Osteoarthritis (OA) is a chronic degenerative disease characterized by progressive cartilage erosion leading to pain. At present, there is no efficient treatment to cure or even delay the progression of this most common disability-associated disease. The aetiology of OA is still unknown although clinical studies have shown that numerous factors are strong determinants. Among them, can be included genetic predisposition, obesity and primarily, age [1]. Remarkably, all of these factors are also associated with the prevalence of other age-related human diseases such as atherosclerosis [2] and preneoplasic lesions [3]. Recent works have focussed on the molecular events that govern the genesis of these lesions accumulating with age in numerous tissues [4, 5]. Preneoplasic lesions are benign. Nevertheless these cells may acquire, with time, new properties, such as genetic instability inducing in fine cellular transformation leading to neoplasia and eventually tumour formation. In summary, preneoplasic lesions are seen as natural barriers preventing tumour expansion and malignancy. Analysis of these recent studies reveals the strikingly high number of common characteristics between preneoplasic tissues and OA cartilage. Even if these common characteristics of cellular senescence in both pathologies may be merely co-incidental, they have to be highlighted in the prospect of using new therapeutic intervention in OA. Thus, the aim of this review is first, to highlight their common signatures and second, to focus on the molecular mechanisms shared by both pathologies.

The role of articular cartilage is to transmit forces across diarhodial joints and maintain a friction-free surface at the epiphyseal ends of long bones to support limb movement. Articular cartilage is organised in various layers and contains one cell component, the chondrocyte which contributes by its anabolic function to the production and/or maintenance of the extracellular matrix (ECM) of the tissue [6]. The ECM is composed of a network of collagen fibres, primarily type II collagen and secondarily, type IX and XI collagens that give the tissue its shape, strength and tensile force. It also contains a highly hydrated gel of large proteoglycans, aggrecan being the most prominent, and glycoproteins which give resistance to compression [7]. Once the cartilage is formed in the adult, the turn-over of ECM components is very low.

Among the numerous diseases which affect cartilage, OA is the most prevalent one. A number of studies have described the progression of this common disease [8]. The first detectable changes during OA by clinical examination are softening, fibrillation and ulceration of the cartilage. At latest stages of the disease, appearance of chondrophytes from neodifferentiated periosteal cells which eventually turn after calcification into osteophytes are present on the joint edge [9]. These osteophytes, as a sort of extension of the articular surface, are responsible of the increasing pain. Finally, subchondral bone remodelling is proposed to be one driving force that accelerates cartilage [10].

Chondrocytes are the central players in the changes that occur during primary or secondary OA [8]. Anabolic function of chondrocytes is decreasing following pathology progression. This loss of function is mainly associated with a premature cellular senescence of chondrocytes [11]. Indeed, OA chondrocytes express a panel of senescence markers including acidic β-galactosidase activity [12], increase in reactive oxygen species (ROS), telomere attrition [13] and p53/p16^ink4 accumulation [11]. Although the subject of debate, apoptotic chondrocytes have also been detected by tunnel assay in OA cartilage [14, 15]. Furthermore, an increased number of chondrocytes with altered phenotype and chondrocyte progenitors have also been found in OA cartilage [8, 16]. Finally, an increased number of hypertrophic chondrocytes, characterised by the expression of specific markers, such as collagen type X, alkaline phosphatase or runx2, is frequently observed [17]. In summary, OA is a multi-phenotypic complex disease where articular chondrocytes exhibit characteristics of stress-induced senescence with altered phenotypes and impaired normal anabolic capacities [11].

Preneoplasic and neoplasic lesions are common. Both types of lesions are located within a high proliferative tissue and they increase with age. They are the result of abnormal cell proliferation that exceeds the surrounding normal tissue. Physiologically, preneoplasia preceed neoplasia and both stages of lesion progression are hardly distinguishable. Neoplasia can remain benign or degenerate into tumour. Preneoplasia is induced in vivo following viral infection, recurrent genotoxic insults such as ultra-violet (UV), metabolic oxidative stress or genetic predisposition [18]. Genetic and molecular events that initiate this dysplasia have been broadly documented for the last 15 years. Indeed, these abnormal cells harbour an apparent attempt to hyperproliferate but rather are kept confined by a permanent cell cycle arrest associated with a senescent phenotype and impaired secretor activities [5, 19-21].

