Abstract
Osteoarthritis (OA) is the most common degenerative joint disease and a major cause of pain and disability in adult individuals. The etiology of OA includes joint injury, obesity, aging, and heredity. However, the detailed molecular mechanisms of OA initiation and progression remain poorly understood and, currently, there are no interventions available to restore degraded cartilage or decelerate disease progression. The diathrodial joint is a complicated organ and its function is to bear weight, perform physical activity and exhibit a joint-specific range of motion during movement. During OA development, the entire joint organ is affected, including articular cartilage, subchondral bone, synovial tissue and meniscus. A full understanding of the pathological mechanism of OA development relies on the discovery of the interplaying mechanisms among different OA symptoms, including articular cartilage degradation, osteophyte formation, subchondral sclerosis and synovial hyperplasia, and the signaling pathway(s) controlling these pathological processes.
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Introduction
Osteoarthritis (OA) is the most common degenerative joint disease, affecting more than 25% of the population over 18 years-old. Pathological changes seen in OA joints include progressive loss and destruction of articular cartilage, thickening of the subchondral bone, formation of osteophytes, variable degrees of inflammation of the synovium, degeneration of ligaments and menisci of the knee and hypertrophy of the joint capsule.1 The etiology of OA is multi-factorial and includes joint injury, obesity, aging, and heredity.1–5 Because the molecular mechanisms involved in OA initiation and progression remain poorly understood, there are no current interventions to restore degraded cartilage or decelerate disease progression. Studies using genetic mouse models suggest that growth factors, including transforming growth factor-β (TGF-β), Wnt3a and Indian hedgehog, and signaling molecules, such as Smad3, β-catenin and HIF-2α,6–10 are involved in OA development. One feature common to several OA animal models is the upregulation of Runx2.7,8,11–13 Runx2 is a key transcription factor directly regulating the transcription of genes encoding matrix degradation enzymes in articular chondrocytes.14–17 In this review article, we will discuss the etiology of OA, the available mouse models for OA research and current techniques used in OA studies. In addition, we will also summarize the recent progress on elucidating the molecular mechanisms of OA pain. Our goal is to provide readers a comprehensive coverage on OA research approaches and the most up-to-date progress on understanding the molecular mechanism of OA development.
Etiology
OA is the most prevalent joint disease associated with pain and disability. It has been forecast that 25% of the adult population, or more than 50 million people in the US, will be affected by this disease by the year 2020 and that OA will be a major cause of morbidity and physical limitation among individuals over the age of 40.18,19 Major clinical symptoms include chronic pain, joint instability, stiffness and radiographic joint space narrowing.20 Although OA primarily affects the elderly, sports-related traumatic injuries at all ages can lead to post-traumatic OA. Currently, apart from pain management and end stage surgical intervention, there are no effective therapeutic treatments for OA. Thus, there is an unmet clinical need for studies of the etiology and alternative treatments for OA. In recent years, studies using the surgically induced destabilization of the medial meniscus (DMM) model and tissue or cells from human patients demonstrated that genetic, mechanical, and environmental factors are associated with the development of OA. At the cellular and molecular level, OA is characterized by the alteration of the healthy homeostatic state toward a catabolic state.
Aging
One of the most common risk factors for OA is age. A majority of people over the age of 65 were diagnosed with radiographic changes in one or more joints.21–25 In addition to cartilage, aging affects other joint tissues, including synovium, subchondral bone and muscle, which is thought to contribute to changes in joint loading. Studies using articular chondrocytes and other cells suggest that aging cells show elevated oxidative stress that promotes cell senescence and alters mitochondrial function.26–29 In a rare form of OA, Kashin-Back disease, disease progression was associated with mitochondrial dysfunction and cell death.30 Another hallmark of aging chondrocytes is reduced repair response, partially due to alteration of the receptor expression pattern. In chondrocytes from aged and OA cartilage, the ratio of TGF-β receptor ALK1 to ALK5 was increased, leading to down-regulation of the TGF-β pathway and shift from matrix synthesis activity to catabolic matrix metalloproteinase (MMP) expression.31,32 Recent studies also indicate that methylation of the entire genomic DNA displayed a different signature pattern in aging cells.33,34 Genome-wide sequencing of OA patients also confirmed that this epigenetic alteration occurred in OA chondrocytes,35–37 partially due to changes in expression of Dnmts (methylation) and Tets (de-methylation) enzymes.38–40
Obesity
In recent years, obesity has become a worldwide epidemic characterized by an increased body composition of adipose tissue. The association between obesity and OA has long been recognized.41,42 Patients with obesity develop OA earlier and have more severe symptoms, higher risk for infection and more technical difficulties for total joint replacement surgery. In addition to increased biomechanical loading on the knee joint, obesity is thought to contribute to low-grade systemic inflammation through secretion of adipose tissue-derived cytokines, called adipokines.43–45 Specifically, levels of pro-inflammatory cytokines, including interleukin (IL)-1β, IL-6, IL-8, and tumor necrosis factor alpha (TNF-α) were elevated46–50 in high-fat diet-induced mouse obesity models51–54 and in obese patients.55–57 These inflammatory factors may trigger the nuclear factor-κB (NF-κB) signaling pathway to stimulate an articular chondrocyte catabolic process and lead to extracellular matrix (ECM) degradation through the upregulation of MMPs.58–60
Sport injury
Knee injury is the major cause of OA in young adults, increasing the risk for OA more than four times. Recent clinical reports showed that 41%–51% of participants with previous knee injuries have radiographic signs of knee OA in later years.61 Cartilage tissue tear, joint dislocation and ligament strains and tears are the most common injuries seen clinically that may lead to OA. Trauma-related sport injuries can cause bone, cartilage, ligament, and meniscus damage, all of which can negatively affect joint stabilization.62–66 Signs of inflammation observed in both patients with traumatic knee OA and in mouse injury models include increased cytokine and chemokine production, synovial tissue expansion, inflammatory cell infiltration, and NF-κB pathway activation.67
Inflammation
It has been established that the chronic low-grade inflammation found in OA contributes to disease development and progression. During OA progression, the entire synovial joint, including cartilage, subchondral bone, and synovium, are involved in the inflammation process.68 In aging and diabetic patients, conventional inflammatory factors, such as IL-1β and TNF-α, as well as chemokines, were reported to contribute to the systemic inflammation that leads to activation of NF-κB signaling in both synovial cells and chondrocytes. Innate inflammatory signals were also involved in OA pathogenesis, including damage associated molecular patterns (DAMPs), alarmins (S100A8 and S100A9) and complement.69–71 DAMPs and alarmins were reported to be abundant in OA joints, signaling through either toll-like receptors (TLR) or the canonical NF-κB pathway to modulate the expression of MMPs and a disintegrin and metalloprotease with thrombospondin motif (ADAMTS) in chondrocytes.72–76 Complement can be activated in OA chondrocytes and synovial cells by DAMPs, ECM fragments and dead-cell debris.77,78 Recent studies further clarified that systemic inflammation can re-program chondrocytes through inflammatory mediators toward hypertrophic differentiation and catabolic responses through the NF-κB pathway,9,10,79 the ZIP8/Zn+/MTF1 axis,80 and autophagy mechanisms.81–85 Indeed, the recent Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses of OA and control samples provide evidence that inflammation signals contribute to OA pathogenesis through cytokine-induced mitogen-activated protein (MAP) kinases, NF-κB activation, and oxidative phosphorylation.149 and post-traumatic150–152 OA, mechanics of individual chondrocytes,151,153 and quality evaluation of engineered neo-tissues.154–156
Notably, AFM-nanoindentation has made it possible to study the mechanical properties of murine cartilage. Previously, the ~100 μm thickness of murine cartilage prevented such attempts. Because in vivo OA studies are largely dependent on murine models,157 nanoindentation provides a critical bridge across two crucial fields of OA research: biology and biomechanics. The benefit of nanoindentation for murine model studies has been demonstrated by a number of recent studies. For example, cartilage in mice lacking collagen IX (Col9a1−/−)148 showed abnormally higher moduli, while those lacking lubricin (Prg4−/−)158 or chondroadherin (Chad−/−)159 showed lower moduli. Col9a1−/− and Prg4−/− mice also developed macroscopic signs of OA,148,158 underscoring the high correlation between abnormalities in cartilage biomechanics and OA. Li et al. also recently demonstrated the applicability of nanoindentation to the murine meniscus.160 Further applications of nanoindentation to clinically relevant OA models, such as the DMM model,110 hold the potential of assessing OA as an entire joint disease through biomechanical symptoms in multiple murine synovial tissues.
