The age-related changes in cartilage and osteoarthritis

Abstract

Osteoarthritis (OA) is closely associated with aging, but its underlying mechanism is unclear. Recent publications were reviewed to elucidate the connection between aging and OA. With increasing OA incidence, more senior people are facing heavy financial and social burdens. Age-related OA pathogenesis is not well understood. Recently, it has been realized that age-related changes in other tissues besides articular cartilage may also contribute to OA development. Many factors including senescence-related secretory phenotypes, chondrocytes' low reactivity to growth factors, mitochondrial dysfunction and oxidative stress, and abnormal accumulation of advanced glycation end products (AGEs) may all play key roles in the pathogenesis of age-related OA. Lately, epigenetic regulation of gene expression was recognized for its impact on age-related OA pathogenesis. Up to now, few studies have been reported about the role of miRNA and long-noncoding RNA (lncRNA) in age-related OA. Research focusing on this area may provide valuable insights into OA pathogenesis. OA-induced financial and social burdens have become an increasingly severe threat to older population. Age-related changes in noncartilage tissue should be incorporated in the understanding of OA development. Growing attention on oxidative stress and epigenetics will provide more important clues for the better understanding of the age-related OA.

Figure 1

Schematic diagram showing the key role of ROS in age-related chondrocyte changes. Excessive levels of ROS inhibited matrix synthesis (aggrecan, type II collagen) by suppressing the IRS-1-PI-3 kinase-Akt signaling pathway or by activating the ERK MAPK signaling pathway. Sustained activation of ERK can induce cell senescence. In addition, extracellular ROS could also contribute to the inhibition of the Akt pathway through oxidized low-density lipoprotein (LDL). The binding of oxidized LDL to cell surface receptor LOX-1 was found to induce chondrocyte senescence (blue arrow).

Figure 2

Schematic diagram showing that cartilage matrix homeostasis is adjusted dynamically by TGF-β signaling pathway. Activated TGF-β binds to the TGF-β type I receptor ALK1, resulting in phosphorylation of Smad1, Smad5, or Smad8, which form a complex with the co-Smad Smad4 and translocate to the nucleus to promote cartilage matrix anabolism by modifying gene expression. Meanwhile, the activated TGF-β type II receptor ALK5 results in phosphorylation of Smad2 or Smad3 which form a complex with the co-Smad Smad4 and translocate to the nucleus to promote cartilage matrix catabolism by modifying gene expression.

Figure 3

Schematic diagram showing the role of Wnt signaling in age-related changes of cartilage. Wnt could bind to Frizzled receptors and LRP5/6 coreceptors and lead to stabilization of β-catenin via inhibition of GSK-3β mediated ubiquitination and degradation. Then β-catenin translocated to the nucleus and bound to TCF/LEF-1 transcription factors, which can inhibit and promote early chondrogenesis as well as promote hypertrophy and chondrocyte dedifferentiation.