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Review ArticleReview

The Effect of Aging and Mechanical Loading on the Metabolism of Articular Cartilage

Adam El Mongy Jørgensen, Michael Kjær and Katja Maria Heinemeier
The Journal of Rheumatology April 2017, 44 (4) 410-417; DOI: https://doi.org/10.3899/jrheum.160226
Adam El Mongy Jørgensen
From the Institute of Sports Medicine, Department of Orthopedic Surgery M, Bispebjerg Hospital, and the Department of Biomedical Sciences, Center for Healthy Aging, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
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  • For correspondence: ajoe@dadlnet.dk
Michael Kjær
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Katja Maria Heinemeier
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Abstract

Objective. The morphology of articular cartilage (AC) enables painless movement. Aging and mechanical loading are believed to influence development of osteoarthritis (OA), yet the connection remains unclear.

Methods. This narrative review describes the current knowledge regarding this area, with the literature search made on PubMed using appropriate keywords regarding AC, age, and mechanical loading.

Results. Following skeletal maturation, chondrocyte numbers decline while increasing senescence occurs. Lower cartilage turnover causes diminished maintenance capacity, which produces accumulation of fibrillar crosslinks by advanced glycation end products, resulting in increased stiffness and thereby destruction susceptibility.

Conclusion. Mechanical loading changes proteoglycan content. Moderate mechanical loading causes hypertrophy and reduced mechanical loading causes atrophy. Overloading produces collagen network damage and proteoglycan loss, leading to irreversible cartilage destruction because of lack of regenerative capacity. Catabolic pathways involve inflammation and the transcription factor nuclear factor-κB. Thus, age seems to be a predisposing factor for OA, with mechanical overload being the likely triggering cause.

Key Indexing Terms:
  • AGE
  • OSTEOARTHRITIS
  • BIOMECHANICS
  • CARTILAGE
  • CYTOKINES

Articular cartilage (AC) covers bone surfaces and allows for almost friction-free movement. Unfortunately, AC is susceptible to acute injury and degenerative conditions, e.g., osteoarthritis (OA), and because cartilage has very poor healing potential, OA is a considerable medical challenge. OA is no longer solely seen as 1 single disease, instead 5 OA phenotypes have been suggested, i.e., genetic, metabolic, pain, age, and structural/post-traumatic1. Our narrative review is meant as a covering overview of the main OA phenotypes (related to aging and mechanical loading), and is aimed to include studies of molecular, biochemical, physiological, and clinical designs. To clarify these OA phenotypes, basic information about AC morphology and key components is provided. This is followed by a review of the effect of age and mechanical influence on the morphology, along with the underlying cell signaling, because, as demonstrated, OA is not merely a mechanical/physical “wear and tear” disease. The literature search was performed on PubMed using appropriate keywords regarding exercise/mechanical load, articular cartilage, metabolism/turnover, OA, extracellular matrix, and cell signaling/transduction.

Morphology

AC consists of the chondrocyte surrounded by an extracellular matrix (ECM), subdivided into areas in a pericellular matrix (PCM) immediately adjacent to the cell, a territorial matrix farther away, and an interterritorial matrix2. ECM contains a fibrillar network of both collagens and noncollagenous matrix components embedded in a viscous gel-like ground/basic substance. The fibers are oriented differently and divide the uncalcified AC into 3 zones: superficial zone (SZ) with parallel fiber orientation, intermediate zone (IZ) with random, and finally deep zone (DZ) with vertical orientation. A tidemark represents the DZ transition into the mineralized/calcified fourth zone followed by the subchondral bone below3. The ground/basic substance contains the extracellular fluid and large proteoglycan aggregates built from a single hyaluronan/hyaluronic acid (HA) backbone with some 100 proteoglycans (PG) attached2. Aggrecan contains 3 globular domains (G1–G3). G1 binds noncovalently to hyaluronan stabilized by link protein (Figure 1). G3 is able to bind to matrix proteins, while G2’s function is unknown2. Aggrecan is the major PG in AC, built from a core protein attached with glycosaminoglycans (GAG), mainly chondroitin sulphate (CS) and keratan sulphate (KS), and oligosaccharide chains4. The GAG attract cations and water, resulting in swelling, and are counteracted by the fibrillar network through enzymatic crosslinks, which provide tensile strength and low compliance5. With joint loading, the proteoglycan aggregates are compressed and distribute the force onto the joint surface, thereby reducing the pressure on the AC6. The joint surface is lined/coated with the glycoprotein lubricin/proteoglycan–4 and HA made from both chondrocytes and synoviocytes, which reduce mechanical friction considerably7, thus enabling AC to distribute and transfer force between bones seamlessly.

Figure 1.
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Figure 1.

Schematic illustration of the HA backbone onto which aggrecan attaches with its first globular domain (G1) under the stabilizing influence of LP. Aggrecan contains 3 globular domains (G1–G3), an IGD, a KS-rich domain, and 2 CS-rich domains (CS1 and CS2). Matrix metalloproteinases cleave aggrecan in various regions or sites (a–f), yielding different breakdown products. ADAMTS cleave in the “a-site,” “f-site,” and 4 other sites in the CS2 region. HA: hyaluronic acid; LP: link protein; IGD: interglobular domain; KS: keratan sulphate; CS: chondroitin sulphate.

The influence of aging on articular cartilage

Effect of aging on chondrocytes

Mesenchymal stem cells differentiate into chondrogenic progenitor cells, and after the placement of AC, the chondrocytes remain in a post-mitotic stage8. However, chondrogenic progenitor cells in SZ can migrate to a damaged area, proliferate, and cover this with a continuous sheet and lubricin coating9. Why, then, does AC exhibit such poor healing capacity? With increasing age, more chondrocytes are found in the state of senescence shown by both diminished mitotic activity and telomere length10,11. Diminished telomere length occurs naturally following replications, and by chronic overloading or following a trauma, the chondrocytes undergo proliferation, thereby providing a link between mechanical loading and senescence11.

