|Year : 2017 | Volume
| Issue : 1 | Page : 1-5
Pathological perspective of chondrocyte apoptosis in osteoarthritis
Abhijeet Kunwar1, Mohan Kumar2, Saurabh Singh1
1 Department of Orthopaedics, Institute of Medical Sciences, BHU, Varanasi, Uttar Pradesh, India
2 Department of Pathology, Institute of Medical Sciences, BHU, Varanasi, Uttar Pradesh, India
|Date of Web Publication||29-May-2017|
Department of Pathology, Institute of Medical Sciences, BHU, Varanasi - 221 005, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
Osteoarthritis constitutes a major burden for health care besides posing great impediments to quality of life in progressively widening population of the aged. There have been on-going efforts to rationally address the preventive and corrective interventions. Destruction of articular cartilage is a cardinal consideration in this regard. The dilemma persists over that being a cause or effect of the osteoarthritic syndrome. The aging diseases are typically accompanied by comorbidities and decline in physiological functions. This article appraises the pathological process of cartilage destruction in such context to reflect on interventional perspectives ahead.
Keywords: Apoptosis, cartilage, chondrocyte, osteoarthritis
|How to cite this article:|
Kunwar A, Kumar M, Singh S. Pathological perspective of chondrocyte apoptosis in osteoarthritis. J Orthop Traumatol Rehabil 2017;9:1-5
|How to cite this URL:|
Kunwar A, Kumar M, Singh S. Pathological perspective of chondrocyte apoptosis in osteoarthritis. J Orthop Traumatol Rehabil [serial online] 2017 [cited 2018 Sep 18];9:1-5. Available from: http://www.jotr.in/text.asp?2017/9/1/1/207173
| Introduction|| |
Osteoarthritis (OA) is the most common degenerative joint disease characterized by the loss of articular cartilage. Articular cartilage is a hyaline cartilage, an avascular tissue composed of ordered matrix surrounding chondrocyte in their lacunae. It has a very complex composition and architecture and divided into four zones-superficial, middle, deep, and calcified depending on the distribution and arrangement of matrix and chondrocyte. In OA, the morphological change includes thinning, fissuring, and fragmentation of articular cartilage. The death of chondrocyte is said to be the key player in cartilage degeneration.,,
Chondrocyte death by apoptosis, necrosis, or combination of the two have been implicated in the pathogenesis of OA.,,,,,,,, Cell usually die by one of the two process, apoptosis, and necrosis. Apoptosis or a programmed cell death display distinct morphological manifestation which includes nuclear fragmentation, chromatin condensation, membrane blebbing, cell shrinkage, and the presence of apoptotic bodies.
There are two classical pathways of apoptosis, death receptor pathway, and mitochondrial pathway. In the former pathway, the death receptors (such as tumor necrosis factor [TNF] or Fas receptors) are activated by specific death ligands. The mitochondrial pathway is initiated by stimuli that change mitochondrial membrane permeability to preapoptotic proteins. Necrosis, on the other hand, is a nonprogrammed caspase- and energy-independent form of cell death. Cell die by necrosis when there is tissue damage as a result of exposure to highly toxic substances or extreme physiological conditions. The main difference between apoptotic and necrotic cell is that the later is accompanied by an inflammatory reaction due to the accumulation of cytoplasmic contents in intercellular regions due to the loss of cell membrane integrity.