Two other recent technological advances provide paths to further in-depth studies. First, Wilusz et al.161 stained cartilage cryosections with immunofluorescence antibodies of the pericellular matrix signature molecules, type VI collagen and perlecan.162 Using immunofluorescence guidance, nanoindentation was used to delineate the mechanical behavior of cartilage pericellular matrix and ECM,161–163 and to reveal the role of type VI collagen in each matrix by employing Col6−/− mice.164 Therefore, it is now possible to directly examine the relationships across micro-domains between biochemical content and biomechanical properties of cartilage,161 meniscus165 or other synovial tissues in situ. Second, Nia et al.166 converted the AFM to a high-bandwidth nanorheometer. This tool enabled separation of the fluid flow-driven poroelasticity and macromolecular frictional intrinsic viscoelasticity that govern cartilage energy-dissipative mechanics.166–168 Hydraulic permeability, the property that regulates poroelasticity, was found to be mainly determined by aggrecan rather than collagen169 and to change more drastically than modulus upon depletion of aggrecan.166,170 This new tool provides a comprehensive approach beyond the scope of elastic modulus for assessing cartilage functional changes in OA.
Molecules mediating OA pain
The perception of OA pain is a complex and dynamic process involving structural and biochemical alterations at the joint as well as in the peripheral and central nervous systems. While there have been extensive studies of mediators of OA joint degeneration, only recently have studies begun to characterize biochemical influences on and in the peripheral and central nervous systems in OA. In this regard, OA appears to show similarities and differences with other conditions causing pain.171,172 There are a wide variety of signaling pathways linked to joint destruction and/or pain. In this section we will discuss three emerging and highly relevant pathways that provide insight into the mechanisms underlying OA pain.
Chemotactic cytokine ligand 2/chemokine (C–C motif) receptor 2
Chemotactic cytokine ligand 2 (CCL2), also known as monocyte chemoattractant protein 1 (MCP-1), is well-known to mediate the migration and infiltration of monocytes and macrophages by signaling through chemokine (C–C motif) receptor 2 (CCR2).173 In arthritis, CCL2 promotes inflammation of the joint.174 Evidence also suggests that CCL2 is an important mediator of neuroinflammation.175,176 In neuropathic pain, CCL2 expression is increased in microglia and in sensory neurons in the dorsal root ganglia (DRGs), where CCL2 can be further transported and released into central spinal nerve terminals. Increased CCL2/CCR2 signaling has been correlated with direct excitability of nociceptive neurons and microglial activation, leading to persistent hyperalgesia and allodynia.177,178
In a DMM mouse OA model, CCL2 and CCR2 levels were elevated in DRGs at 8 weeks post surgery, correlating with increased OA-associated pain behaviors. Increased CCL2 and CCR2 levels in the DRG were thought to mediate pro-nociceptive effects both by increasing sensory neuron excitability through CCL2/CCR2 signaling directly in DRG sensory neurons and through CCL2/CCR2-mediated recruitment of macrophages in the DRG. Compared with wild-type mice, Ccr2-null mice showed reduced pain behaviors following DMM with similar levels of joint damage.179 Although CCR2 antagonists are currently being assessed in clinical studies, no clinical studies have targeted CCL2 or CCR2 in OA pain.180
Nerve growth factor/tropomyosin receptor kinase A
In both clinical and animal studies, the targeted inhibition of nerve growth factor (NGF) and inhibition of its cognate receptor, tropomyosin receptor kinase A (TrkA), reduced OA pain. Clinically, the systemic administration of NGF caused persistent whole-body muscle hyperalgesia in healthy human subjects,174,177 while anti-NGF antibody, tanezumab, therapy significantly reduced OA pain.181–184 There are a number of potential mechanisms through which NGF mediates pain. Over-expressed NGF in peripheral tissues can bind directly to TrkA at sensory neuron nerve terminals and be retrogradely transported to the DRG. There it stimulates sensory neurons to activate mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signaling.185 The activation of the NGF-MAPK/ERK axis upregulates the expression of pain-related molecules, including transient receptor potential cation channel subfamily V member I (TRPV1), substance P, calcitonin gene-related peptide (CGRP), brain-derived neurotrophic factor (BDNF), and nociceptor-specific ion channels, such as Cav 3.2, 3.3, and Nav1.8.186–188
In addition to direct signaling of sensory neurons, NGF promotes algesic effects by targeting other cell types. For example, NGF/TrkA signaling occurs in mast cells, triggering release of pro-inflammatory and pain mediators, including histamine and prostaglandins, in addition to NGF.186,189 NGF signaling is upregulated by pro-inflammatory mediators, and NGF promotes leukocyte chemotaxis and vascular permeability, further stimulating inflammation.190–192 NGF/TrkA signaling further promotes angiogenesis and nerve growth. The process of angiogenesis is not only inflammatory, but also serves as a track for nerve growth into the joint.193
Given the high efficacy of targeting NGF in a clinical study on reducing OA pain, it is of great interest to further define NGF/TrkA pain signaling mechanisms and to find additional therapeutic targets in this pathway. Recent evidence indicates that loss of PKCδ signaling significantly increases both NGF and TrkA in the DRG and synovium, is associated with increased MAPK/ERK signaling at the innervating DRGs, and is associated with OA hyperalgesia.194 However, in recent clinical studies, a small population of patients treated with systemic anti-NGF therapy exhibited rapid progression of OA and were more prone to bone fractures.195 Considering the analgesic effects by anti-NGF therapy on OA-associated pain, understanding of the precise roles of the NGF/TrkA pathway in different joint tissues in OA and OA-associated pain is of great interest.
ADAMTS5
The use of Adamts5 KO mice and therapeutic treatment with anti-ADAMTS5 antibody in wild-type mice produce inhibition of ADAMTS5 signaling/expression in the DMM model, resulting in reduction of both joint degeneration and pain.98,196,197 ADAMTS5 is a major aggrecanase, and because aggrecan is a major component of the proteoglycans in cartilage that provides compressive resistance, ADAMTS5 is thought to be a critical mediator of cartilage degeneration during the development of OA.198 Although variations in pain signaling can be independent from the degree of joint degeneration, the use of Adamts5 KO mice and direct inhibition of joint degeneration with anti-ADAMTS5 antibody may provide insight into how joint degeneration produces OA pain. For example, hyalectan fragments generated by ADAMTS5 have been suggested to directly stimulate nociceptive neurons as well as glial activation, promoting increased pain perception.196,199 Furthermore, inhibition of ADAMTS5 following DMM resulted in reduced levels of CCL2 in DRG neurons, thus suggesting a role for CCL2 in OA-specific pain.197
Pain-related behavior tests
Pain is the most common reason patients seek medical treatment and is a major indication for joint replacement surgery.200,201 Therefore, evaluating pain in pre-clinical animal models is of critical importance to better understand mechanisms of and to develop treatments for OA pain. The evaluation of OA pain in animals involves indirect and direct measures.