Exposure of human cell cultures to considerable amounts of mechanical load lead to increased oxidative stress and senescence without a diminished telomere length10. This oxidative stress induces damage to the mitochondria, leading to either senescence or apoptosis, both limiting the functional lifespan of chondrocytes11. Cumulated oxidative stress increases with age12, while the number of chondrocytes drops proportionally13, most profoundly in SZ, possibly because of lubricin loss7. Because chondrocytes are in post-mitotic state, it seems unlikely that the intrinsic/replicative–induced senescence is involved, while the extrinsic/stress–induced seems paramount. With age, the remaining chondrocytes have less ability to synthesize matrix components in response to growth factors, but increase their inflammatory cytokine response14 because of changed sensitivity.

Aging and collagen turnover

The biomechanical stiffness of the collagen network increases with age unrelated to normal enzymatic crosslinking5, but instead proportionally to non-enzymatic crosslinks by advanced glycation end products (AGE)15. Magnetic resonance imaging (MRI) shows that AC in healthy elderly individuals (50–78 yrs) has a diminished capacity for deformation in vivo when compared with younger individuals (20–30 yrs), likely resulting from this increased content of AGE crosslinks and collagen stiffness16. Stiff biomechanics that are nonenzymatic from AGE or enzymatic through extracellular lysyl oxidase have been shown to stimulate cartilage destruction through the Rho-Rho kinase-myosin light chain pathway (Figure 2)17. Further, receptors for AGE found on the chondrocyte with increasing age and OA lead to the activation of the transcription factor nuclear factor-κB (NF-κB; p50/p65) and the synthesis of matrix breakdown enzymes (Figure 2)18.

Figure 2.
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Figure 2.

Simplified overview showing a chondrocyte with various receptors in the cell membrane (double black line) and their downstream effect on processes in the nucleus (broken line). Moderate loading leads to increased activity of FGF-2, IL-4, IL-10, which suppress NF-κB and its catabolic action. These factors also lead to an anabolic response with increased synthesis of aggrecan. Further, a primary cilia along with its other receptors and factors form a complex (PCC; dotted line), which inhibits the catabolism mediated by unloading. Overloading results in the destruction of matrix components leading to the formation of breakdown products (peptides) from FN-f, fibromodulin, decorin, collagen, and COMP that activate integrin receptors as well as TLR. This increases NF-κB action and leads to a catabolic response with synthesis of MMP and aggrecanases (ADAMTS). Biomechanical stiffness leads to activation of the Rho-ROCK-MLC, which inhibits anabolism and promotes catabolism. With increasing age, lubricin expression decreases along with its inhibitory effect on the TLR. Further, increased reactive oxygen species are seen, as well as the accumulation of AGE, which activate RAGE, yet again leading to an NF-κB–mediated catabolic response. NF-κB induces expression of proinflammatory mediators IL-1, IL-6, IL-8, and TNF-α, resulting in an osteoarthritis phenotype with increasing levels of COX-2, iNOS, and thereby PGE2 and NO, as well as collagen type X, VEGF, BMP-2, and TGF-β. This leads to the formation of osteophytes and subchondral changes. FGF-2: fibroblast growth factor 2; IL-4: interleukin 4; NF-κB: nuclear factor-κB; PCC: primary cilia complex; FN-f: fibronectin fragments; COMP: cartilage oligomeric protein; TLR: Toll-like receptors; MMP: matrix metalloproteinases; Rho-ROCK-MLC: Rho-Rho kinase-myosin light chain; AGE: advanced glycation end products; RAGE: receptors for AGE; TNF-α: tumor necrosis factor-α; COX-2: cyclooxygenase 2; iNOS: inducible nitric oxide synthase; PGE2: prostaglandin E2; NO: nitric oxide; VEGF: vascular endothelial growth factor; BMP-2: bone morphogenetic protein 2; TGF-β: transforming growth factor-β; CITED2: CBP/p300-interacting transactivator with ED-rich tail 2; eLOX: extracellular lysyl oxidase; ERK: extracellular signal–regulated kinase; JNK: c-Jun N-terminal kinase; MyD88: myeloid differentiation factor 88; PKC: protein kinase C; ROS: reactive oxygen species.

The content of pentosidine, a known fluorescent AGE, rises linearly after the age of 20 but is undetectable before, indicating that collagen only undergoes significant breakdown and renewal in the first 2 decades5. The collagen turnover was estimated to a half-life of 200–400 years using a racemization approach dependent on temperature, protein structure, and pH19, which therefore may not be conclusive. The carbon-14 bomb-pulse method uses the atmospheric rise in carbon-14 created by earlier nuclear bomb testing, and has shown negligible collagen turnover after adolescence in humans regardless of either disease (OA) or damage20. However, any definitive studies in humans regarding collagen renewal in cartilage remain to be performed.

Aging and aggrecan metabolism

The 2 major enzyme families cleaving aggrecan are the matrix metalloproteinases (MMP) and the real aggrecanases (ADAMTS)21. They have different preferential cleaving sites and produce different fragments or pieces of aggrecan called neoepitopes (Figure 1). These remain attached to the matrix, float around the ECM unattached, or are lost into the synovial fluid by diffusion22. Aggrecan cleaving in the “a-site” and “f-site” is particularly interesting because this leads to complete detachment, leaving only the G1 and part of the interglobular domain (IGD) attached22. In humans, “f-site” cleavage is the initial event21. The IGD contains cleaving sites for MMP and ADAMTS, and it has been proposed that ADAMTS cleave IGD in full-length aggrecan, while MMP do not23. Others have shown that cleavage by MMP happens in a particular order, namely at G3, then both at IGD and between CS1 and CS2 region, then in CS1, between CS1, and KS region, and finally between KS region and G2 (Figure 1)21. This cleaving sequence will lead to diminished amounts of CS because of the elimination of CS2 followed by the CS1 region. The finding of a relatively larger ratio of KS compared with CS with increasing age supports this theory24. In contrast, MMP-induced neoepitopes remain in the matrix, whereas neoepitopes made by ADAMTS do not21. Because breakdown by both MMP and ADAMTS releases both G1 and G3, it can seem unclear why only cleaving by ADAMTS leads to loss, especially when the resulting neoepitopes are larger with both the CS1 and KS regions intact. The difference, then, must lie in the IGD, which is slightly larger when cleaved by MMP, and the N- and O-bound side chains located there must function as linkage21. Thus, aggrecan cleaving by MMP seems beneficial as part of the normal turnover, while ADAMTS results in AC loss21,23. Healthy AC contains a larger amount of MMP-induced neoepitopes with increasing age and supports this conclusion25.

