FRACTURE OF THE SUBCHONDRAL

BONE IN OSTEOARTHRITIS OF THE

KNEE

ADVISER:

Dr. dr. R. Fx. Hendroyono, SpOT, MARS, FAAOS

COMPILED BY:

MUHAMAD REDZUAN BIN JOKIRAM

030.08.281

KEPANITERAAN KLINIK ILMU BEDAH

RUMAH SAKIT UMUM DAERAH KOTA BEKASI

FAKULTAS KEDOKTERAN UNIVERSITAS TRISAKTI

PERIODE 3 SEPTEMBER – 10 NOVEMBER 2012

TABLE OF CONTENTS

CHAPTER I PREFACE

1.1...............................................................................................................................................2

CHAPTER II REVIEW OF THE LITERATURE

2.1 Anatomy...............................................................................................................................3

2.2 Physiological bases of bone regeneration............................................................................8

2.3 General changes in bone in osteoartritis.............................................................................10

2.4 Osteoblasts and osteoarthritis.............................................................................................11

Biomechanical Aspects

2.5 Ranges of physiological forces on joint cartilage..............................................................13

2.6 Supranormal stress and strain can lead to injury................................................................14

2.7 Changes in biomechanical properties with age..................................................................14

2.8 Chondrocyte response to mechanical loading....................................................................15

2.9 Chondrocyte response to pathological forces.....................................................................15

CHAPTER III CONCLUSION

..................................................................................................................................................17

CHAPTER IV REFERENCES

..................................................................................................................................................18

1

CHAPTER I

INTRODUCTION

Osteoarthritis (OA) is a degenerative joint disease characterized by pain, cartilage loss, and

joint stiffness. Although OA has long been considered to be primarily a cartilage disorder

associated with focal articular cartilage degradation, this disease is accompanied by well-

defined changes in the subchondral and periarticular bone, including sclerosis and cyst and

osteophyte formation (1). Osteoarthritis (OA) represents a clinical classification of

pathological conditions involving a progressive degeneration of articular cartilage, a

remodelling of sub-chondral bone and a synovitis which is usually limited.

The condition is variously described as a part of a process of age-related change or a disease.

It is twice as prevalent in women than men and increases in incidence with age, there being a

major rise after 60 years (2). It is believed that the changes that lead to the development of OA

are slow (insidious). That in idiopathic OA clinical presentation may result from changes

over 15-20 years. The disease may involve primarily one or two large joints or may be

generalized. Following joint trauma there is an increased incidence of OA (2). The importance

of the bone changes in the initiation and progression of OA is still being debated. It has been

suggested that increased subchondral bone stiffness reduces the ability to dissipate the load

and distribute the strain generated within the joint. This increases peak dynamic forces in the

overlying articular cartilage and can accelerate its damage over time (3). The functional

integrity of the articular cartilage can therefore depend on the mechanical properties of the

underlying bone. Accordingly, cartilage damage leads to full-thickness cartilage loss only

upon repetitive loading over an already stiffened subchondral bone plate (4).

Recent studies have demonstrated increased subchondral bone turnover accompanied by

specific architectural changes in the subchondral trabecular bone in OA joints (5,6).

Furthermore, epidemiologic studies have clearly documented increased subchondral bone

sclerosis with disease progression (7). These observations suggested a role for subchondral

bone changes in the initiation and progression of OA, raising the possibility that early

intervention that reduces bone sclerosis might retard the progressive loss of articular

cartilage.

2

CHAPTER II

REVIEW OF THE LITERATURE

2.1 ANATOMY

Composition of diarthrodial

joint components

To fully comprehend the effect of

chondrocyte metabolism on joint

integrity and its role in synthesis

of multiple proteins involved in

joint homeostasis, we first discuss

the main components of normal

diarthrodial joints: articular

cartilage, synovial fluid,

subchondral bone and the synovial

membrane.