Cells are naturally exposed to various types of stress that lead to genomic assault during lifespan. Thus, cell-intrinsic mechanisms have evolved to limit the expansion of genetically altered cells. Cellular senescence is one of the natural barriers developed by multicellular organisms to suppress the unscheduled proliferation of damaged cells [19, 22, 23]. Cellular senescence is therefore a strong tumour suppressor pathway that is activated in benign preneoplasic-like lesions [5, 19, 21]. Remarkably, cellular senescence also occurs prematurely in OA chondrocytes. It is therefore tempting to make analogies between OA and preneoplasia associated characteristics (Fig. 1).

Fig. (1). Cellular senescence is a common characteristic of preneoplasic tissue and cartilage in early osteoarthritis (OA). (A) Neoplasia genesis. Upon environmental stress (carcinogens, oncogenes, genotoxics), in highly proliferative tissues such as epithelium, some cells will respond by abortive proliferation and emergence of senescent cells. If one cell overcomes the senescent process by inactivation of the DNA damage response (DDR), cell proliferation will lead to neoplasia and eventually tumour. (B) OA genesis. Upon environmental stress (mechanical stress, aging factors), OA chondrocytes become senescent and display an imbalance between anabolic and catabolic activity in favour of catabolism, leading to cartilage degradation. In both tissues, common senescence-associated markers are expressed: activated DDR and secretion of reactive oxygen species (ROS), interleukin (IL)-1β, IL-8, insulin growth factor binding protein (IGFBP)-3, vascular endothelial growth factor (VEGF) and metalloproteinases (MMPs).

Cellular senescence seems to be a common process developed by OA chondrocytes and pre-tumour cells that may be at the genesis of both pathologies. Prevalence of these diseases increases with age and among the senescence-associated markers, ROS accumulation plays a central role. ROS production induces DDR-dependent premature senescence in preneoplasic cells and in OA chondrocytes contributing to the loss of their anabolic functions.

A number of studies now suggest that senescent cells secrete specific factors that set the stage for a cross-talk between senescent cells and their environment [20]. Such signals would be integrated into a coordinated response that can cause other cell components to prematurely senesce thereby establishing a pro-aging loop [20]. The consequence of the pro-aging loop is the degradation of the ECM, degeneration of the targeted tissue and production of survival factors such as VEGF [37]. Indeed, OA chondrocytes and preneoplasic-associated senescent cells both secrete VEGF but in pre-tumour tissues, VEGF helps tissue growth and survival by promoting new blood vessel formation [47]. In contrast, in the cartilage, the increase in vascularisation participates to the aberrant ossification of cartilage leading to osteophyte formation [46]. This phenomenon would favour subchondral bone pressure in OA patients.

Two exciting points of view emerge from all the similarities reported here between both diseases. First, as we mentioned, the aetiology seems to be similar. In proliferative tissue such as epithelium, the accumulation of senescent cells within preneoplasic-like lesions harbouring specific secretary properties will lead to tissue degeneration and may induce tumour development [5, 20]. By chance, accumulation of premature senescent chondrocytes in OA lesions occurs in a slowly proliferative tissue, dramatically reducing the risk of cell transformation yet promoting tissue degeneration. Second, research on OA physiopathology should take into account the literature on the deciphering of the neoplasia-associated molecular mechanisms and the prevention of tumour formation. Indeed, according to the numerous similarities between preneoplasic and OA lesions, it would be questionable whether the battery of pharmaceutical compounds available for anti-cancer treatments such as anti-VEGF treatments could be tested by clinicians as potential OA treatments in order to delay or prevent the progression of this disease.