Both PG synthesis and breakdown decrease with increasing age, while pentosidine content rises26. AGE has been a suggested cause. It is speculated that it prevents breakdown enzymes from access either by a conformational change or by steric means26. However, to our knowledge, this has not been proven; rather it might be that AGE accumulation is actually caused by the reduced PG turnover possibly due to senescence. Regardless of the connection to AGE accumulation, it seems clear that PG turnover is decreased as aging occurs. Full-size aggrecan half-life was estimated at 3.2 years with the complete breakdown at 23.5 years27. This supports previous results showing that cleavage of the C-terminal is an early event leading to the accumulation of G1 in AC as aging occurs24.

Aging results in senescence with changed chondrocyte metabolism and reduced turnover leading to mechanical stiffness and thus, susceptibility for damage.

The influence of mechanical loading on AC

Effect of reduced mechanical load on AC composition

In paraplegic patients, MRI of the knees have shown diminished AC thickness between 9% and 13% following 1 year of reduced load28, and partial loading following an ankle fracture leads to thinning of the AC in the knee of the affected leg29. Animal models provide further details, where knee joint immobilization in dogs leads to reduced GAG content, especially from SZ, unaltered collagen content, and AC softening30.

Thus, lack of mechanical stimulation results in thinner and softer AC. This might make the AC more susceptible to traumas because collagen damage occurs earlier in thin cartilage31. Further, in vitro studies suggest that collagen fibrils are more prone to degradation when in a slack state compared with under tension32.

Immobilization has been proven to yield increasing amounts of MMP-133 and MMP-3, with MMP-3 being necessary for the increase in ADAMTS-5 levels also seen with immobilization34. The medial tibial cartilage has the main loss of proteoglycan aggregates in SZ34, thereby keeping in accordance with the morphological changes described in animals. In rats, unloaded passive movements were preventive of this immobilization-derived cartilage atrophy mediated by MMP and ADAMTS-533,34. This rise in breakdown enzymes during unloading could occur because of lack of expression of cAMP-responsive element-binding protein/p300-interacting transactivator with ED-rich tail 2 (CITED2), which inhibits the coactivator p300 leading to synthesis of MMP35. CITED2 expression results from the strain activation of a primary cilia33, with several signaling processes including the mitogen-activated protein kinase (MAPK) extracellular signal-regulated kinase (ERK1/2; Figure 2)35. Another factor could be a lack of interleukin (IL)-4 or IL-10, which hinders their suppressive effect on NF-κB, thus resulting in MMP-induced catabolism (Figure 2).

In dogs, remobilization does not fully restore the stiffness or the GAG content in the areas of the joint without weight-bearing30. Thus, the atrophy only appears partially reversible and prevention thereby seems the best strategy.

Effect of moderate mechanical loading on AC composition

In dogs, moderate running showed increased PG content in DZ36. In humans, an MRI study on 18 adults showed no difference in AC thickness between lifelong highly active triathletes and physically inactive controls, but did show an increase in the total surface areas of tibia and patellar cartilage among the athletes37. Because the area and thereby the volume expand, exercise could preserve the optimal (normal) thickness and thereby deformation capacity as well, and because of the larger surface area, the AC is able to withstand a greater amount of loading and stress6. Using MRI, 12 weeks of either endurance or strength exercise in women aged 40–55 years showed no change in thickness or area in knee cartilage38, while 10 weeks of running showed improvement in composition using delayed gadolinium-enhanced MRI of cartilage index in knee cartilage in women aged 20–40 years39.

The deformation capacity in groups of different training status, i.e., professional weight lifters, bobsled sprinters, and untrained controls, was not shown to differ40. However, increased thickness of the patellar cartilage but not in the remainder of the knee was found with the surface area being equal to controls41. The cartilage of the patella shows a “dose-dependent” deformation with increased loading and range of motion, whereas the tibial and especially the femoral cartilage do not40. Eighty women aged 50–66 years with mild knee OA have, in 2 randomized controlled trials, been subjected to longterm (1 yr) high-impact exercise, which showed improvement of patellar cartilage42 without any change in femoral or tibial cartilage43. The high-impact exercise was measured using an accelerometer, showing little of the impact in the very high region, thus staying within “the safe loading zone” comparable with jumps and sprints43.

Thus, it seems that a trend exists toward increased patellar cartilage thickness in athletes performing power sports, and another trend exists toward larger tibial and patellar surface areas from endurance sports. Further, it appears that younger individuals are able to gain an effect of exercise quicker than older individuals, though the aforementioned results used different MRI techniques and exercise protocols.

Moderate mechanical loading and cell signaling

PCM and the chondrocyte constitutes a metabolically active unit called a chondron with the presence of collagen type VI and the PG perlecan, which all form a mesh-like capsular ultrastructure that modifies the mechanical load reaching each chondrocyte regardless of location44. Fibroblast growth factor 2 (FGF-2) is found in perlecan’s large content of heparan sulfate, and when loaded, FGF-2 is brought into chondrocyte vicinity thereby activating the FGF receptor, which through ERK5 produces an anabolic response (Figure 2)45.