Recognizing pain as a clinical sign and quantitatively assessing pain intensity are essential in research for effective OA pain management. Rodent animal models are routinely used for basic and pre-clinical studies because of the relatively low cost of animal maintenance, the abundance of historical data for comparison, and smaller amounts of drugs required for experimental studies. For pain measurements, rodents have advantages over other small animal models, such as rabbits, which present challenges to obtain a pain response and are immobile if startled by an unfamiliar observer. Mice are usually used for the development of genetically engineered strains to enable molecular understanding of OA progression and pain in vivo.202 Larger animals, including dogs, sheep, goats, and horses are also sometimes used for modeling OA pain.202,203
A wide range of direct and indirect measures of pain are used in small animal models of OA. Indirect and/or direct measures of pain include static or dynamic weight bearing, foot posture, gait analysis, spontaneous activity, as well as sensitivity to mechanical allodynia, mechanical hyperalgesia, and thermal, and cold stimuli.202,203 Among indirect tests involving pain-evoked behaviors, mechanical stimuli may be the most correlated with OA pain. A commonly used measure of indirect pain is the von Frey test for mechanical allodynia using filaments to assess referred pain.186,194,196,202,204 Direct mechanical hyperalgesia is performed using an analgesymeter for paw pressure pain threshold. Additional direct measures of OA pain include the hind limb withdrawal test, vocalization evoked by knee compression on the affected knee, the struggle reaction to knee extension, and ambulation and rearing spontaneous movements.194,202,203 Weight-bearing and gait analyses may have important translational relevance for assessing OA pain because these tests are also used to assess clinical OA pain.203 However, obtaining clear pain responses from weight bearing or gait is challenging when using the unilateral DMM mouse model because the nature of OA pain is a dull pain unlike that of, for example, sharp inflammatory pain.
In large animals, pain behavior testing is more challenging and there is no consensus for the best method of evaluating pain.202 However, dogs, the most commonly used large animal, have been suggested to provide the best predictive modeling for OA pain translated into the clinical setting.205 Methods used for assessing pain in large animals are restricted to assessing degree of lameness, gait analysis, and subjective rating scales, which assess descriptors of pain similar to those of humans.
Overall, there is a wide range of pain-behavior tests for small and large animal models. Although no animal model or pain behavior test perfectly translates to OA-associated pain in patients, these tests yield a valuable understanding of the mechanisms of OA pain and allow assessment of treatments for relief from OA-associated pain. Rodents will continue to be widely used for basic OA pain research, but large animals continue to be important because of their greater potential for modeling clinical OA pain.
Future perspective
Although significant progress has been made in OA research in recent years, very little is yet known about the molecular mechanisms of OA initiation and progression. OA is a heterogeneous disease caused by multiple factors. One important potential factor for OA development is Runx2, which is upregulated in several OA mouse models and in cartilage samples derived from patients with OA disease.7,8,11,13,91 Key questions that need to be addressed are: (1) Is Runx2 a central molecule mediating OA development in joint tissue?; and (2) Could manipulation of Runx2 expression be used to treat OA disease? OA is a disease affecting the entire joint, including articular cartilage, subchondral bone, synovial tissues and menisci. In which of these joint tissues OA damage first occurs during disease initiation is currently unknown; this is important because it is directly related to OA treatment. In addition, the interplaying mechanisms among different OA symptoms, such as articular cartilage degradation, osteophyte formation, subchondral sclerosis and synovial hyperplasia, await clarification. The understanding of the molecular mechanisms underlying these issues will accelerate the development of novel therapeutic strategies for OA.
References
Loeser RF, Goldring SR, Scanzello CR et al. Osteoarthritis: a disease of the joint as an organ. Arthritis Rheum 2012; 64: 1697–1707.
Felson DT . Clinical practice. Osteoarthritis of the knee. N Engl J Med 2006; 354: 841–848.
Goldring MB, Goldring SR . Osteoarthritis. J Cell Physiol 2007; 213: 626–634.
Krasnokutsky S, Samuels J, Abramson SB . Osteoarthritis in 2007. Bull NYU Hosp Jt Dis 2007; 65: 222–228.
Loeser RF . Aging and osteoarthritis: the role of chondrocyte senescence and aging changes in the cartilage matrix. Osteoarthritis Cartilage 2009; 17: 971–979.
Yang X, Chen L, Xu X et al. TGF-β/Smad3 signals repress chondrocyte hypertrophic differentiation and are required for maintaining articular cartilage. J Cell Biol 2001; 153: 35–46.
Zhu M, Tang D, Wu Q et al. Activation of β-catenin signaling in articular chondrocytes leads to osteoarthritis-like phenotype in adult β-catenin conditional activation mice. J Bone Miner Res 2009; 24: 12–21.
Lin AC, Seeto BL, Bartoszko JM et al. Modulating hedgehog signaling can attenuate the severity of osteoarthritis. Nat Med 2009; 15: 1421–1425.
Saito T, Fukai A, Mabuchi A et al. Transcriptional regulation of endochondral ossification by HIF-2alpha during skeletal growth and osteoarthritis development. Nat Med 2010; 16: 678–686.
Yang S, Kim J, Ryu JH et al. Hypoxia-inducible factor-2alpha is a catabolic regulator of osteoarthritic cartilage destruction. Nat Med 2010; 16: 687–693.
Kamekura S, Kawasaki Y, Hoshi K et al. Contribution of runt-related transcription factor 2 to the pathogenesis of osteoarthritis in mice after induction of knee joint instability. Arthritis Rheum 2006; 54: 2462–2470.
Chen CG, Thuillier D, Chin EN et al. Chondrocyte-intrinsic Smad3 represses Runx2-inducible matrix metalloproteinase 13 expression to maintain articular cartilage and prevent osteoarthritis. Arthritis Rheum 2012; 64: 3278–3289.
Hirata M, Kugimiya F, Fukai A et al. C/EBPβ and RUNX2 cooperate to degrade cartilage with MMP-13 as the target and HIF-2α as the inducer in chondrocytes. Hum Mol Genet 2012; 21: 1111–1123.
Pei Y, Harvey A, Yu XP et al. Differential regulation of cytokine-induced MMP1 and MMP13 expression by p38 kinase inhibitors in human chondrosarcoma cells: potential role of Runx2 in mediating p38 effects. Osteoarthritis Cartilage 2006; 14: 749–758.
Thirunavukkarasu K, Pei Y, Wei T . Characterization of the human ADAMTS-5 (aggrecanase-2) gene promoter. Mol Biol Rep 2007; 34: 225–231.
Tetsunaga T, Nishida K, Furumatsu T et al. Regulation of mechanical stress-induced MMP13 and ADAMTS5 expression by Runx2 transcriptional factor in SW1353 chondrocyte-like cells. Osteoarthritis Cartilage 2011; 19: 222–232.
Wang M, Tang D, Shu B et al. Conditional activation of β-catenin signaling in mice leads to severe defects in intervertebral disc tissue. Arthritis Rheum 2012; 64: 2611–2623.
Helmick CG, Felson DT, Lawrence RC et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part I. Arthritis Rheum 2008; 58: 15–25.