| Mechanism of Apoptotic Cell Death|| |
Several families of proteins and specific biochemical signal transduction pathway regulate cell death. Predominant factors in cell death and cell survival include Fas receptor, BCl-2 and Bax, cytochrome C, caspases, p53, and extracellular signal-regulated protein kinases. Some forms of cell death require gene activation, RNA synthesis and protein synthesis; whereas, other forms are transcriptionally and translationally independent and are driven by posttranslational mechanisms such as protein phosphorylation and protein translocation. Following an appropriate stimulus, the first stage or decision phase of apoptosis is the genetic control point of cell death. This is followed by the second state or execution phase which is responsible for the morphological changes of apoptosis. The decision phase or genetic control is mediated by two genes, BCl-2 and p53. Whereas, the execution phase appears to result from the activation of caspases. It has become apparent that the BCl-2 family of proteins constitutes an intracellular checkpoint within a distal common pathway of programmed cell death.,,,
It is now established that proteins encoded by the BCl-2 gene family are the major regulatory components of the apoptotic pathway., They are found on the mitochondrial membrane and endoplasmic reticulum and may control calcium channel. There is a family of proteins similar to BCl-2 that promotes or inhibits apoptosis. Proteins such as BCl-2 and BCl-XL prevent apoptosis, whereas BCl-2 associated X-proteins (such as Bax, Bad, Bak) promote apoptosis. The susceptibility of an individual cell to apoptosis-triggering stimuli is largely determined by its genetic content, metabolic state and proliferative state as well as its distinct receptor and signal transduction pathways. The ratio of BCl-2 and Bax is important in determining the susceptibility to apoptosis. These proteins are activated by physiological or injurious stimuli and appear to operate upstream of the event leading to the final execution phase of the apoptotic process which involves the activation of cysteine proteases and caspases.
p53 tumor suppressor gene has also been implicated in apoptosis. The gene p53 is a 53-kDa nuclear phosphoprotein that binds to DNA to act as a transcription factor and control cell proliferation and DNA repair. There is evidence that p53 can induce and repress Bax and BCl-2 transcription. p53 activity can be modulated by glucocorticoids or indirectly by stress-induced activation of the hypothalamic pituitary adrenal axis.
The central events in apoptosis are proteolysis and mitochondrial inactivation. Cellular disruption results from activation of a family of cysteine protease called caspases. CED-3, which encodes a cysteine protease that is homologous to interleukin-1 beta converting enzyme (ICE), is essential for apoptosis to occur., At least 11 members of the CED/ICE family of proteases have been recognized and implicated in apoptosis.,
Enhanced expression of the transcriptional factors C-Jun and C-Fas and increased levels of C-Jun mRNA have been observed., These early genes initiate a complex cascade of events that transduce extracellular signals into the alteration of cellular functions by regulating target gene expression (late response genes). Some of these late response genes express after C-Fas induction are associated with apoptosis, whereas other enhance cell survival.
| Current Opinion on Apoptosis in Osteoarthritis|| |
Chondrocyte death in osteoarthritic cartilage is supported by the presence of large numbers of empty lacunae and hypocellularity , and correlated with mechanical injury, increased production of reactive oxygen species, disruption of extracellular matrix integrity, and loss of production of growth factors by the cell. Systematic investigations demonstrate the relationship between apoptosis and OA. The future development relating new treatment option for patients of OA has to see resolution. Whether chondrocyte apoptosis is a cause or result of cartilage degeneration in OA remains to be answered.
Apoptosis as an etiological factor
Many studies demonstrated that there is a significant decrease in chondrocyte numbers in articular cartilage during aging.,,,, While others reported moderate to strong positive correlation between the degree of cartilage damage and chondrocyte death by apoptosis.,,,, These, together with data from epidemiological studies, show a high prevalence of OA among elderly, and led to the theory that chondrocyte apoptosis may be a possible cause of OA. More direct evidence implicating apoptosis in the initiation of OA comes from the studies examining articular cartilage from animals. These imply that decrease in chondrocyte number is an early process of OA, and this deduction is also supported by studies of human OA cartilage.
Aigner et al. found that relatively normal looking human cartilage had severely altered gene expression, including genes that related to programmed cell death. Chondrocyte apoptosis is positively correlated with early stages of OA, suggesting that this process is intrinsically linked to cartilage degradation in OA. In addition, joints which frequently develop OA are more susceptible to apoptosis-induction by TNF than joints that rarely develop the disease. The results not only suggest that apoptosis is important in the pathogenesis of OA but also provide a possible explanation for the joint specific nature of the disease. There may be a number of possible mechanisms involved in chondrocyte apoptosis mediated cartilage damage and development of OA. During aging, chondrocytes may undergo phenotypic changes which make them more vulnerable to pro-apoptotic and other catabolic stimuli and less responsive to anti-apoptotic and anabolic factors. More direct damage to cartilage may be caused by the end product of apoptosis, the apoptotic bodies. Cartilage being an avascular tissue does not have phagocytic cells, therefore apoptotic bodies in cartilage are not cleared quickly and accumulation of these bodies leads to cartilage matrix damage. Besides, the apoptotic bodies produce alkaline phosphatase and induce precipitation of calcium which results in abnormal calcification in the sub-chondral bone and subsequent cartilage degeneration. These studies support the theory that apoptosis may be an important cause of OA, but it does not provide direct evidence of chondrocyte apoptosis leading to OA. This would require studies of suitable animal model and controls. Finally to prove whether chondrocyte apoptosis indeed causes OA, apoptosis needs to be induced in an animal free of disease and cartilage damage need to be monitored carefully from early stages of OA.