Mechanical stimulation of chondrocytes from human cultures releases IL-4 because of activation of stretch-activated ion channels and integrins and allows IL-4 to work in an auto- and paracrine manner46. Integrins are transmembrane proteins capable of activating internal cell signaling and connecting the chondrocyte to the ECM by forming bonds to, for example, collagen type II, VI, and fibronectin47. IL-4 leads to increased expression of aggrecan and decreased MMP-3 through the activation of phospholipase C and protein kinase C (PKC; Figure 2)48. IL-4 has an antiinflammatory effect and suppresses both IL-1 and tumor necrosis factor-α (TNF-α) by enhancing the breakdown of mRNA for NF-κB49.

IL-10 also has antiinflammatory effects reducing both the formation of IL-1 and TNF-α by suppressing the trans-location of NF-κB, and thus IL-4 and IL-10 work additively49. Enhanced expression of IL-10 has been found following a single instance of resistance exercise in patients with OA, and this response has been proposed as a contributory factor for the beneficial effect of exercise on OA50. Finally, in rats, moderate loading shows increased lubricin regardless of age51, along with reduced apoptosis52.

Overloading and the effect on cartilage composition

Bovine explants containing AC and subchondral bone exposed to mechanical load ex vivo have shown that destruction arises in stages depending on intensity: The earliest damage is softening without collagen loss, next follows collagen loss without visible damage, and finally macroscopic destruction appears31. The physiological interval ranges from 1–3 MPa to 5–7 MPa on average, corresponding to mild to moderate load, which leads neither to softening nor damage. Softening occurs in the range of 9–15 MPa, resulting from the loss of fibrillar cross links, while nonvisual collagen damage follows at 11–36 MPa31, characterized by the loss of PG with the loss of collagen organization and crosslinks from SZ leading to swelling due to an increased amount of water36.

In dogs, overloading because of running showed diminished GAG content both in SZ and IZ, along with softening because of the change in the organization of the collagen network and subchondral bone remodeling36. This results in DZ calcification by tidemark duplication in superficial direction. Finally, the collagen network itself is exposed and broken down, thus marking the irreversible transition to OA3.

A model predicting occurrence and progression of knee OA shows that collagen network damage initiates OA because of abnormal joint mechanics and excessive loading, and progresses depending on body weight53. Of interest, during gait, the load in normal-weight individuals never exceeded 7 MPa, while in overweight people it was always between 7 and 15 MPa. The model did not adjust for age or specific physical activity, which would influence the susceptibility and the actual mechanical load in the knee.

Excessive mechanical loading could begin as low as 7–9 MPa31,33,53. A finite distinction between reversible and irreversible damage is hard to make because inflammation and biomechanical stiffness due to age and genetics also influence AC quality, and thus susceptibility for irreversible damage.

Mechanical overloading and cell signaling

The release of matrix components can be a result of either overloading because of a structural lesion, reduced loading as previously described, or even a product of normal turnover by breakdown enzymes. Fibronectin fragments (FN-f) indicate a damaged ECM, in which the repair process begins with the removal of broken structures before laying down of new ones47. FN-f can activate both integrin and Toll-like receptors (TLR) 2 and 4. The binding of integrin receptor α5β1 leads to activity of PKCδ and subsequently to all 3 MAPK, i.e., ERK1/2, c-Jun N-terminal kinase, and p38α, ultimately yielding NF-κB and resulting catabolism (Figure 2)47. The binding of matrix-breakdown products such as FN-f to TLR2 and TLR4 leads to myeloid differentiation factor 88–dependent activation of the same 3 MAPK, followed by increased NF-κB and the resulting MMP54 and inflammation (Figure 2), which further upregulates TLR55. Matrix-breakdown products from fibromodulin and decorin (members of the small leucine-rich proteoglycans), collagen, or cartilage oligomeric protein can activate both integrins as well as TLR and the complement system, resulting in the same catabolic effect3. On the other hand, TLR2 and TLR4 are inhibited by lubricin56. Finally, high-impact loading (10 MPa) is shown to provide an increase in MMP-1 mediated by p38α33.

As shown simplified and schematically in Figure 2, all catabolic pathways lead to an increased activity of NF-κB, inducing the process of early OA through the effect of IL-1, TNF-α, IL-6, and IL-8, where the chondrocytes acquire a hypertrophic phenotype that resembles endochondral ossification57. It thereby seems that NF-κB could be related to a hypertrophic phenotype, but substantial evidence toward or against this is lacking. It cannot be ruled out that this histological feature could result from increased PG and thus water content in the PCM, giving the impression that the chondrocytes are indeed hypertrophic. If so, the hypertrophic chondrocytes could exhibit mechanical loading different from a normal healthy cell, which would change cell signaling58. In any case, a potential coupling between NF-κB and chondrocyte hypertrophy is yet to be investigated. Further, the chondrocytes have an increased anabolic response with synthesis of matrix elements, but also an increased catabolic response with synthesis of degrading enzymes14 — this might be an attempt at repair, but inevitably results in a reduced matrix.

It is possible that chondrocyte apoptosis occurs as a result of mechanical overloading of the tissue. The proinflammatory mediators cyclooxygenase 2 and inducible nitric oxide (NO) synthase stimulated, for example, by mechanical loading, could lead to increased amounts of prostaglandin E2 and NO, respectively, and thereby to amplified oxidative stress and apoptosis57. Further, mechanical overloading of human cell cultures resulted in increased oxidative stress10, which induces damage to the mitochondria leading to either apoptosis or senescence, thus reducing the number of functional chondrocytes11.