Lawrence RC, Felson DT, Helmick CG et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part II. Arthritis Rheum 2008; 58: 26–35.
Felson DT . Osteoarthritis of the knee. N Engl J Med 2006; 354: 841–848.
Felson DT, Naimark A, Anderson J et al. The prevalence of knee osteoarthritis in the elderly. The Framingham Osteoarthritis Study. Arthritis Rheum 1987; 30: 914–918.
Jordan JM, Helmick CG, Renner JB et al. Prevalence of knee symptoms and radiographic and symptomatic knee osteoarthritis in African Americans and Caucasians: the Johnston County Osteoarthritis Project. J Rheumatol 2007; 34: 172–180.
Dillon CF, Rasch EK, Gu Q et al. Prevalence of knee osteoarthritis in the United States: arthritis data from the Third National Health and Nutrition Examination Survey 1991-94. J Rheumatol 2006; 33: 2271–2279.
van Saase JL, van Romunde LK, Cats A et al. Epidemiology of osteoarthritis: Zoetermeer survey. Comparison of radiological osteoarthritis in a Dutch population with that in 10 other populations. Ann Rheum Dis 1989; 48: 271–280.
Andrianakos AA, Kontelis LK, Karamitsos DG et al. Prevalence of symptomatic knee, hand, and hip osteoarthritis in Greece. The ESORDIG study. J Rheumatol 2006; 33: 2507–2513.
Loeser RF . Aging and osteoarthritis. Curr Opin Rheumatol 2011; 23: 492–496.
Kim J, Xu M, Xo R et al. Mitochondrial DNA damage is involved in apoptosis caused by pro-inflammatory cytokines in human OA chondrocytes. Osteoarthritis Cartilage 2010; 18: 424–432.
Goodwin W, McCabe D, Sauter E et al. Rotenone prevents impact-induced chondrocyte death. J Orthop Res 2010; 28: 1057–1063.
Naik E, Dixit VM . Mitochondrial reactive oxygen species drive proinflammatory cytokine production. J Exp Med 2011; 208: 417–420.
Liu JT, Guo X, Ma WJ et al. Mitochondrial function is altered in articular chondrocytes of an endemic osteoarthritis, Kashin-Beck disease. Osteoarthritis Cartilage 2010; 18: 1218–1226.
Blaney Davidson EN, Remst DF, Vitters EL et al. Increase in ALK1/ALK5 ratio as a cause for elevated MMP-13 expression in osteoarthritis in humans and mice. J Immunol 2009; 182: 7937–7945.
van der Kraan PM, Blaney Davidson EN, van den Berg WB . A role for age-related changes in TGF-β signaling in aberrant chondrocyte differentiation and osteoarthritis. Arthritis Res Ther 2010; 12: 201–209.
Richardson B . Impact of aging on DNA methylation. Ageing Res Rev 2003; 2: 245–261.
Christensen BC, Houseman EA, Marsit CJ et al. Aging and environmental exposures alter tissue-specific DNA methylation dependent upon CpG island context. PLoS Genet 2009; 5: e1000602.
Fernandez-Tajes J, Soto-Hermida A, Vazquez-Mosquera ME et al. Genome-wide DNA methylation analysis of articular chondrocytes reveals a cluster of osteoarthritic patients. Ann Rheum Dis 2014; 73: 668–677.
Jeffries MA, Donica M, Baker LW et al. Genome-wide DNA methylation study identifies significant epigenomic changes in osteoarthritic cartilage. Arthritis Rheumatol 2014; 66: 2804–2815.
den Hollander W, Ramos YF, Bos SD et al. Knee and hip articular cartilage have distinct epigenomic landscapes: implications for future cartilage regeneration approaches. Ann Rheum Dis 2014; 73: 2208–2212.
Haseeb A, Makki MS, Haqqi TM . Modulation of ten-eleven translocation 1 (TET1), Isocitrate Dehydrogenase (IDH) expression, alpha-Ketoglutarate (alpha-KG), and DNA hydroxymethylation levels by interleukin-1beta in primary human chondrocytes. J Biol Chem 2014; 289: 6877–6885.
Taylor SE, Smeriglio P, Dhulipala L et al. A global increase in 5-hydroxymethylcytosine levels marks osteoarthritic chondrocytes. Arthritis Rheumatol 2014; 66: 90–100.
Taylor SE, Li YH, Wong WH et al. Genome-wide map** of DNA hydroxymethylation in osteoarthritic chondrocytes. Arthritis Rheumatol 2015; 67: 2129–2140.
Felson DT, Anderson JJ, Naimark A et al. Obesity and knee osteoarthritis. The Framingham Study. Ann Intern Med 1988; 109: 18–24.
Anandacoomarasamy A, Caterson I, Sambrook P et al. The impact of obesity on the musculoskeletal system. Int J Obes (Lond) 2008; 32: 211–222.
Conde J, Scotece M, Gomez R et al. Adipokines and osteoarthritis: novel molecules involved in the pathogenesis and progression of disease. Arthritis 2011; 2011: 203901.
Das UN . Is obesity an inflammatory condition? Nutrition 2001; 17: 953–966.
Fain JN . Release of inflammatory mediators by human adipose tissue is enhanced in obesity and primarily by the nonfat cells: a review. Mediators Inflamm 2010; 2010: 513948.
Bunout D, Munoz C, Lopez M et al. Interleukin 1 and tumor necrosis factor in obese alcoholics compared with normal-weight patients. Am J Clin Nutr 1996; 63: 373–376.
Visser M . Higher levels of inflammation in obese children. Nutrition 2001; 17: 480–481.
Aygun AD, Gungor S, Ustundag B et al. Proinflammatory cytokines and leptin are increased in serum of prepubertal obese children. Mediators Inflamm 2005; 2005: 180–183.
Pou KM, Massaro JM, Hoffmann U et al. Visceral and subcutaneous adipose tissue volumes are cross-sectionally related to markers of inflammation and oxidative stress: the Framingham Heart Study. Circulation 2007; 116: 1234–1241.
Straczkowski M, Dzienis-Straczkowska S, Stepien A et al. Plasma interleukin-8 concentrations are increased in obese subjects and related to fat mass and tumor necrosis factor-alpha system. J Clin Endocrinol Metab 2002; 87: 4602–4606.
Zhou Q, Leeman SE, Amar S . Signaling mechanisms in the restoration of impaired immune function due to diet-induced obesity. Proc Natl Acad Sci U S A 2011; 108: 2867–2872.
Neels JG, Badeanlou L, Hester KD et al. Keratinocyte-derived chemokine in obesity: expression, regulation, and role in adipose macrophage infiltration and glucose homeostasis. J Biol Chem 2009; 284: 20692–20698.
Brown ML, Yukata K, Farnsworth CW et al. Delayed fracture healing and increased callus adiposity in a C57BL/6 J murine model of obesity-associated type 2 diabetes mellitus. PLoS One 2014; 9: e99656.
Louer CR, Furman BD, Huebner JL et al. Diet-induced obesity significantly increases the severity of posttraumatic arthritis in mice. Arthritis Rheum 2012; 64: 3220–3230.
Stehouwer CD, Gall MA, Twisk JW et al. Increased urinary albumin excretion, endothelial dysfunction, and chronic low-grade inflammation in type 2 diabetes: progressive, interrelated, and independently associated with risk of death. Diabetes 2002; 51: 1157–1165.
Duncan BB, Schmidt MI, Pankow JS et al. Low-grade systemic inflammation and the development of type 2 diabetes: the atherosclerosis risk in communities study. Diabetes 2003; 52: 1799–1805.