Articular cartilage composition

Articular cartilage, or hyaline cartilage, is designed to bear and distribute loads on the bone

surfaces inside joints, and is composed of a solid phase, including the extracellular matrix

(ECM) and chondrocytes, and a fluid phase, the interstitial fluid, containing water and small

electrolytes, which are primarily Na+ and Cl-.(8) The ECM consists of a highly hydrated

collagen network and of proteoglycan aggregates. The interstitial fluid contains water and

ions. Less than 5% of the tissue volume of cartilage consists of chondrocytes, that are

responsible for maintaining the homeostasis with regard to the cartilage components. (9)

Chondrocytes represent the only cell type inside articular cartilage, as cartilage tissue is not

vascularised or innervated.

The collagen network consists primarily of collagen type II fibrils, and also contains minor

amounts of type I, V, IX and XI fibrils.(10) Collagen is an important contributor to the tensile

3

properties of the cartilage, where proteoglycans attract electrolytes in the interstitial fluid to

generate a swelling pressure and to resist compressive loads.(11) Thus, the solid components of

cartilage have a low permeability for water, while there is continuous interaction with water

through covalent, ionic and hydrogen bonding, resulting in a high interstitial fluid

pressurisation, which is essential for adequate distribution of the loads inside the joint.8

Proteoglycans consist of a core protein to which one or more glycosaminoglycan (GAG)

chains are attached. The most abundant proteoglycan in articular cartilage is the large

aggregating aggrecan, having numerous GAGs attached to its long core protein, mainly

chondroitin sulphate (CS) and keratan sulphate (KS).(12) Another GAG in articular cartilage is

hyaluronan (HA), which has its major function in synovial fluid viscosity.(13) Proteoglycan

molecules form aggregates by binding to hyaluronic acid molecules, and together with

collagen they form the dense ECM network.(11) Smaller, nonaggregating proteoglycans in

articular cartilage are for instance fibromodulin, decorin and biglycan.(14,15)

The articular cartilage surface, also called the superficial or tangential zone, encompass 10-

20% of the articular cartilage thickness and has the highest collagen and interstitial fluid

content.(8,9)In this zone, the collagen fibrils are arranged parallel to the articular surface,

creating a low compressive modulus, meaning that this layer is easily deformed. (11)

Chondrocytes in the surface zone produce relatively little proteoglycans, and synthesise more

collagen type II and smaller proteins with lubricating and protective functions, such as the

superficial zone protein (SZP).(16,17)

The middle zone of the articular cartilage accounts for 40-60% of the cartilage thickness.7

Collagen fibrils in this zone are thicker and packed more loosely than in the superficial zone,

and are obliquely oriented to the cartilage surface. The compressive modulus of the tissue is

higher in this layer.(11)

The radial or deep zone fills 30% of the cartilage thickness and contains collagen fibrils with

a large diameter that are oriented perpendicular to the surface.(9)This layer has the highest

compressive modulus and also contains the most proteoglycans, and less water, compared to

the other zones.(8,11) Chondrocytes in this zone are 10- fold more synthetically active than in

the superficial zone.(18)

4

Below the deep zone is a layer of calcified cartilage, which contains rather collagen type X

than collagen type II, and here is also the tide mark, which lays directly on the subchondral

bone.(19)

As already mentioned, chondrocytes synthesise the cartilage compounds with varying ratios

in the distinct zones, and these cell populations are therefore very heterogeneous, also with

regard to size and shape, according to their position in the cartilage. Besides, the behaviour of

chondrocytes is influenced by the age, pathology or mechanical stress of the surrounding

cartilage,(20) which will be further discussed in the section about the effect of joint loading on

chondrocyte metabolism .

Subchondral bone composition

Directly below the calcified cartilage layer and the tide mark is the interface with the

subchondral bone plate, which separates the articular cartilage from the bone marrow.(19)

Below this dense bone plate is a subarticular spongiosa, with its trabecular or plate-like bone

structures enclosing spaces between them. Near the subchondral bone-cartilage interface,

these spaces are very narrow, and deeper in the bone they are considerably enlarged.

