resistance using high fat diet and explored their

systemic role on OA development. Under high fat diet, mice developed spontaneous OA

which is inhibited in leptin deficient mice[52]. This demonstrated that the mechanical impact

of weight in obesity-induced OA could not explain all the association. Leptin is one of the

major adipokines, secreted mostly by adipose tissue. Its expression in cartilage increased with

OA severity and its synovial rate is correlated with BMI [53]. In vitro, leptin is able to

promote chondrocytes apoptosis but also to increase cytokines (IL-1β and IL-8)[53,54] or

metalloproteinase [55] production by chondrocytes[56]. They also reported in an high fat diet

model that exercise which do not permit a weight loss -but a decrease in glucose intolerance -

reduced OA progression, meaning that the insulin resistance state related to obesity is

involved in joint damage[57].

Several adipokines has been also studies in the context of obesity and OA (for complete

review see[58]). Indeed, resistin, visfatin (also called nicotinamide phosphoribosyltransferase

Nampt) display pro-inflammatory and pro-catabolic effect in vitro on chondrocytes[59–63]

while the role of adiponectin remains more controversial. In vivo, the local knee injection of

visfatin inhibitor protected mice from mechanical OA[64]. However, no study has focused on

adipokines as a link between OA and diabetes.

Along this line, insulin resistant state and obesity are also associated with elevated free fatty

acids (FFA). The dietary content of FFA may modulate OA progression[65]. In vitro,

palmitate has been shown to display pro-inflammatory effect on chondrocyte through

12
oxidative stress and pro-apoptotic effect[66,67]. Interestingly, a protective effect of n-3

polyunsaturated acid rich diet and a pro-catabolic effect of n-6 polyunsaturated acid and

saturated fatty acid diet was observed in joint mice[68].

Finally, as a new perspective and for now a very hypothetical theory, the role of microbiome

in obesity and insulin resistance has emerged as a crucial actor in the pathophysiology of

these 2 diseases and may be also involved in the metabolic OA. Indeed, OA patients have

higher synovial and serum rate of lipopolysaccaharide (LPS) and LPS-binding protein (LBP)

than non-OA patients. In high fat diet mice, modifications of microbiota correlate with OA

severity[69,70]. These studies could be the emerging evidence of the involvement of

microbiota in metabolic OA.

6. Conclusion and perspectives:

Epidemiological association between OA and type 2 diabetes is robust, beyond their common

association with age or obesity. Type 2 diabetes is now considered as an additional risk factor

of OA. Several mechanisms coming from in vivo and in vitro animal studies but also from

studies of diabetic patients joint tissues support such an association. Diabetes may act on joint

tissues through hyperglycemia and insulin resistance, notably through oxidative stress which

is a therapeutic target in OA in general[71,72]. However, we do not know yet whether

diabetes control and prevention can modulate OA occurrence and progression in humans.

Such an issue needs to be explored for a better personalized care.

Funding: The present work was supported by the ROAD network (Fondation Arthritis

Jacques Courtin). A.Courties was supported by the French Society of Rheumatology and the

Assistance Publique des Hôpitaux de Paris (AP-HP).

Conflicts of interest: A.C : none, J.S : none.

13
Table 1: OA phenotype classification and characteristics, adapted from Bijlsma et al[2].

Post-traumatic OA OA -related to ageing Genetic OA Metabolic OA

Patient age Young (<45 years) Middle-Age (45-65 Variable Old (> 65 years)
years)

Main causative factor Acute Mechanical AGE Polymorphism – Adipokines

Oxidative stress Hyperglycemia

Inflammaging Insulin resistance

FFA and dyslipidemia

Main localization Knee, Ankle, thumb, Hand, knee, Hip Hand, Hip, Spine Generalized, knee,
Shoulder hand, spine

Abbreviations: AGE : Advanced End Glycation products; FFA: free fatty acids; OA : osteoarthritis.

Figure Legends:

Figure 1: Pathological joint features of osteoarthritis. Osteoarthritis is characterized by

impairment of all joint tissues with osteophytes and sclerosis of subchondral bone, synovial

membrane inflammation and cartilage degradation leading to cartilage debris in the joint

cavity.

Figure 2: Diabetes-induced osteoarthritis (OA): involvement of hyperglycemia in local

chondrocyte activation.

14
High-glucose concentration induces advanced glycation end products (AGEs) formation in

cartilage. AGEs interact with receptor of AGE (RAGE) and Toll-like receptor 4 to

downstream peroxisome proliferator-activated receptor gamma (PPAR-γ), which induces

oxidative stress (mitochondrial reactive oxygen species [mROS] and nitric oxide [NO]) and

cytokine release by chondrocytes. AGEs also modify cartilage stiffness and resistance. High-

glucose rate increases metalloprotease (MMP) expression and oxidative stress in

chondrocytes but also synergizes the interleukin 1β (IL-1β) effect on cytokine release.

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