Wellen KE, Hotamisligil GS . Inflammation, stress, and diabetes. J Clin Invest 2005; 115: 1111–1119.
Kapoor M, Martel-Pelletier J, Lajeunesse D et al. Role of proinflammatory cytokines in the pathophysiology of osteoarthritis. Nat Rev Rheumatol 2011; 7: 33–42.
Fernandes JC, Martel-Pelletier J, Pelletier JP . The role of cytokines in osteoarthritis pathophysiology. Biorheology 2002; 39: 237–246.
Martel-Pelletier J, Alaaeddine N, Pelletier JP . Cytokines and their role in the pathophysiology of osteoarthritis. Front Biosci 1999; 4: D694–D703.
Roos EM . Joint injury causes knee osteoarthritis in young adults. Curr Opin Rheumatol 2005; 17: 195–200.
Radin EL . Who gets osteoarthritis and why? J Rheumatol Suppl, 2004; 70: 10–15.
Andriacchi TP, Mundermann A, Smith RL et al. A framework for the in vivo pathomechanics of osteoarthritis at the knee. Ann Biomed Eng 2004; 32: 447–457.
Miyazaki T, Wada M, Kawahara H et al. Dynamic load at baseline can predict radiographic disease progression in medial compartment knee osteoarthritis. Ann Rheum Dis 2002; 61: 617–622.
Fridén T, Sommerlath K, Egund N et al. Instability after anterior cruciate ligament rupture. Measurements of sagittal laxity compared in 11 cases. Acta Orthop Scand 1992; 63: 593–598.
Sernert N, Kartus JT Jr, Ejerhed L et al. Right and left knee laxity measurements: a prospective study of patients with anterior cruciate ligament injuries and normal control subjects. Arthroscopy 2004; 20: 564–571.
Lieberthal J, Sambamurthy N, Scanzello CR . Inflammation in joint injury and post-traumatic osteoarthritis. Osteoarthritis Cartilage 2015; 23: 1825–1834.
Malfait AM . Osteoarthritis year in review 2015: biology. Osteoarthritis Cartilage 2016; 24: 21–26.
van Lent PL, Blom AB, Schelbergen RF et al. Active involvement of alarmins S100A8 and S100A9 in the regulation of synovial activation and joint destruction during mouse and human osteoarthritis. Arthritis Rheum 2012; 64: 1466–1476.
Schelbergen RF, van Dalen S, ter Huurne M et al. Treatment efficacy of adipose-derived stem cells in experimental osteoarthritis is driven by high synovial activation and reflected by S100A8/A9 serum levels. Osteoarthritis Cartilage 2014; 22: 1158–1166.
Nasi S, Ea HK, Chobaz V et al. Dispensable role of myeloid differentiation primary response gene 88 (MyD88) and MyD88-dependent toll-like receptors (TLRs) in a murine model of osteoarthritis. Joint Bone Spine 2014; 81: 320–324.
Liu-Bryan R, Terkeltaub R . The growing array of innate inflammatory ignition switches in osteoarthritis. Arthritis Rheum 2012; 64: 2055–2058.
Schelbergen RF, Blom AB, van den Bosch MH et al. Alarmins S100A8 and S100A9 elicit a catabolic effect in human osteoarthritic chondrocytes that is dependent on Toll-like receptor 4. Arthritis Rheum 2012; 64: 1477–1487.
Zreiqat H, Belluoccio D, Smith MM et al. S100A8 and S100A9 in experimental osteoarthritis. Arthritis Res Ther 2010; 12: R16.
Cecil DL, Appleton CT, Polewski MD et al. The pattern recognition receptor CD36 is a chondrocyte hypertrophy marker associated with suppression of catabolic responses and promotion of repair responses to inflammatory stimuli. J Immunol 2009; 182: 5024–5031.
** C, Frayssinet P, Pelker R et al. NLRP3 inflammasome plays a critical role in the pathogenesis of hydroxyapatite-associated arthropathy. Proc Natl Acad Sci U S A 2011; 108: 14867–14872.
Wang Q, Rozelle AL, Lepus CM et al. Identification of a central role for complement in osteoarthritis. Nat Med 2011; 17: 1674–1679.
Lepus CM, Song JJ, Wang Q et al. Brief report: carboxypeptidase B serves as a protective mediator in osteoarthritis. Arthritis Rheumatol 2014; 66: 101–106.
Pap T, Bertrand J . Syndecans in cartilage breakdown and synovial inflammation. Nat Rev Rheumatol 2013; 9: 43–55.
Kim JH, Jeon J, Shin M et al. Regulation of the catabolic cascade in osteoarthritis by the zinc-ZIP8-MTF1 axis. Cell 2014; 156: 730–743.
Kroemer G . Autophagy: a druggable process that is deregulated in aging and human disease. J Clin Invest 2015; 125: 1–4.
Lopez-Otin C, Blasco MA, Partridge L et al. The hallmarks of aging. Cell 2013; 153: 1194–1217.
Carames B, Olmer M, Kiosses WB et al. The relationship of autophagy defects to cartilage damage during joint aging in a mouse model. Arthritis Rheumatol 2015; 67: 1568–1576.
Vasheghani F, Zhang Y, Li YH et al. PPARγ deficiency results in severe, accelerated osteoarthritis associated with aberrant mTOR signalling in the articular cartilage. Ann Rheum Dis 2015; 74: 569–578.
Takayama K, Kawakami Y, Kobayashi M et al. Local intra-articular injection of rapamycin delays articular cartilage degeneration in a murine model of osteoarthritis. Arthritis Res Ther 2014; 16: 482–491.
Li ZC, **ao J, Peng JL et al. Functional annotation of rheumatoid arthritis and osteoarthritis associated genes by integrative genome-wide gene expression profiling analysis. PLoS One 2014; 9: e85784.
Spector TD, Cicuttini F, Baker J et al. Genetic influences on osteoarthritis in women: a twin study. BMJ 1996; 312: 940–943.
Felson DT, Couropmitree NN, Chaisson CE et al. Evidence for a Mendelian gene in a segregation analysis of generalized radiographic osteoarthritis: the Framingham Study. Arthritis Rheum 1998; 41: 1064–1071.
Loughlin J, Mustafa Z, Smith A et al. Linkage analysis of chromosome 2q in osteoarthritis. Rheumatology 2000; 39: 377–381.
Serra R, Johnson M, Filvaroff EH et al. Expression of a truncated, kinase-defective TGF-beta type II receptor in mouse skeletal tissue promotes terminal chondrocyte differentiation and osteoarthritis. J Cell Biol 1997; 139: 541–552.
Shen J, Li J, Wang B et al. Deletion of the transforming growth factor beta receptor type II gene in articular chondrocytes leads to a progressive osteoarthritis-like phenotype in mice. Arthritis Rheum 2013; 65: 3107–3119.
Wang M, Tang D, Shu B et al. Conditional activation of beta-catenin signaling in mice leads to severe defects in intervertebral disc tissue. Arthritis Rheum 2012; 64: 2611–2623.
Mirando AJ, Liu Z, Moore T et al. RBP-Jkappa-dependent Notch signaling is required for murine articular cartilage and joint maintenance. Arthritis Rheum 2013; 65: 2623–2633.
Lories RJ, Corr M, Lane NE . To Wnt or not to Wnt: the bone and joint health dilemma. Nat Rev Rheumatol 2013; 9: 328–339.
Sassi N, Laadhar L, Allouche M et al. WNT signaling and chondrocytes: from cell fate determination to osteoarthritis physiopathology. J Recept Signal Transduct Res 2014; 34: 73–80.