Articular cartilage is supported by the underlying bone in both a biomechanical and

biochemical way.(21)Biomechanically, the rigid bone, mainly composed of collagen type I,

gives strength support to the soft and compression-sensitive articular cartilage, and attenuates

the loads to a much greater extent than cartilage.(19) The quality of subchondral bone directly

influences the response of cartilage to load, which is illustrated by the effect of an increased

5

bone density, which often leads to OA, because bone with a higher density is very stiff and

lays more load on the articular cartilage, resulting in cartilage damage.(22)

Subchondral bone is highly vascularised, especially in regions that experience considerable

mechanical load. Cartilage has no blood supply, but exchange of nutrient solutions is possible

between subchondral bone and articular cartilage by crossing of blood vessels into the

calcified cartilage layer through openings in the bone at the subchondral interface. (19,21) If a

region in the calcified cartilage is devoid of blood vessel entry from the subchondral bone

plate, the chondrocytes in this region are dependent on diffusion of nutrients from the

synovial fluid through the cartilage matrix, which is also the case for the superficial, middle

and deep cartilage zones.

Synovial fluid composition

The joint cavity of diarthrodial joints is filled with synovial fluid, which is a dialysate of

blood plasma containing additional proteins that are synthesised in synoviocytes and

chondrocytes. Synovial fluid has various functions, including cartilage lubrication, and

facilitation of transport of nutrients, waste products, enzymes, cytokines, growth factors and

morphogens to maintain joint homeostasis and to allow communication between distinct cell

populations within the joint.

Since synovial fluid is a dialysate of blood plasma, the major protein components are

identical, except for the larger plasma proteins, because the synovial membrane hinders these

from entering the synovial fluid compartment.(23) Albumin, as well as β1, γ, α1 and α2

globulins and transferrins are the major protein components of synovial fluid. (24) There are

also pro- and anti-inflammatory cytokines and growth factors present, which have important

roles in regulation of the local cell populations.(23) Additionally, synovial fluid contains

several lubricant molecules that are synthesised and secreted by synoviocytes or

chondrocytes, including HA and proteoglycan-4 (PRG-4).(23) HA is a GAG that contributes to

the viscosity of the synovial fluid, and thereby prevents fluid outflow to maintain the synovial

volume, and the two variants of PRG-4, SZP and lubricin, are glycoproteins that mediate

boundary lubrication of the articular cartilage.(13,17) SZP is uniquely expressed in chondrocytes

in the superficial zone of cartilage, and lubricin and HA are synthesised by fibroblast-like

synoviocytes at the luminal surface of the synovial membrane.(17,25,26) There are also few

leukocytes, lymphocytes, macrophages and macrophagic synoviocytes in the synovial fluid.(23,27) Macrophagic synoviocytes are of bone marrow origin and can phagocytose cell debris

6

and other wastes, and have an antigenpresenting function.(26,27) Synovial fluid further contains

matrix metalloproteinases (MMPs), amounts of a distintegrin and metalloproteinase with

thrombospondin motifs (ADAMTS) and tissue inhibitors of metalloproteinases (TIMPs), that

are produced by chondrocytes and synoviocytes, and together determine the extent of ECM

maintenance and breakdown in the articular cartilage.(28)

The synovial fluid is in direct contact with the articular surface and with the synovial

membrane, and, in some joints, also with the meniscus and with ligaments. Therefore, in

various arthropathies, major changes occur to the synovial fluid composition, which is

exacerbated by or contributes to the pathology. In most arthropathies, including OA,

rheumatoid arthritis (RA) and posttraumatic arthritis, the protein concentration in the synovial

fluid is increased, and larger proteins are present inside the fluid as well. (24) This points to a

changed permeability of the synovial membrane during disease.(23) Thus, the synovial

membrane plays important roles in maintaining the joint homeostasis as well.

Synovial membrane composition

The synovial membrane is composed of two layers, including an outer vascularised and

innervated fibrous capsule which contains fibroblasts, macrophages, adipocytes and mast

cells, and an inner layer, the synovial intima, that covers the outer layer. (26,27) The intima

contains the earlier mentioned fibroblast-like synoviocytes, which are specialised to

synthesise HA, and the macrophagic synoviocytes, within an ECM composed of collagen,

HA and proteoglycans.(23,27) As described above, the permeability of the synovial membrane is

the main determinant of plasma protein and water entry into the synovial fluid, but this

barrier also retains the larger synovial fluid contents that are synthesised inside the joint,

including lubricin, SZF and HA.(23) Thus, the synovial membrane physically and functionally

lines the joint edge and provides a homeostatic environment to the cartilage, the subchondral

bone and the synovial fluid. In RA patients, the synovial membrane dramatically increases in

mass and metabolic activity due to hyperplasia of the intima cells, leading to a change in

synovial membrane permeability. The entry of larger plasma proteins into the synovial fluid

has been associated with synovial inflammation, which is characteristic for RA. (29) Indeed, in

OA and in other aetiologies of arthritis, there are changes in synovial membrane permeability

as well, but to a much lesser extent than in RA.(30)

2.2 Physiological bases of bone regeneration .

7

1. REMODELING PHASES

Bone remodeling can be divided into the following phases : quiescent, activation, resorption,

formation, mineralization.