Collagen type X is usually not present in AC, but is seen in OA along with vascular endothelial growth factor (VEGF). VEGF causes the growth of blood vessels from the subchondral bone and thereby calcification of the ECM, and because of the growth factors (bone morphogenetic protein 2 and transforming growth factor-β), both osteophyte formation8,57 and bone resorption are seen (Figure 2)57. With the destruction of SZ, damage propagates through IZ and DZ, ultimately leaving behind a thin lining of AC providing the radiological characteristics of OA with joint space narrowing, osteophytes, and subchondral sclerosis59, marking the endstage and final demise of AC.

DISCUSSION

Increasing age leads to a decline in chondrocyte function due to senescence and hence to a diminished capacity for remodeling and maintenance. This lack of tissue turnover and renewal causes accumulation of AGE, leading to increased stiffness because of these fibrillar crosslinks, followed by a decline in AC deformation capacity and quality, and thereby ultimately to an increased susceptibility for destruction. Age is thus a major predisposing factor for the development of OA.

Within a certain degree, AC can adapt to the amount of mechanical influence in the same way as the rest of the musculoskeletal system — moderate use leads to hypertrophy and maintenance of AC quality while immobilization causes atrophy, both primarily because of changes in the content of PG. Many of the underlying cell signaling mechanisms and pathways have been characterized, showing OA to be both a degenerative and inflammatory disease. Somewhat in contrast with other parts of the musculoskeletal system, mechanical overloading of cartilage causes substantial damage to the collagen network and because of a lack of regenerative capacity, this leads to irreversible destruction and is thus the most apparent triggering cause of OA. Because aging is inevitable, moderate mechanical loading is the best tool to maintain cartilage integrity and health, which can be achieved by different types of activities60, thus reducing or even preventing OA.

Acknowledgment

The authors acknowledge Julie-Charlotte Plovst for her help and efforts in making the figures used in this article.

Footnotes

  • Support has been received from The Danish Rheumatism Association, The Lundbeck Foundation, and The Nordea Foundation (Healthy Aging Grant).

  • Accepted for publication January 11, 2017.