Hirata M, Kugimiya F, Fukai A et al. C/EBPbeta and RUNX2 cooperate to degrade cartilage with MMP-13 as the target and HIF-2alpha as the inducer in chondrocytes. Hum Mol Genet 2012; 21: 1111–1123.
Little CB, Barai A, Burkhardt D et al. Matrix metalloproteinase 13-deficient mice are resistant to osteoarthritic cartilage erosion but not chondrocyte hypertrophy or osteophyte development. Arthritis Rheum 2009; 60: 3723–3733.
Glasson SS, Askew R, Sheppard B et al. Deletion of active ADAMTS5 prevents cartilage degradation in a murine model of osteoarthritis. Nature 2005; 434: 644–648.
Barnholtz-Sloan JS, Severson RK, Stanton B et al. Pediatric brain tumors in non-Hispanics, Hispanics, African Americans and Asians: differences in survival after diagnosis. Cancer Causes Control 2005; 16: 587–592.
Loughlin J, Dowling B, Chapman K et al. Functional variants within the secreted frizzled-related protein 3 gene are associated with hip osteoarthritis in females. Proc Natl Acad Sci U S A 2004; 101: 9757–9762.
Bijsterbosch J, Kloppenburg M, Reijnierse M et al. Association study of candidate genes for the progression of hand osteoarthritis. Osteoarthritis Cartilage 2013; 21: 565–569.
Valdes AM, Spector TD, Tamm A et al. Genetic variation in the SMAD3 gene is associated with hip and knee osteoarthritis. Arthritis Rheum 2010; 62: 2347–2352.
Rodriguez RR, Seegmiller RE, Stark MR et al. A type XI collagen mutation leads to increased degradation of type II collagen in articular cartilage. Osteoarthritis Cartilage 2004; 12: 314–320.
Jeong C, Lee JY, Kim J et al. Novel COL9A3 mutation in a family diagnosed with multiple epiphyseal dysplasia: a case report. BMC Musculoskelet Disord 2014; 15: 371.
Carlson KM, Yamaga KM, Reinker KA et al. Precocious osteoarthritis in a family with recurrent COL2A1 mutation. J Rheumatol 2006; 33: 1133–1136.
Zhang R, Yao J, Xu P et al. A comprehensive meta-analysis of association between genetic variants of GDF5 and osteoarthritis of the knee, hip and hand. Inflamm Res 2015; 64: 405–414.
arcOGEN Consortium and arcOGEN Collabortors. Identification of new susceptibility loci for osteoarthritis (arcOGEN): a genome-wide association study. Lancet 2012; 380: 815–823.
Glasson SS, Blanchet TJ, Morris EA . The surgical destabilization of the medial meniscus (DMM) model of osteoarthritis in the 129/SvEv mouse. Osteoarthritis Cartilage 2007; 15: 1061–1069.
Glasson SS, Askew R, Sheppard B et al. Characterization of and osteoarthritis susceptibility in ADAMTS-4-knockout mice. Arthritis Rheum 2004; 50: 2547–2558.
Welch ID, Cowan MF, Beier F et al. The retinoic acid binding protein CRABP2 is increased in murine models of degenerative joint disease. Arthritis Res Ther 2009; 11: R14.
Ma HL, Blanchet TJ, Peluso D et al. Osteoarthritis severity is sex dependent in a surgical mouse model. Osteoarthritis Cartilage 2007; 15: 695–700.
Wilhelmi G, Faust R . Suitability of the C57 black mouse as an experimental animal for the study of skeletal changes due to ageing, with special reference to osteo-arthrosis and its response to tribenoside. Pharmacology 1976; 14: 289–296.
Walton M . Studies of degenerative joint disease in the mouse knee joint; scanning electron microscopy. J Pathol 1977; 123: 211–217.
Poulet B, Westerhof TA, Hamilton RW et al. Spontaneous osteoarthritis in Str/ort mice is unlikely due to greater vulnerability to mechanical trauma. Osteoarthritis Cartilage 2013; 21: 756–763.
Poulet B, Ulici V, Stone TC et al. Time-series transcriptional profiling yields new perspectives on susceptibility to murine osteoarthritis. Arthritis Rheum 2012; 64: 3256–3266.
Sokoloff L, Crittenden LB, Yamamoto RS et al. The genetics of degenerative joint disease in mice. Arthritis Rheum 1962; 5: 531–546.
Kamekura S, Hoshi K, Shimoaka T et al. Osteoarthritis development in novel experimental mouse models induced by knee joint instability. Osteoarthritis Cartilage 2005; 13: 632–641.
Jimenez PA, Glasson SS, Trubetskoy OV et al. Spontaneous osteoarthritis in Dunkin Hartley guinea pigs: histologic, radiologic, and biochemical changes. Lab Anim Sci 1997; 47: 598–601.
Thijssen E, van Caam A, van der Kraan PM . Obesity and osteoarthritis, more than just wear and tear: pivotal roles for inflamed adipose tissue and dyslipidaemia in obesity-induced osteoarthritis. Rheumatology 2015; 54: 588–600.
Griffin TM, Huebner JL, Kraus VB et al. Induction of osteoarthritis and metabolic inflammation by a very high-fat diet in mice: effects of short-term exercise. Arthritis Rheum 2012; 64: 443–453.
Säämänen AM, Hyttinen M, Vuorio E . Analysis of arthritic lesions in the Del1 mouse: a model for osteoarthritis. Methods Mol Med 2007; 136: 283–302.
Chen M, Lichtler AC, Sheu T et al. Generation of a transgenic mouse model with chondrocyte-specific and tamoxifen-inducible expression of Cre recombinase. Genesis 2007; 45: 44–50.
Henry SP, Jang CW, Deng JM et al. Generation of aggrecan-CreERT2 knockin mice for inducible Cre activity in adult cartilage. Genesis 2009; 47: 805–814.
Kozhemyakina E, Zhang M, Ionescu A et al. Identification of a Prg4-expressing articular cartilage progenitor cell population in mice. Arthritis Rheumatol 2015; 67: 1261–1273.
Saamanen AK, Salminen HJ, Dean PB et al. Osteoarthritis-like lesions in transgenic mice harboring a small deletion mutation in type II collagen gene. Osteoarthritis Cartilage 2000; 8: 248–257.
Hu K, Xu L, Cao L et al. Pathogenesis of osteoarthritis-like changes in the joints of mice deficient in type IX collagen. Arthritis Rheum 2006; 54: 2891–2900.
Wu Q, Kim KO, Sampson ER et al. Induction of an osteoarthritis-like phenotype and degradation of phosphorylated Smad3 by Smurf2 in transgenic mice. Arthritis Rheum 2008; 58: 3132–3144.
Lories RJ, Peeters J, Bakker A et al. Articular cartilage and biomechanical properties of the long bones in Frzb-knockout mice. Arthritis Rheum 2007; 56: 4095–4103.
Weng T, Yi L, Huang J et al. Genetic inhibition of fibroblast growth factor receptor 1 in knee cartilage attenuates the degeneration of articular cartilage in adult mice. Arthritis Rheum 2012; 64: 3982–3992.
Wang M, Sampson ER, ** H et al. MMP13 is a critical target gene during the progression of osteoarthritis. Arthritis Res Ther 2013; 15: R5.
Valdes AM, Spector TD, Tamm A et al. Genetic variation in the Smad3 gene is associated with hip and knee osteoarthritis. Arthritis Rheum 2010; 62: 2347–2352.
van de Laar IM, Oldenburg RA, Pals G et al. Mutations in SMAD3 cause a syndromic form of aortic aneurysms and dissections with early-onset osteoarthritis. Nat Genet 2011; 43: 121–126.
van de Laar IM, van der Linde D, Oei EH et al. Phenotypic spectrum of the Smad3-related aneurysms-osteoarthritis syndrome. J Med Genet 2012; 49: 47–57.