1.1 Quiescent phase: said of the bone when at rest. The factors

that initiate the remodeling process remain unknown.

1.2 Activation phase: the first phenomena that occurs is the activation of the bone surface

prior to resorption, through the retraction of the bone lining cells (elongated mature

osteoblasts existing on the endosteal surface) and the digestion

of the endosteal membrane by collagenase action. Once exposed, the mineralized surface

attracts the circulating osteoclasts coming from the nearby vessels.

1.3 Resorption phase: the osteoclasts then begin to dissolve the mineral matrix and

decompose the osteoid matrix. This process is completed by the macrophages and permits the

release of the growth factors contained within the matrix, fundamentally transforming growth

factor beta (TGF-β), platelet derived growth factor (PDGF), insulin-like growth factor I and

II (IGF-I and II).

1.4 Formation phase: simultaneously in the resorbed areas the preosteoblast grouping

phenomena is produced, attracted

by the growth factors liberated from the matrix which act as chemotactics and in addition

stimulate their proliferation . The preosteoblasts synthesize a cementing

substance upon which the new tissue is attached, and express bone morphogenic proteins

(BMP) responsible for differentiation. A few days later, the already differentiated osteoblasts

synthesize the osteoid material which fills the perforated areas.

1.5 Mineralization phase: mineralization begins thirty days after deposition of the osteoid,

ending at 90 days in the trabecular and at 130 days in the cortical bone.

The quiescent or ‘at rest’ phase then begins again.

8

The balance between bone resorption and formation is influenced by such interrelated factors

as genetic, mechanical, vascular, nutritional, hormonal and local.

2.3 General changes in bone in osteoartritis

9

OA involves not only the degeneration of articular cartilage leading to eburnation of

bone but also a synovitis that is usually limited. There is extensive re-modelling of sub-

chondral bone resulting in the so-called sclerosis of this tissue observed radiographically.

These bone changes are often accompanied by the formation of sub-chondral cysts as a result

of focal resorption.The bone changes may also be systemic in nature. The work of Dequeker

and his colleagues (31) has produced evidence of changes in bone metabolism in sites such as

the iliac crest which are suggestive of systematic changes. Analyses of the molecular

composition of OA bone have provided indications of fundamental changes in bone

metabolism (32). Deoxypyridinoline cross-links, resulting from bone resorption, are elevated in

urine (33) as is osteocalcin elevated in serum (34).

There is evidence from scintigraphy to indicate that changes in bone metabolism are

identifiable several years prior to evidence for clinical onset of the disease (35-37). Whether

these changes precede those in cartilage remains to be determined once comparable analyses

can be made of metabolic changes in cartilage metabolism.

The dynamic interplay between bone and cartilage is reflected in how changes in one

tissue may influence the other and thus determine the development of OA. Bone cells from

OA patients can alter chondrocyte metabolism (38). This is most strikingly observed in

osteoporosis, where bone density is reduced by excessive osteoclastic resorption of bone.

Patients with osteoporosis usually show little or no evidence of OA. Moreover, patients with

OA do not usually develop osteoporosis (39-41). These observations may be explainable in part

at the level of biomechanical interactions, indicating that reduced bone density may protect

against degeneration leading to OA.

A principle anatomical feature of OA is the development of osteophytes. The

osteophytes, which have a cap of articular cartilage, and an actively remodelling bone base,

may serve to reintroduce some stability into an otherwise unstable joint.

These form from an endochondral process in sites at the edges of the damaged

articular cartilage. Addition to periosteum in culture or injection in vivo of transforming

growth factor-beta results in expression of the hypertrophic phenotype by newly formed

chondrocytes in periosteal tissue and subsequent mineralization of extracellular matrix (42, 43).