Apoptosis as a consequence
The concept that chondrocyte apoptosis could be secondary to cartilage degeneration is supported by the fact that cell-matrix interaction is vital for chondrocyte survival. The phenomena of anchorage dependence state that cell needs to attach to extracellular matrix or to each other for survival. Thus, when the extracellular matrix is damaged by either mechanical load or inadequate synthesis, chondrocyte may undergo apoptosis and exacerbate existing cartilage matrix breakdown. Chondrocyte survival is thought to be mediated by integrins, α/β-heterodimeric receptors. These connect the extracellular matrix component like collagen, and fibronection to various intracellular cytoskeletal proteins., Loss of this adhesion may enhance chondrocyte apoptosis. Recent studies show that extent of chondrocyte apoptosis is possibly correlated with expression of fibronectin, one of the key extracellular matrix molecules involved in communication between the cartilage cells and surrounding matrix. Upregulation of expression of fibronectin is associated with the severity of articular cartilage damage. Expression of fibronectin occurs early in the development of OA. The positive association with apoptosis reveals that both expressions of fibronectin and chondrocyte apoptosis are early events involved in the initiation of OA.,,, These studies suggest that decreased expression or availability of important matrix macromolecules in cartilage is sufficient to induce chondrocyte apoptosis and cause exacerbation of matrix damage. Other evidence supporting the theory that apoptosis is a consequence of OA comes from studies of cartilage following mechanical damage/loading.
Abnormal mechanical loading is a major risk factor for the development of OA. Vigorous cyclic loading of normal cartilage can cause collagen denaturation, expel glycosaminoglycans from articular cartilage, and induce possibly apoptosis.,,, Injurious mechanical loading on human cartilage explants had been shown to induce chondrocyte apoptosis by specialized investigations. In another study cartilage from the fractured human tibia, was found to have significantly higher number of TUNEL-positive chondrocyte relative to controls. These TUNEL-positive cells were localized adjacent to OA lesions. Collectively, these finding suggest that abnormal mechanical stress on normal cartilage can lead to chondrocyte apoptosis and degeneration and loss of cartilage.
Disruption of chondrocyte-matrix interaction may be either due to direct injury to the cartilage causing biochemical changes or loss of extracellular matrix component. In addition, early cartilage fibrillation may also expose the chondrocyte to catabolic factors such as nitric oxide and cytokines secreted by synoviocytes as well as chondrocytes These mediators are likely to induce further chondrocyte death by apoptosis and progression of cartilage damage. Other studies suggest that presence of collagenase and other degradative enzymes in joints may predispose chondrocyte to apoptosis.
Experiments carried out by Lo and Kim  found collagenase treatment of primary human chondrocyte to induce chondrocyte apoptosis in close dependent manner. This can be inhibited by caspase inhibitors as well as insulin-like growth lactose-1. Later, D'Lima et al. confirmed that caspase inhibitors can reduce the severity of cartilage lesions in anterior cruciate ligament transaction induced OA in the rabbit. These clearly support the notion that apoptosis is a consequence of OA.
