Inflammatory and Metabolic Signaling Interfaces of the Hypertrophic and Senescent Chondrocyte Phenotypes Associated with Osteoarthritis

Abstract

Osteoarthritis (OA) is a complex disease of whole joints with progressive cartilage matrix degradation and chondrocyte transformation. The inflammatory features of OA are reflected in increased synovial levels of IL-1β, IL-6 and VEGF, higher levels of TLR-4 binding plasma proteins and increased expression of IL-15, IL-18, IL-10 and Cox2, in cartilage. Chondrocytes in OA undergo hypertrophic and senescent transition; in these states, the expression of Sox-9, Acan and Col2a1 is suppressed, whereas the expression of RunX2, HIF-2α and MMP-13 is significantly increased. NF-kB, which triggers many pro-inflammatory cytokines, works with BMP, Wnt and HIF-2α to link hypertrophy and inflammation. Altered carbohydrate metabolism and the upregulation of GLUT-1 contribute to the formation of end-glycation products that trigger inflammation via the RAGE pathway. In addition, a glycolytic shift, increased rates of oxidative phosphorylation and mitochondrial dysfunction generate reactive oxygen species with deleterious effects. An important surveyor mechanism, the YAP/TAZ signaling system, controls chondrocyte differentiation, inhibits ageing by protecting the nuclear envelope and suppressing NF-kB, MMP-13 and aggrecanases. The inflammatory microenvironment and synthesis of key matrix components are also controlled by SIRT1 and mTORc. Senescent chondrocytes represent the functional end stage of hypertrophic differentiation and characteristically upregulate p16 and p21, but also a variety of inflammatory cytokines, chemokines and metalloproteinases, developing the senescence-associated secretory phenotype. Senolysis with dendrobin, miR29b-5p and other agents has been shown to be efficient under experimental conditions, and appears to be a promising tool for the treatment of OA, as it restores COL2A1 and aggrecan synthesis, suppressing NF-kB and destructive metalloproteinases.

The Heterogeneity of Post-Menopausal Disease Risk: Could the Basis for Why Only Subsets of Females Are Affected Be Due to a Reversible Epigenetic Modification System Associated with Puberty, Menstrual Cycles, Pregnancy and Lactation, and, Ultimately, Menopause?

“…Whether the development of OA, particularly in the knee, in the post-menopausal state is a unique subset of OA patients is unknown, but the possibility has been raised [10]. However, it is clear that OA is an inflammatory disease (discussed in [51][52][53][54]) and in early post-traumatic knee injuries leading to OA in preclinical models, treatment to inhibit inflammation ameliorates the development of the condition [55][56][57]. Furthermore, metabolic osteoarthritis has an inflammatory component [58][59][60] and this may relate to post-menopausal women with obesity.…”

The role of YAP/TAZ on joint and arthritis

“…Chondrocytes in OA undergo hypertrophic and senescent phenotypic transition when exposed to abnormal biomechanical and biochemical joint environment from matrix degradation products and pro-inflammatory mediators. [132][133][134][135] Although chondrocyte hypertrophy is a necessary developmental stage in endochondral ossification, the aberrant hypertrophy-like phenotype in OA chondrocytes results in irreversible cartilage destruction and initiation of OA. 132 It was reported that YAP significantly suppresses the expression of Runx2 and chondrocyte hypertrophy.…”

“…[138][139][140] Guarnieri et al demonstrated that YAP/TAZ activity in stromal cells prevents emergence of senescent cells and SASP by restraining cGAS-STING signaling, 141 probably through the protection of nuclear envelope integrity. 135,141 In addition, mechanical cues, such as ECM stiffness and cell geometry, also induced cell senescence via YAP inhibition. 142 Moreover, YAP overexpression rejuvenates aged MSCs and inhibits cell senescence by up-regulation of forkhead box D1 (FOXD1) in a TEADdependent manner, whereas YAP knockdown results in premature senescence of MSCs due to FOXD1 inactivation.…”

Exosomes loaded a smart bilayer-hydrogel scaffold with ROS-scavenging and macrophage-reprogramming properties for repairing cartilage defect

“…The chronic inflammatory microenvironment resulting from AC damage is inundated with various activated inflammatory cells and pro-inflammatory mediators, along with reactive oxygen species (ROS) [ 20 , 21 ]. During cartilage injury, overexpressed ROS not only attacks the extracellular matrix (ECM) of the AC directly but also induces lipid peroxidation and DNA cleavage, which destabilizes the microenvironment [ 22 ].…”