Zhen G, Wen C, Jia X et al. Inhibition of TGF-β signaling in mesenchymal stem cells of subchondral bone attenuates osteoarthritis. Nat Med 2013; 19: 704–712.
Wang TY, Chen D . Differential roles of TGF-β signaling in joint tissues during osteoarthritis development. Ann Rheum Dis 2016; 75: e72.
Manning WK, Bonner WM Jr . Isolation and culture of chondrocytes from human adult articular cartilage. Arthritis Rheum 1967; 10: 235–239.
Oseni AO, Butler PE, Seifalian AM . Optimization of chondrocyte isolation and characterization for large-scale cartilage tissue engineering. J Surg Res 2013; 181: 41–48.
Guo JF, Jourdian GW, MacCallum DK . Culture and growth characteristics of chondrocytes encapsulated in alginate beads. Connect Tissue Res 1989; 19: 277–297.
Bonaventure J, Kadhom N, Cohen-Solal L et al. Reexpression of cartilage-specific genes by dedifferentiated human articular chondrocytes cultured in alginate beads. Exp Cell Res 1994; 212: 97–104.
Lafeber FP, Vander Kraan PM, Van Roy JL et al. Articular cartilage explant culture; an appropriate in vitro system to compare osteoarthritic and normal human cartilage. Connect Tissue Res 1993; 29: 287–299.
Dhillon RS, Zhang L, Schwarz EM et al. The murine femoral bone graft model and a semiautomated histomorphometric analysis tool. Methods Mol Biol 2014; 1130: 45–59.
Glasson SS, Chambers MG, Van Den Berg WB et al. The OARSI histopathology initiative - recommendations for histological assessments of osteoarthritis in the mouse. Osteoarthritis Cartilage 2010; 18: S17–S23.
Waldstein W, Perino G, Gilbert SL et al. OARSI osteoarthritis cartilage histopathology assessment system: A biomechanical evaluation in the human knee. J Orthop Res 2016; 34: 135–140.
Han L, Grodzinsky AJ, Ortiz C . Nanomechanics of the cartilage extracellular matrix. Annu Rev Mater Res 2011; 41: 133–168.
Lin DC, Horkay F . Nanomechanics of polymer gels and biological tissues: a critical review of analytical approaches in the Hertzian regime and beyond. Soft Matter 2008; 4: 669–682.
McLeod MA, Wilusz RE, Guilak F . Depth-dependent anisotropy of the micromechanical properties of the extracellular and pericellular matrices of articular cartilage evaluated via atomic force microscopy. J Biomech 2013; 46: 586–592.
Kwok J, Grogan S, Meckes B et al. Atomic force microscopy reveals age-dependent changes in nanomechanical properties of the extracellular matrix of native human menisci: implications for joint degeneration and osteoarthritis. Nanomedicine 2014; 10: 1777–1785.
Stolz M, Gottardi R, Raiteri R et al. Early detection of aging cartilage and osteoarthritis in mice and patient samples using atomic force microscopy. Nat Nanotechnol 2009; 4: 186–192.
Wilusz RE, Zauscher S, Guilak F . Micromechanical map** of early osteoarthritic changes in the pericellular matrix of human articular cartilage. Osteoarthritis Cartilage 2013; 21: 1895–1903.
Desrochers J, Amrein MA, Matyas JR . Structural and functional changes of the articular surface in a post-traumatic model of early osteoarthritis measured by atomic force microscopy. J Biomech 2010; 43: 3091–3098.
Desrochers J, Amrein MW, Matyas JR . Viscoelasticity of the articular cartilage surface in early osteoarthritis. Osteoarthritis Cartilage 2012; 20: 413–421.
Darling EM, Topel M, Zauscher S et al. Viscoelastic properties of human mesenchymally-derived stem cells and primary osteoblasts, chondrocytes, and adipocytes. J Biomech 2008; 41: 454–464.
Lee B, Han L, Frank EH et al. Dynamic nanomechanics of individual bone marrow stromal cells and cell-matrix composites during chondrogenic differentiation. J Biomech 2015; 48: 171–175.
Diekman BO, Christoforou N, Willard VP et al. Cartilage tissue engineering using differentiated and purified induced pluripotent stem cells. Proc Natl Acad Sci U S A 2012; 109: 19172–19177.
Ng L, Hung H-H, Sprunt A et al. Nanomechanical properties of individual chondrocytes and their develo** growth factor-stimulated pericellular matrix. J Biomech 2007; 40: 1011–1023.
Peñuela L, Wolf F, Raiteri R et al. Atomic force microscopy to investigate spatial patterns of response to interleukin-1beta in engineered cartilage tissue elasticity. J Biomech 2014; 47: 2157–2164.
Ameye LG, Young MF . Animal models of osteoarthritis: lessons learned while seeking the ‘Holy Grail’. Curr Opin Rheumatol 2006; 18: 537–547.
Coles JM, Zhang L, Blum JJ et al. Loss of cartilage structure, stiffness, and frictional properties in mice lacking PRG4. Arthritis Rheum 2010; 62: 1666–1674.
Batista MA, Nia HT, Önnerfjord P et al. Nanomechanical phenotype of chondroadherin-null murine articular cartilage. Matrix Biol 2014; 38: 84–90.
Li Q, Doyran B, Gamer LW et al. Biomechanical properties of murine meniscus surface via AFM-based nanoindentation. J Biomech 2015; 48: 1364–1370.
Wilusz RE, DeFrate LE, Guilak F . Immunofluorescence-guided atomic force microscopy to measure the micromechanical properties of the pericellular matrix of porcine articular cartilage. J R Soc Interface 2012; 9: 2997–3007.
Wilusz RE, Defrate LE, Guilak F . A biomechanical role for perlecan in the pericellular matrix of articular cartilage. Matrix Biol 2012; 31: 320–327.
Wilusz RE, Guilak F . High resistance of the mechanical properties of the chondrocyte pericellular matrix to proteoglycan digestion by chondroitinase, aggrecanase, or hyaluronidase. J Mech Behav Biomed Mater 2014; 38: 183–197.
Zelenski NA, Leddy HA, Sanchez-Adams J et al. Type VI collagen regulates pericellular matrix properties, chondrocyte swelling, and mechanotransduction in mouse articular cartilage. Arthritis Rheumatol 2015; 67: 1286–1294.
Sanchez-Adams J, Wilusz RE, Guilak F . Atomic force microscopy reveals regional variations in the micromechanical properties of the pericellular and extracellular matrices of the meniscus. J Orthop Res 2013; 31: 1218–1225.
Nia HT, Bozchalooi IS, Li Y et al. High-bandwidth AFM-based rheology reveals that cartilage is most sensitive to high loading rates at early stages of impairment. Biophys J 2013; 104: 1529–1537.
Han L, Frank EH, Greene JJ et al. Time-dependent nanomechanics of cartilage. Biophys J 2011; 100: 1846–1854.
Nia HT, Han L, Li Y et al. Poroelasticity of cartilage at the nanoscale. Biophys J 2011; 101: 2304–2313.
Nia HT, Han L, Bozchalooi IS et al. Aggrecan nanoscale solid-fluid interactions are a primary determinant of cartilage dynamic mechanical properties. ACS Nano 2015; 9: 2614–2625.