| Potential Therapies in Osteoarthritis|| |
The ability to intervene in the process of apoptosis may provide a potential target for therapeutic interventions in OA. One of the candidates for intervention is the inhibition of caspase, the major player in the final executive phase of the apoptotic cascade. Nonspecific caspase inhibition using Z-VAD, fmk and specific inhibition of caspase-3 with AC-DMQD-CHO have both been found to effectively block apoptosis., The evidence in the rabbit model suggests that caspase inhibition may also improve disease outcome. A potential therapeutic value of caspase inhibition in OA is so suggested. Other pro-apoptotic stimuli including nitric oxide, prostaglandins, cytokines, and reactive oxygen species are also potential targets for drugs to block apoptosis of chondrocytes. Other strategies are focused on the regulation of the natural inhibitors of apoptosis (e.g., C-FIIP, BAR, ARC, and HC-gp39).
| Epilog|| |
The narrative projects upon vistas in the progression of OA with cartilage destruction as cause/effect perspective. Researches for therapy development demand extensive data and application of newer investigative technologies. Individualized appraisal of pathology emerges as crucial to evolving personalized preventative/corrective therapies.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Eckstein F, Reiser M, Englmeier KH, Putz R.In vivo
morphometry and functional analysis of human articular cartilage with quantitative magnetic resonance imaging – from image to data, from data to theory. Anat Embryol (Berl) 2001;203:147-73.
Kouri JB, Argüello C, Luna J, Mena R. Use of microscopical techniques in the study of human chondrocytes from osteoarthritic cartilage: An overview. Microsc Res Tech 1998;40:22-36.
Lotz M, Loeser RF. Effects of aging on articular cartilage homeostasis. Bone 2012;51:241-8.
Kourí JB, Aguilera JM, Reyes J, Lozoya KA, González S. Apoptotic chondrocytes from osteoarthrotic human articular cartilage and abnormal calcification of subchondral bone. J Rheumatol 2000;27:1005-19.
Tatari H. The structure, physiology, and biomechanics of articular cartilage: Injury and repair. Acta Orthop Traumatol Turc 2007;41 Suppl 2:1-5.
Kühn K, Shikhman AR, Lotz M. Role of nitric oxide, reactive oxygen species, and p38 MAP kinase in the regulation of human chondrocyte apoptosis. J Cell Physiol 2003;197:379-87.
Kuettner KE, Cole AA. Cartilage degeneration in different human joints. Osteoarthritis Cartilage 2005;13:93-103.
Ribe EM, Serrano-Saiz E, Akpan N, Troy CM. Mechanisms of neuronal death in disease: Defining the models and the players. Biochem J 2008;415:165-82.
Walker NI, Harmon BV, Gobé GC, Kerr JF. Patterns of cell death. Methods Achiev Exp Pathol 1988;13:18-54.
Paddenberg R, Wulf S, Weber A, Heimann P, Beck LA, Mannherz HG. Internucleosomal DNA fragmentation in cultured cells under conditions reported to induce apoptosis may be caused by mycoplasma endonucleases. Eur J Cell Biol 1996;71:105-19.
Sastry PS, Rao KS. Apoptosis and the nervous system. J Neurochem 2000;74:1-20.
Zlatkovic J, Filipovic D. Bax and B-cell-lymphoma 2 mediate proapoptotic signaling following chronic isolation stress in rat brain. Neuroscience 2012;223:238-45.
Liu QA, Hengartner MO. The molecular mechanism of programmed cell death in C. elegans
. Ann N
Y Acad Sci 1999;887:92-104.
Knudson CM, Korsmeyer SJ. Bcl-2 and bax function independently to regulate cell death. Nat Genet 1997;16:358-63.
Golstein P. Controlling cell death. Science 1997;275:1081-2.
Oh SH, Yin HQ, Lee BH. Role of the Fas/Fas ligand death receptor pathway in ginseng saponin metabolite-induced apoptosis in HepG2 cells. Arch Pharm Res 2004;27:402-6.
Oltvai ZN, Korsmeyer SJ. Checkpoints of dueling dimers foil death wishes. Cell 1994;79:189-92.
Petros AM, Olejniczak ET, Fesik SW. Structural biology of the Bcl-2 family of proteins. Biochim Biophys Acta 2004;1644:83-94.
Newton K, Strasser A. The Bcl-2 family and cell death regulation. Curr Opin Genet Dev 1998;8:68-75.