This is an essential requirement for endochondral ossification. Intra-articular injection of

TGF-beta1 induces osteophyte formation (44) .Thus TGF-beta, and probably other bone

10

morphogenetic proteins, may play an important role in osteophyte formation. These bone

morphogenetic proteins are also excessively produced in joint inflammation.

2.4 Osteoblasts and osteoarthritis

Osteoarthritis (OA) is a chronic degenerative joint disease characterized by loss and

degradation of cartilage, inflammation of the synovium and peri-articular bone alteration

consisting of the formation of osteophytes and subchondral bone sclerosis (45,46).Radin and

Rose (1986) were the first to suggest the involvement of the subchondral bone in the

progression and initiation of cartilage degradation. Successive studies have confirmed this

hypothesis and demonstrated the abnormal behaviour and metabolism of OA osteoblasts (47,47,48,50,51) .

Some investigators have examined the molecular basis of bone OA changes by

comparing microarray gene expression profiling of bone obtained from individuals with no

evidence of joint disease and from individuals with degenerative hip OA(52) . Several genes

that influence osteoblast function, bone remodelling and mineralization exhibit a different

expression in OA. Many of these genes are components of the Wnt and TGF-β/BMP

signalling pathway. Moreover, a subset of genes are differentially expressed between females

and males; this might in part explain the sex disparity in OA.

La Jeunesse’s group has reported elevated alkaline phosphatase activity and increased

osteocalcin levels in primary human OA subchondral osteoblasts (50) and this data has been

confirmed by the results of several clinical ex/in vivo and in vitro studies (53,54,55) . Differences

in the metabolic response to 1,25(OH) Vitamin D3 stimulation, consisting of a significant

increase of osteocalcin after Vitamin D3 treatment, have been found in osteoarthritic

osteoblasts, proportional to the degree of joint damage (53,56,57) ,suggesting that the abnormal

behaviour of OA osteoblasts includes an altered response to systemic or local factors (53) .

Other investigators have distinguished two different groups of OA osteoblasts: low

OA osteoblasts, associated with low levels of prostaglandin E2(PGE2) and IL-6, similar to

normal cells, and high OA osteoblasts associated with high levels of PGE2 and IL-6 (58) .

Recent data have suggested a close relationship between the OPG/RNK/RANKL system and

the subchondral bone changes observed in OA. Studies performed on osteoblasts derived

11

from patients with OA have demonstrated an abnormal expression of OPG and RANKL and

consequently OPG/RANKL ratio (59,60) .Low OA osteoblasts show a marked decrease in OPG

and increased level of RANKL, whereas high OA osteoblasts exhibit a marked increase of

OPG and a reduction of RANKL-t (61) .Moreover, low and high OA subchondral osteoblasts

express membranous and RANKL isoforms differently and are modulated differently by

osteotropic factors (62) .This might explain the different metabolic states of human

subchondral bone osteoblast subpopulations: low OA osteoblasts promote bone resorption,

whereas high OA osteoblasts favour bone formation.

Recently, human osteoblasts derived from subchondral OA bone have been

shown, for the first time, to express ephrin B2 and its receptor EphB4. EphB4 receptor is

expressed in OA osteoblasts and its levels are increased in low OA cells but no differences

have been observed between normal and high OA cells. Moreover, EphB4 activation by the

specific ligand ephrin B2 inhibits the expression of IL-1β, IL-6 and RANKL, but not of OPG (59,60) . These data suggest that the activation of EphB4 by ephrin B2 affects the abnormal

metabolism in OA subchondral bone by inhibiting resorption factors and their activities.

Dequeker’s group (1993) has demonstrated an elevated production of IGF-I, IGF-II

and TGF-β in bone explants from the iliac crest of OA patients. The same results have

subsequently been obtained in vitro (63) .