REFERENCES

  1. 1.↵
    1. Bijlsma JW,
    2. Berenbaum F,
    3. Lafeber FP
    . Osteoarthritis: an update with relevance for clinical practice. Lancet 2011;377:2115–26.
    OpenUrlCrossRefPubMed
  2. 2.↵
    1. Heinegård D
    . Proteoglycans and more—from molecules to biology. Int J Exp Pathol 2009;90:575–86.
    OpenUrlCrossRefPubMed
  3. 3.↵
    1. Goldring MB
    . Chondrogenesis, chondrocyte differentiation, and articular cartilage metabolism in health and osteoarthritis. Ther Adv Musculoskelet Dis 2012;4:269–85.
    OpenUrlAbstract/FREE Full Text
  4. 4.↵
    1. Lee HY,
    2. Han L,
    3. Roughley PJ,
    4. Grodzinsky AJ,
    5. Ortiz C
    . Age-related nanostructural and nanomechanical changes of individual human cartilage aggrecan monomers and their glycosaminoglycan side chains. J Struct Biol 2013;181:264–73.
    OpenUrlCrossRefPubMed
  5. 5.↵
    1. Bank RA,
    2. Bayliss MT,
    3. Lafeber FP,
    4. Maroudas A,
    5. Tekoppele JM
    . Ageing and zonal variation in post-translational modification of collagen in normal human articular cartilage. The age-related increase in non-enzymatic glycation affects biomechanical properties of cartilage. Biochem J 1998;330:345–51.
    OpenUrlAbstract/FREE Full Text
  6. 6.↵
    1. Eckstein F,
    2. Hudelmaier M,
    3. Putz R
    . The effects of exercise on human articular cartilage. J Anat 2006;208:491–512.
    OpenUrlCrossRefPubMed
  7. 7.↵
    1. Waller KA,
    2. Zhang LX,
    3. Elsaid KA,
    4. Fleming BC,
    5. Warman ML,
    6. Jay GD
    . Role of lubricin and boundary lubrication in the prevention of chondrocyte apoptosis. Proc Natl Acad Sci U S A 2013;110:5852–7.
    OpenUrlAbstract/FREE Full Text
  8. 8.↵
    1. Goldring MB,
    2. Goldring SR
    . Osteoarthritis. J Cell Physiol 2007;213:626–34.
    OpenUrlCrossRefPubMed
  9. 9.↵
    1. Seol D,
    2. McCabe DJ,
    3. Choe H,
    4. Zheng H,
    5. Yu Y,
    6. Jang K,
    7. et al.
    Chondrogenic progenitor cells respond to cartilage injury. Arthritis Rheum 2012;64:3626–37.
    OpenUrlCrossRefPubMed
  10. 10.↵
    1. Martin JA,
    2. Brown TD,
    3. Heiner AD,
    4. Buckwalter JA
    . Chondrocyte senescence, joint loading and osteoarthritis. Clin Orthop Relat Res 2004;427 Suppl:S96–103.
    OpenUrlCrossRefPubMed
  11. 11.↵
    1. Martin JA,
    2. Buckwalter JA
    . The role of chondrocyte senescence in the pathogenesis of osteoarthritis and in limiting cartilage repair. J Bone Joint Surg Am 2003;85-A Suppl 2:106–10.
    OpenUrlAbstract/FREE Full Text
  12. 12.↵
    1. Loeser RF,
    2. Carlson CS,
    3. Del Carlo M,
    4. Cole A
    . Detection of nitrotyrosine in aging and osteoarthritic cartilage: correlation of oxidative damage with the presence of interleukin-1beta and with chondrocyte resistance to insulin-like growth factor 1. Arthritis Rheum 2002;46:2349–57.
    OpenUrlCrossRefPubMed
  13. 13.↵
    1. Bobacz K,
    2. Erlacher L,
    3. Smolen J,
    4. Soleiman A,
    5. Graninger WB
    . Chondrocyte number and proteoglycan synthesis in the aging and osteoarthritic human articular cartilage. Ann Rheum Dis 2004;63:1618–22.
    OpenUrlAbstract/FREE Full Text
  14. 14.↵
    1. Loeser RF,
    2. Olex AL,
    3. McNulty MA,
    4. Carlson CS,
    5. Callahan MF,
    6. Ferguson CM,
    7. et al.
    Microarray analysis reveals age-related differences in gene expression during the development of osteoarthritis in mice. Arthritis Rheum 2012;64:705–17.
    OpenUrlCrossRefPubMed
  15. 15.↵
    1. Verzijl N,
    2. DeGroot J,
    3. Ben ZC,
    4. Brau-Benjamin O,
    5. Maroudas A,
    6. Bank RA,
    7. et al.
    Crosslinking by advanced glycation end products increases the stiffness of the collagen network in human articular cartilage: a possible mechanism through which age is a risk factor for osteoarthritis. Arthritis Rheum 2002;46:114–23.
    OpenUrlCrossRefPubMed
  16. 16.↵
    1. Hudelmaier M,
    2. Glaser C,
    3. Hohe J,
    4. Englmeier KH,
    5. Reiser M,
    6. Putz R,
    7. et al.
    Age-related changes in the morphology and deformational behavior of knee joint cartilage. Arthritis Rheum 2001;44:2556–61.
    OpenUrlCrossRefPubMed
  17. 17.↵
    1. Kim JH,
    2. Lee G,
    3. Won Y,
    4. Lee M,
    5. Kwak JS,
    6. Chun CH,
    7. et al.
    Matrix cross-linking-mediated mechanotransduction promotes posttraumatic osteoarthritis. Proc Natl Acad Sci U S A 2015;112:9424–9.
    OpenUrlAbstract/FREE Full Text
  18. 18.↵
    1. Loeser RF,
    2. Yammani RR,
    3. Carlson CS,
    4. Chen H,
    5. Cole A,
    6. Im HJ,
    7. et al.
    Articular chondrocytes express the receptor for advanced glycation end products: potential role in osteoarthritis. Arthritis Rheum 2005;52:2376–85.
    OpenUrlCrossRefPubMed
  19. 19.↵
    1. Maroudas A,
    2. Palla G,
    3. Gilav E
    . Racemization of aspartic acid in human articular cartilage. Connect Tissue Res 1992;28:161–9.
    OpenUrlCrossRefPubMed
  20. 20.↵
    1. Heinemeier KM,
    2. Schjerling P,
    3. Heinemeier J,
    4. Møller MB,
    5. Krogsgaard MR,
    6. Grum-Schwensen T,
    7. et al.
    Radiocarbon dating reveals minimal collagen turnover in both healthy and osteoarthritic human cartilage. Sci Transl Med 2016;8:346ra90.
    OpenUrlAbstract/FREE Full Text
  21. 21.↵
    1. Struglics A,
    2. Hansson M
    . MMP proteolysis of the human extracellular matrix protein aggrecan is mainly a process of normal turnover. Biochem J 2012;446:213–23.
    OpenUrlAbstract/FREE Full Text
  22. 22.↵
    1. Vynios DH
    . Metabolism of cartilage proteoglycans in health and disease. Biomed Res Int 2014;2014:452315.
    OpenUrl
  23. 23.↵
    1. Sandy JD