Miyashita T, Reed JC. Tumor suppressor p53 is a direct transcriptional activator of the human bax gene. Cell 1995;80:293-9.
Firestone GL, Giampaolo JR, O'Keeffe BA. Stimulus-dependent regulation of serum and glucocorticoid inducible protein kinase (SGK) transcription, subcellular localization and enzymatic activity. Cell Physiol Biochem 2003;13:1-12.
Savitz SI, Daniel BA, Rosenbaum MD. Apoptosis in neurological disease. Neurosurgery 1998;42:555-72.
Ellis RE, Jacobson DM, Horvitz HR. Genes required for the engulfment of cell corpses during programmed cell death in Caenorhabditis elegans
. Genetics 1991;129:79-94.
Yuan J, Shaham S, Ledoux S, Ellis HM, Horvitz HR. The C. elegans
cell death gene CED-3 encodes a protein similar to mammalian interleukin-1 beta-converting enzyme. Cell 1993;75:641-52.
Chinnaiyan AM, O'Rourke K, Lane BR, Dixit VM. Interaction of CED-4 with CED-3 and CED-9: A molecular framework for cell death. Science 1997;275:1122-6.
Kuida K, Zheng TS, Na S, Kuan C, Yang D, Karasuyama H, et al.
Decreased apoptosis in the brain and premature lethality in CPP32-deficient mice. Nature 1996;384:368-72.
Oo TF, Henchcliffe C, James D, Burke RE. Expression of C-fos, C-jun, and C-jun N-terminal kinase (JNK) in a developmental model of induced apoptotic death in neurons of the substantia nigra. J Neurochem 1999;72:557-64.
Miller TM, Johnson EM Jr. Metabolic and genetic analyses of apoptosis in potassium/serum-deprived rat cerebellar granule cells. J Neurosci 1996;16:7487-95.
Smeyne RJ, Vendrell M, Hayward M, Baker SJ, Miao GG, Schilling K, et al.
Continuous C-fos expression precedes programmed cell death in vivo
. Nature 1993;363:166-9.
Kim HA, Blanco FJ. Cell death and apoptosis in osteoarthritic cartilage. Curr Drug Targets 2007;8:333-45.
Aigner T, Kim HA. Apoptosis and cellular vitality: Issues in osteoarthritic cartilage degeneration. Arthritis Rheum 2002;46:1986-96.
Del Carlo M Jr., Loeser RF. Cell death in osteoarthritis. Curr Rheumatol Rep 2008;10:37-42.
Jimenez PA, Glasson SS, Trubetskoy OV, Haimes HB. Spontaneous osteoarthritis in Dunkin Hartley Guinea pigs: Histologic, radiologic, and biochemical changes. Lab Anim Sci 1997;47:598-601.
Todd Allen R, Robertson CM, Harwood FL, Sasho T, Williams SK, Pomerleau AC, et al.
Characterization of mature vs aged rabbit articular cartilage: Analysis of cell density, apoptosis-related gene expression and mechanisms controlling chondrocyte apoptosis. Osteoarthritis Cartilage 2004;12:917-23.
Hashimoto S, Ochs RL, Rosen F, Quach J, McCabe G, Solan J, et al.
Chondrocyte-derived apoptotic bodies and calcification of articular cartilage. Proc Natl Acad Sci U S A 1998;95:3094-9.
Mobasheri A. Role of chondrocyte death and hypocellularity in ageing human articular cartilage and the pathogenesis of osteoarthritis. Med Hypotheses 2002;58:193-7.
Adams CS, Horton WE Jr. Chondrocyte apoptosis increases with age in the articular cartilage of adult animals. Anat Rec 1998;250:418-25.
Hashimoto S, Ochs RL, Komiya S, Lotz M. Linkage of chondrocyte apoptosis and cartilage degradation in human osteoarthritis. Arthritis Rheum 1998;41:1632-8.
Matsuo M, Nishida K, Yoshida A, Murakami T, Inoue H. Expression of caspase-3 and -9 relevant to cartilage destruction and chondrocyte apoptosis in human osteoarthritic cartilage. Acta Med Okayama 2001;55:333-40.