The altered osteoblast metabolism might also explain the presence of an abnormal

mineralization of subchondral bone in OA. Type I collagen levels are elevated in OA bone

tissue (64) and should lead to excessive mineralization. This might be the reason for the

subchondral bone sclerosis that characterizes OA, even if, in the early stage of disease, this

tissue is hypomineralized. A rapid and aggressive OA has recently been demonstrated to

develop in the Brittle IV (Brtl) mouse model of osteogenesis imperfecta, which is

characterized by a defect in Type I collagen (65) . These data confirm the idea that the

alterations in subchondral bone tissue microarchitecture play a key role in the progressive

destruction of joint cartilage observed in OA. Human OA osteoblasts present increased

collagen type I deposition, but with an altered ratio of α1 and α2 chains, in particular with an

increase of the α1 chain. This abnormal production of type I collagen leads to abnormal

mineralization and can be correlated with the high levels of TGF-β detected in OA

osteoblasts (66) .TGF-β is a potent inducer of osteophytes and acts directly or via the inhibition

of BMP-2-induced mineralization.

12

A human in vitro study has demonstrated the abnormal production of leptin in OA

osteoblasts: leptin expression is increased five-fold in OA osteoblasts compared with normal

osteoblasts (67) .increased production of leptin might be responsible, at least in part, for the

elevated levels of bone markers observed in OA osteoblasts (osteocalcin, alkaline

phosphatase) and confirms the key role of leptin in OA pathophysiology, as previously

demonstrated by the Dumond group (2003).

Biomechanical Aspects

2.5 Ranges of physiological forces on joint cartilage

Human articular cartilage experiences wide ranges of stress and strain during normal joint

loading. Studies using cadavaric limbs loaded in simulated gait have shown that stresses in

the range of 5–10 MPa are normal in the hip, corresponding to loads that are 300–800% body

weight [67-70] . In vivo measurements with an instrumented hip endoprosthesis have indicated

that higher stresses are possible (up to 18 MPa) during other physiological movements,

especially when muscle forces are high [71] .

Accompanying strains during certain regimes of joint loading can also be high. Herberhold et

al. [72] reported decreases of approximately 40% in patella cartilage thickness after 30 min of

static loading of cadaver joints at 3.6 MPa [72] . In loaded areas of knee joints, cartilage

thickness recorded at the end of the day was decreased by up to 0.6 mm compared to the start [73] . This phenomena was attributed to accumulated fluid loss from the matrix of loaded areas

13

2.6 Supranormal stress and strain can lead to injury

In contrast to the above normal ranges of joint forces, stress and strain above the

physiological range have the potential to damage the matrix and chondrocytes. Acute trauma

to the joint is known to increase the risk of osteoarthritis (OA) [74,75] , while destabilization of

the knee joint due to anterior cruciate ligament rupture or meniscal damage causes

radiographic signs of OA in many patients [76,77] . Other mechanical influences that cause

abnormal forces, such as joint laxity, obesity, and muscle weakness, are also linked to the

progression of OA [78] .

In vivo studies have shown that impact trauma can cause osteoarthritic changes. Radin et al. [79-81] impacted patellofemoral joints of rabbits, causing damage to the bone and cartilage and

subsequently leading to OA-like degradation. Even impacts that do not appear to fracture the

bone can result in cartilage degradation [82] .

2.7 Changes in biomechanical properties with age

As age is the most significant risk factor for OA, many studies have examined how the

material properties of cartilage change with age. In individuals without cartilage lesions,

cartilage thickness does not decrease significantly with age in men (–6%, n.s.), but does

decrease in women by approximately 12% (p < 0.05), possibly as a result of the more rapid

decrease in muscle forces with age in females [83] . Femoral head cartilage shows a large

decrease in tensile stiffness and fracture stress with age, whereas talar cartilage (ankle) shows

significantly less degradation in properties [84] . The superficial zone of human condyle

cartilage shows a steady increase in tensile stiffness, peaking in the third decade of life, then

decreasing thereafter [85] . Deep-zone stiffness decreases continuously with age.

As the collagen network has a very low turnover [86] , alterations to it could cause

changes in its mechanical stiffness and fatigue properties, possibly leading to premature

breakdown. The presence of various sugars in the body cause cross-linking of proteins via a

process called nonenzymatic glycation [87] . These cross-links are only significant in tissues

with low turnover where they can build up. In cartilage, the collagen network is affected,

leading to the browning of tissue associated with old age [87] .