    . A contentious issue finds some clarity: on the independent and complementary roles of aggrecanase activity and MMP activity in human joint aggrecanolysis. Osteoarthritis Cartilage 2006;14:95–100.
    OpenUrlPubMed
  24. 24.↵
    1. Dudhia J,
    2. Davidson CM,
    3. Wells TM,
    4. Vynios DH,
    5. Hardingham TE,
    6. Bayliss MT
    . Age-related changes in the content of the C-terminal region of aggrecan in human articular cartilage. Biochem J 1996;313:933–40.
    OpenUrlAbstract/FREE Full Text
  25. 25.↵
    1. Lark MW,
    2. Bayne EK,
    3. Flanagan J,
    4. Harper CF,
    5. Hoerrner LA,
    6. Hutchinson NI,
    7. et al.
    Aggrecan degradation in human cartilage. Evidence for both matrix metalloproteinase and aggrecanase activity in normal, osteoarthritic, and rheumatoid joints. J Clin Invest 1997;100:93–106.
    OpenUrlCrossRefPubMed
  26. 26.↵
    1. DeGroot J,
    2. Verzijl N,
    3. Jacobs KM,
    4. Budde M,
    5. Bank RA,
    6. Bijlsma JW,
    7. et al.
    Accumulation of advanced glycation endproducts reduces chondrocyte-mediated extracellular matrix turnover in human articular cartilage. Osteoarthritis Cartilage 2001;9:720–6.
    OpenUrlCrossRefPubMed
  27. 27.↵
    1. Maroudas A,
    2. Bayliss MT,
    3. Uchitel-Kaushansky N,
    4. Schneiderman R,
    5. Gilav E
    . Aggrecan turnover in human articular cartilage: use of aspartic acid racemization as a marker of molecular age. Arch Biochem Biophys 1998;350:61–71.
    OpenUrlCrossRefPubMed
  28. 28.↵
    1. Vanwanseele B,
    2. Eckstein F,
    3. Knecht H,
    4. Spaepen A,
    5. Stüssi E
    . Longitudinal analysis of cartilage atrophy in the knees of patients with spinal cord injury. Arthritis Rheum 2003;48:3377–81.
    OpenUrlCrossRefPubMed
  29. 29.↵
    1. Hinterwimmer S,
    2. Krammer M,
    3. Krötz M,
    4. Glaser C,
    5. Baumgart R,
    6. Reiser M,
    7. et al.
    Cartilage atrophy in the knees of patients after seven weeks of partial load bearing. Arthritis Rheum 2004;50:2516–20.
    OpenUrlCrossRefPubMed
  30. 30.↵
    1. Haapala J,
    2. Arokoski J,
    3. Pirttimäki J,
    4. Lyyra T,
    5. Jurvelin J,
    6. Tammi M,
    7. et al.
    Incomplete restoration of immobilization induced softening of young beagle knee articular cartilage after 50-week remobilization. Int J Sports Med 2000;21:76–81.
    OpenUrlCrossRefPubMed
  31. 31.↵
    1. Hosseini SM,
    2. Veldink MB,
    3. Ito K,
    4. van Donkelaar CC
    . Is collagen fiber damage the cause of early softening in articular cartilage? Osteoarthritis Cartilage 2013;21:136–43.
    OpenUrlPubMed
  32. 32.↵
    1. Ruberti JW,
    2. Hallab NJ
    . Strain-controlled enzymatic cleavage of collagen in loaded matrix. Biochem Biophys Res Commun 2005;336:483–9.
    OpenUrlCrossRefPubMed
  33. 33.↵
    1. Leong DJ,
    2. Li YH,
    3. Gu XI,
    4. Sun L,
    5. Zhou Z,
    6. Nasser P,
    7. et al.
    Physiological loading of joints prevents cartilage degradation through CITED2. FASEB J 2011;25:182–91.
    OpenUrlAbstract/FREE Full Text
  34. 34.↵
    1. Leong DJ,
    2. Gu XI,
    3. Li Y,
    4. Lee JY,
    5. Laudier DM,
    6. Majeska RJ,
    7. et al.
    Matrix metalloproteinase-3 in articular cartilage is upregulated by joint immobilization and suppressed by passive joint motion. Matrix Biol 2010;29:420–6.
    OpenUrlCrossRefPubMed
  35. 35.↵
    1. He Z,
    2. Leong DJ,
    3. Zhuo Z,
    4. Majeska RJ,
    5. Cardoso L,
    6. Spray DC,
    7. et al.
    Strain-induced mechanotransduction through primary cilia, extracellular ATP, purinergic calcium signaling, and ERK1/2 transactivates CITED2 and downregulates MMP-1 and MMP-13 gene expression in chondrocytes. Osteoarthritis Cartilage 2016;24:892–901.
    OpenUrl
  36. 36.↵
    1. Arokoski JP,
    2. Jurvelin JS,
    3. Väätäinen U,
    4. Helminen HJ
    . Normal and pathological adaptations of articular cartilage to joint loading. Scand J Med Sci Sports 2000;10:186–98.
    OpenUrlCrossRefPubMed
  37. 37.↵
    1. Eckstein F,
    2. Faber S,
    3. Mühlbauer R,
    4. Hohe J,
    5. Englmeier KH,
    6. Reiser M,
    7. et al.
    Functional adaptation of human joints to mechanical stimuli. Osteoarthritis Cartilage 2002;10:44–50.
    OpenUrlCrossRefPubMed
  38. 38.↵
    1. Cotofana S,
    2. Ring-Dimitriou S,
    3. Hudelmaier M,
    4. Himmer M,
    5. Wirth W,
    6. Sänger AM,
    7. et al.
    Effects of exercise intervention on knee morphology in middle-aged women: a longitudinal analysis using magnetic resonance imaging. Cells Tissues Organs 2010;192:64–72.
    OpenUrlPubMed
  39. 39.↵
    1. Van Ginckel A,
    2. Baelde N,
    3. Almqvist KF,
    4. Roosen P,
    5. McNair P,
    6. Witvrouw E
    . Functional adaptation of knee cartilage in asymptomatic female novice runners compared to sedentary controls. A longitudinal analysis using delayed Gadolinium Enhanced Magnetic Resonance Imaging of Cartilage (dGEMRIC). Osteoarthritis Cartilage 2010;18:1564–9.
    OpenUrlCrossRefPubMed
  40. 40.↵
    1. Eckstein F,
    2. Lemberger B,
    3. Gratzke C,
    4. Hudelmaier M,
    5. Glaser C,
    6. Englmeier KH,
    7. et al.
    In vivo cartilage deformation after different types of activity and its dependence on physical training status. Ann Rheum Dis 2005;64:291–5.
    OpenUrlAbstract/FREE Full Text
  41. 41.↵
    1. Gratzke C,
    2. Hudelmaier M,
    3. Hitzl W,
    4. Glaser C,
    5. Eckstein F
    . Knee cartilage morphologic characteristics and muscle status of professional weight lifters and sprinters: a magnetic resonance imaging study. Am J Sports Med 2007;35:1346–53.
    OpenUrlCrossRefPubMed
  42. 42.↵
    1. Koli J,
    2. Multanen J,
    3. Kujala UM,
    4. Häkkinen A,
    5. Nieminen MT,
    6. Kautiainen H,
    7. et al.