Thomas CM, Fuller CJ, Whittles CE, Sharif M. Chondrocyte death by apoptosis is associated with cartilage matrix degradation. Osteoarthritis Cartilage 2007;15:27-34.
Hashimoto S, Takahashi K, Amiel D, Coutts RD, Lotz M. Chondrocyte apoptosis and nitric oxide production during experimentally induced osteoarthritis. Arthritis Rheum 1998;41:1266-74.
Yatsugi N, Tsukazaki T, Osaki M, Koji T, Yamashita S, Shindo H. Apoptosis of articular chondrocytes in rheumatoid arthritis and osteoarthritis: Correlation of apoptosis with degree of cartilage destruction and expression of apoptosis-related proteins of p53 and c-myc. J Orthop Sci 2000;5:150-6.
Bobinac D, Spanjol J, Zoricic S, Maric I. Changes in articular cartilage and subchondral bone histomorphometry in osteoarthritic knee joints in humans. Bone 2003;32:284-90.
Aigner T, Fundel K, Saas J, Gebhard PM, Haag J, Weiss T, et al.
Large-scale gene expression profiling reveals major pathogenetic pathways of cartilage degeneration in osteoarthritis. Arthritis Rheum 2006;54:3533-44.
Thomas CM, Whittles CE, Fuller CJ, Sharif M. Variations in chondrocyte apoptosis may explain the increased prevalence of osteoarthritis in some joints. Rheumatol Int 2011;31:1341-8.
Zemmyo M, Meharra EJ, Kühn K, Creighton-Achermann L, Lotz M. Accelerated, aging-dependent development of osteoarthritis in alpha1 integrin-deficient mice. Arthritis Rheum 2003;48:2873-80.
Goggs R, Carter SD, Schulze-Tanzil G, Shakibaei M, Mobasheri A. Apoptosis and the loss of chondrocyte survival signals contribute to articular cartilage degradation in osteoarthritis. Vet J 2003;166:140-58.
Blanco FJ, Guitian R, Vázquez-Martul E, de Toro FJ, Galdo F. Osteoarthritis chondrocytes die by apoptosis. A possible pathway for osteoarthritis pathology. Arthritis Rheum 1998;41:284-9.
Kim HA, Lee YJ, Seong SC, Choe KW, Song YW. Apoptotic chondrocyte death in human osteoarthritis. J Rheumatol 2000;27:455-62.
Clements KM, Hollander AP, Sharif M, Adams MA. Cyclic loading can denature type II collagen in articular cartilage. Connect Tissue Res 2004;45:174-80.
Summers GC, Merrill A, Sharif M, Adams MA. Swelling of articular cartilage depends on the integrity of adjacent cartilage and bone. Biorheology 2008;45:365-74.
Clements KM, Bee ZC, Crossingham GV, Adams MA, Sharif M. How severe must repetitive loading be to kill chondrocytes in articular cartilage? Osteoarthritis Cartilage 2001;9:499-507.
Hashimoto S, Nishiyama T, Hayashi S, Fujishiro T, Takebe K, Kanzaki N, et al.
Role of p53 in human chondrocyte apoptosis in response to shear strain. Arthritis Rheum 2009;60:2340-9.
D'Lima DD, Hashimoto S, Chen PC, Colwell CW Jr., Lotz MK. Human chondrocyte apoptosis in response to mechanical injury. Osteoarthritis Cartilage 2001;9:712-9.
Lo MY, Kim HT. Chondrocyte apoptosis induced by collagen degradation: Inhibition by caspase inhibitors and IGF-1. J Orthop Res 2004;22:140-4.
Nuttall ME, Nadeau DP, Fisher PW, Wang F, Keller PM, DeWolf WE Jr., et al.
Inhibition of caspase-3-like activity prevents apoptosis while retaining functionality of human chondrocytes in vitro
. J Orthop Res 2000;18:356-63.
D'Lima DD, Hashimoto S, Chen PC, Lotz MK, Colwell CW Jr. Prevention of chondrocyte apoptosis. J Bone Joint Surg Am 2001;83-A Suppl 2(Pt 1):25-6.