14

2.8 Chondrocyte response to mechanical loading

Compression of cartilage causes deformation of cells and matrix, gradients in hydrostatic

pressure, intratissue fluid flow, and associated electrokinetic effects (e. g., flow-induced

streaming potentials). Since the compressive stiffness of chondrocytes is about three orders of

magnitude less stiff than of the surrounding ECM, the cells will deform with the matrix [88] .

The deformation of the charged ECM will change ionic concentrations, osmolarity, and pH of

the cellular environment according to Donnan equilibrium theory [89,90] . Tissue fluid flow

during loading can also dramatically enhance transport of nutrients and macromolecules (e.g.,

growth factors and cytokines [91] . Therefore, mechanical and chemical changes during

loading can alter chondrocyte behavior, and hence matrix synthesis and turnover.

Areas on joints that are more highly loaded during locomotion generally have a

higher proteoglycan content compared to adjacent cartilage experiencing lower stress [92–94] .

However, these highly loaded chondrocytes synthesize less total proteoglycan (although the

synthesis of certain small proteoglycans, especially decorin, is elevated) [90, 95, 96] . Together,

these findings suggest that less proteoglycans are degraded and lost from the cartilage in

these regions. In young and neonatal cartilages, these trends between areas have not been

observed, suggesting that the loading itself is responsible for the change in cartilage matrix

composition and also the zonal variation in chondrocyte phenotype [94, 97] .

2.9 Chondrocyte response to pathological forces

As mentioned previously, traumatic joint injury has been linked to an increased

risk of developing OA in later life. Until recently, little was known about the state of the

chondrocytes or ECM macromolecules in the time between injury to human joints and the

development of disease. Lohmander et al. [98] removed synovial fluid from patients

immediately after an articular cartilage or meniscal tear and up to 15 years postinjury. The

synovial fluid samples were analyzed for the presence of degradative enzymes and fragments

of enzymatically cleaved or intact matrix molecules. The matrix metalloprotease stromelysin-

1 (MMP-3) is thought to be one of the major proteolytic enzymes responsible for the normal

turnover of ECM molecules and the enhanced turnover during disease. In the days following

injury, the level of MMP-3 in the synovial fluid (measured as the latent or proenzyme form)

was elevated by 50–100 times the level in healthy athletes. These levels decreased with time

15

after injury, but remained almost tenfold higher than in uninjured controls even by 10–15

years after injury. Interestingly, the levels of tissue inhibitor of metalloprotease were also

elevated after injury.

Collagen degradation also occurred soon after injury, as indicated by a 15-fold

increase in the amount of MMP up to 15 years after injury, leaved collagen molecules in the

synovial fluid [98] . Cleavage at this site in the C-telopeptide cross-linking domain indicated

that mature, rather than newly synthesized, collagen molecules were being cleaved and

leaving the tissue. Again, these levels remained higher.

CHAPTER III

CONCLUSION

The development of cartilage degeneration is concomitant with subchondral

bone thickness in osteoarthritis, whereas it is related to higher subchondral bone activity and

16

dysregulation in the synthesis of bone proteins. As an immediate consequence, homotrimers

of type 1 collagen are formed that could lead to undermineralization of this tissue. This

dysregulation also leads to abnormal production of different factors by osteoblasts such as

prostaglandins, leukotrienes, and growth factors. Because microcracks or neovascularization

provide a link between the subchondral bone tissue and articular cartilage, these factors could

contribute to the abnormal remodeling of osteoarthritic cartilage.

Lastly, it is clear that a prophylactic response may be required immediately after a

biomechanical insult, rather than when OA symptoms present themselves. Levels of catabolic

cytokines and enzmyes are upregulated almost immediately after injury and stay increased for

many subsequent years. Chondrocytes lose their ability to increase biosynthesis of matrix

components in response to dynamic compression and die through necrosis and apoptosis. One

of the pathways for decreasing the incidence of OA may be ensuring that chondrocyte

response to both physiological and pathological mechanical loads is optimized for longterm

survival of the cartilage.

Recent research has contributed to furthering our knowledge that OA can no longer

be considered a disease of a single tissue but is rather a whole joint Borgan failure.We still

need to acquire a better understanding of these changes and the biochemical signals and

biomechanical aspects between bone and articular cartilage. This in turn will help us to

devise better therapeutics aimed at treating not only the consequences but the causes of OA.

CHAPTER IV

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