Nia HT, Gauci SJ, Azadi M et al. High-bandwidth AFM-based rheology is a sensitive indicator of early cartilage aggrecan degradation relevant to mouse models of osteoarthritis. J Biomech 2015; 48: 162–165.
Im HJ, Kim JS, Li X et al. Alteration of sensory neurons and spinal response to an experimental osteoarthritis pain model. Arthritis Rheum 2010; 62: 2995–3005.
Lee AS, Ellman MB, Yan D et al. A current review of molecular mechanisms regarding osteoarthritis and pain. Gene 2013; 527: 440–447.
Deshmane SL, Kremlev S, Amini S et al. Monocyte chemoattractant protein-1 (MCP-1): an overview. J Interferon Cytokine Res 2009; 29: 313–326.
Harigai M, Hara M, Yoshimura T et al. Monocyte chemoattractant protein-1 (MCP-1) in inflammatory joint diseases and its involvement in the cytokine network of rheumatoid synovium. Clin Immunol Immunopathol 1993; 69: 83–91.
Thompson WL, Karpus WJ, Van Eldik LJ . MCP-1-deficient mice show reduced neuroinflammatory responses and increased peripheral inflammatory responses to peripheral endotoxin insult. J Neuroinflammation 2008; 5: 35–47.
Conductier G, Blondeau N, Guyon A et al. The role of monocyte chemoattractant protein MCP1/CCL2 in neuroinflammatory diseases. J Neuroimmunol 2010; 224: 93–100.
Thacker MA, Clark AK, Bishop T et al. CCL2 is a key mediator of microglia activation in neuropathic pain states. Eur J Pain 2009; 13: 263–272.
Van Steenwinckel J, Reaus-Le Goazigo A, Pommier B et al. CCL2 released from neuronal synaptic vesicles in the spinal cord is a major mediator of local inflammation and pain after peripheral nerve injury. J Neurosci 2011; 31: 5865–5875.
Miller RE, Tran PB, Das R et al. CCR2 chemokine receptor signaling mediates pain in experimental osteoarthritis. Proc Natl Acad Sci U S A 2012; 109: 20602–20607.
Horuk R . Chemokine receptor antagonists: overcoming developmental hurdles. Nat Rev Drug Discov 2009; 8: 23–33.
Lane NE, Schnitzer TJ, Birbara CA et al. Tanezumab for the treatment of pain from osteoarthritis of the knee. N Engl J Med 2010; 363: 1521–1531.
Schnitzer TJ, Lane NE, Birbara C et al. Long-term open-label study of tanezumab for moderate to severe osteoarthritic knee pain. Osteoarthritis Cartilage 2011; 19: 639–646.
Brown MT, Murphy FT, Radin DM et al. Tanezumab reduces osteoarthritic knee pain: results of a randomized, double-blind, placebo-controlled phase III trial. J Pain 2012; 13: 790–798.
Nagashima H, Suzuki M, Araki S et al. Preliminary assessment of the safety and efficacy of tanezumab in Japanese patients with moderate to severe osteoarthritis of the knee: a randomized, double-blind, dose-escalation, placebo-controlled study. Osteoarthritis Cartilage 2011; 19: 1405–1412.
Obata K, Noguchi K . MAPK activation in nociceptive neurons and pain hypersensitivity. Life Sci 2004; 74: 2643–2653.
McKelvey L, Shorten GD, O'Keeffe GW . Nerve growth factor-mediated regulation of pain signalling and proposed new intervention strategies in clinical pain management. J Neurochem 2013; 124: 276–289.
Hefti FF, Rosenthal A, Walicke PA et al. Novel class of pain drugs based on antagonism of NGF. Trends Pharmacol Sci 2006; 27: 85–91.
Mantyh PW, Koltzenburg M, Mendell LM et al. Antagonism of nerve growth factor-TrkA signaling and the relief of pain. Anesthesiology 2011; 115: 189–204.
Kawamoto K, Aoki J, Tanaka A et al. Nerve growth factor activates mast cells through the collaborative interaction with lysophosphatidylserine expressed on the membrane surface of activated platelets. J Immunol 2002; 168: 6412–6419.
Seidel MF, Wise BL, Lane NE . Nerve growth factor: an update on the science and therapy. Osteoarthritis Cartilage 2013; 21: 1223–1228.
Gee AP, Boyle MD, Munger KL et al. Nerve growth factor: stimulation of polymorphonuclear leukocyte chemotaxis in vitro . Proc Natl Acad Sci U S A 1983; 80: 7215–7218.
Otten U, Baumann JB, Girard J . Nerve growth factor induces plasma extravasation in rat skin. Eur J Pharmacol 1984; 106: 199–201.
Walsh DA, McWilliams DF, Turley MJ et al. Angiogenesis and nerve growth factor at the osteochondral junction in rheumatoid arthritis and osteoarthritis. Rheumatology 2010; 49: 1852–1861.
Kc R, Li X, Kroin JS et al. PKCδ null mutations in a mouse model of osteoarthritis alter osteoarthritic pain independently of joint pathology by augmenting NGF/TrkA-induced axonal outgrowth. Ann Rheum Dis 2016; 75: 2133–2141.
Hochberg MC . Serious joint-related adverse events in randomized controlled trials of anti-nerve growth factor monoclonal antibodies. Osteoarthritis Cartilage 2015; 23: S18–S21.
Malfait AM, Ritchie J, Gil AS et al. ADAMTS-5 deficient mice do not develop mechanical allodynia associated with osteoarthritis following medial meniscal destabilization. Osteoarthritis Cartilage 2010; 18: 572–580.
Miller RE, Tran PB, Ishihara S et al. Therapeutic effects of an anti-ADAMTS-5 antibody on joint damage and mechanical allodynia in a murine model of osteoarthritis. Osteoarthritis Cartilage 2016; 24: 299–306.
Verma P, Dalal K . ADAMTS-4 and ADAMTS-5: key enzymes in osteoarthritis. J Cell Biochem 2011; 112: 3507–3514.
Chan CC, Roberts CR, Steeves JD et al. Aggrecan components differentially modulate nerve growth factor-responsive and neurotrophin-3-responsive dorsal root ganglion neurite growth. J Neurosci Res 2008; 86: 581–592.
Mancuso CA, Ranawat CS, Esdaile JM et al. Indications for total hip and total knee arthroplasties. Results of orthopaedic surveys. J Arthroplasty 1996; 11: 34–46.
Hunter DJ, McDougall JJ, Keefe FJ . The symptoms of osteoarthritis and the genesis of pain. Med Clin North Am 2009; 93: 83–100.
Piel MJ, Kroin JS, van Wijnen AJ et al. Pain assessment in animal models of osteoarthritis. Gene 2014; 537: 184–188.
Neugebauer V, Han JS, Adwanikar H et al. Techniques for assessing knee joint pain in arthritis. Mol Pain 2007; 3: 8.
Malfait AM, Little CB, McDougall JJ . A commentary on modelling osteoarthritis pain in small animals. Osteoarthritis Cartilage 2013; 21: 1316–1326.
Henze DA, Urban MO . Large animal models for pain therapeutic development. In: Kruger L, Light AR (ed.). Translational Pain Research: From Mouse to Man. London: CRC Press, 2010: 371–390.
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This project has been supported by NIH grants AR055915 and AR054465 to DC.
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Chen, D., Shen, J., Zhao, W. et al. Osteoarthritis: toward a comprehensive understanding of pathological mechanism. Bone Res 5, 16044 (2017). https://doi.org/10.1038/boneres.2016.44
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DOI: https://doi.org/10.1038/boneres.2016.44
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