    Effects of exercise on patellar cartilage in women with mild knee osteoarthritis. Med Sci Sports Exerc 2015;47:1767–74.
    OpenUrl
  43. 43.↵
    1. Multanen J,
    2. Nieminen MT,
    3. Häkkinen A,
    4. Kujala UM,
    5. Jämsä T,
    6. Kautiainen H,
    7. et al.
    Effects of high-impact training on bone and articular cartilage: 12-month randomized controlled quantitative MRI study. J Bone Miner Res 2014;29:192–201.
    OpenUrlCrossRefPubMed
  44. 44.↵
    1. Poole CA,
    2. Flint MH,
    3. Beaumont BW
    . Chondrons in cartilage: ultrastructural analysis of the pericellular microenvironment in adult human articular cartilages. J Orthop Res 1987;5:509–22.
    OpenUrlCrossRefPubMed
  45. 45.↵
    1. Vincent TL,
    2. McLean CJ,
    3. Full LE,
    4. Peston D,
    5. Saklatvala J
    . FGF-2 is bound to perlecan in the pericellular matrix of articular cartilage, where it acts as a chondrocyte mechanotransducer. Osteoarthritis Cartilage 2007;15:752–63.
    OpenUrlCrossRefPubMed
  46. 46.↵
    1. Millward-Sadler SJ,
    2. Wright MO,
    3. Lee H,
    4. Nishida K,
    5. Caldwell H,
    6. Nuki G,
    7. et al.
    Integrin-regulated secretion of interleukin 4: a novel pathway of mechanotransduction in human articular chondrocytes. J Cell Biol 1999;145:183–9.
    OpenUrlAbstract/FREE Full Text
  47. 47.↵
    1. Loeser RF
    . Integrins and chondrocyte-matrix interactions in articular cartilage. Matrix Biol 2014;39:11–6.
    OpenUrlCrossRefPubMed
  48. 48.↵
    1. Millward-Sadler SJ,
    2. Wright MO,
    3. Davies LW,
    4. Nuki G,
    5. Salter DM
    . Mechanotransduction via integrins and interleukin-4 results in altered aggrecan and matrix metalloproteinase 3 gene expression in normal, but not osteoarthritic, human articular chondrocytes. Arthritis Rheum 2000;43:2091–9.
    OpenUrlCrossRefPubMed
  49. 49.↵
    1. van Meegeren ME,
    2. Roosendaal G,
    3. Jansen NW,
    4. Wenting MJ,
    5. van Wesel AC,
    6. van Roon JA,
    7. et al.
    IL-4 alone and in combination with IL-10 protects against blood-induced cartilage damage. Osteoarthritis Cartilage 2012;20:764–72.
    OpenUrlCrossRefPubMed
  50. 50.↵
    1. Helmark IC,
    2. Mikkelsen UR,
    3. Børglum J,
    4. Rothe A,
    5. Petersen MC,
    6. Andersen O,
    7. et al.
    Exercise increases interleukin-10 levels both intraarticularly and peri-synovially in patients with knee osteoarthritis: a randomized controlled trial. Arthritis Res Ther 2010;12:R126.
    OpenUrlCrossRefPubMed
  51. 51.↵
    1. Musumeci G,
    2. Castrogiovanni P,
    3. Trovato FM,
    4. Imbesi R,
    5. Giunta S,
    6. Szychlinska MA,
    7. et al.
    Physical activity ameliorates cartilage degeneration in a rat model of aging: a study on lubricin expression. Scand J Med Sci Sports 2015;25:e222–30.
    OpenUrlCrossRefPubMed
  52. 52.↵
    1. Musumeci G,
    2. Loreto C,
    3. Leonardi R,
    4. Castorina S,
    5. Giunta S,
    6. Carnazza ML,
    7. et al.
    The effects of physical activity on apoptosis and lubricin expression in articular cartilage in rats with glucocorticoid-induced osteoporosis. J Bone Miner Metab 2013;31:274–84.
    OpenUrl
  53. 53.↵
    1. Mononen ME,
    2. Tanska P,
    3. Isaksson H,
    4. Korhonen RK
    . A novel method to simulate the progression of collagen degeneration of cartilage in the knee: data from the Osteoarthritis Initiative. Sci Rep 2016;6:21415.
    OpenUrl
  54. 54.↵
    1. Hwang HS,
    2. Park SJ,
    3. Cheon EJ,
    4. Lee MH,
    5. Kim HA
    . Fibronectin fragment-induced expression of matrix metalloproteinases is mediated by MyD88-dependent TLR-2 signaling pathway in human chondrocytes. Arthritis Res Ther 2015;17:320.
    OpenUrl
  55. 55.↵
    1. Kim HA,
    2. Cho ML,
    3. Choi HY,
    4. Yoon CS,
    5. Jhun JY,
    6. Oh HJ,
    7. et al.
    The catabolic pathway mediated by Toll-like receptors in human osteoarthritic chondrocytes. Arthritis Rheum 2006;54:2152–63.
    OpenUrlCrossRefPubMed
  56. 56.↵
    1. Iqbal SM,
    2. Leonard C,
    3. Regmi SC,
    4. De Rantere D,
    5. Tailor P,
    6. Ren G,
    7. et al.
    Lubricin/proteoglycan 4 binds to and regulates the activity of toll-like receptors in vitro. Sci Rep 2016;6:18910.
    OpenUrl
  57. 57.↵
    1. Mariani E,
    2. Pulsatelli L,
    3. Facchini A
    . Signaling pathways in cartilage repair. Int J Mol Sci 2014;15:8667–98.
    OpenUrlCrossRefPubMed
  58. 58.↵
    1. Salter DM,
    2. Millward-Sadler SJ,
    3. Nuki G,
    4. Wright MO
    . Differential responses of chondrocytes from normal and osteoarthritic human articular cartilage to mechanical stimulation. Biorheology 2002;39:97–108.
    OpenUrlPubMed
  59. 59.↵
    1. Goldring SR
    . Alterations in periarticular bone and cross talk between subchondral bone and articular cartilage in osteoarthritis. Ther Adv Musculoskelet Dis 2012;4:249–58.
    OpenUrlAbstract/FREE Full Text
  60. 60.↵
    1. Castrogiovanni P,
    2. Musumeci G
    . Which is the best physical treatment for osteoarthritis? J Funct Morphol Kinesiol 2016;1:54–68.
    OpenUrl
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1 Apr 2017
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The Effect of Aging and Mechanical Loading on the Metabolism of Articular Cartilage
Adam El Mongy Jørgensen, Michael Kjær, Katja Maria Heinemeier
The Journal of Rheumatology Apr 2017, 44 (4) 410-417; DOI: 10.3899/jrheum.160226

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The Effect of Aging and Mechanical Loading on the Metabolism of Articular Cartilage
Adam El Mongy Jørgensen, Michael Kjær, Katja Maria Heinemeier
The Journal of Rheumatology Apr 2017, 44 (4) 410-417; DOI: 10.3899/jrheum.160226
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