Identification of Chondrocyte Genes and Signaling Pathways in Response to Acute Joint Inflammation

Abstract

Traumatic joint injuries often result in elevated proinflammatory cytokine (such as IL-1β) levels in the joint cavity, which can increase the catabolic activities of chondrocytes and damage cartilage. This study investigated the early genetic responses of healthy in situ chondrocytes under IL-1β attack with a focus on cell cycle and calcium signaling pathways. RNA sequencing analysis identified 2,232 significantly changed genes by IL-1β, with 1,259 upregulated and 973 downregulated genes. Catabolic genes related to ECM degeneration were promoted by IL-1β, consistent with our observations of matrix protein loss and mechanical property decrease during 24-day in vitro culture of cartilage explants. IL-1β altered the cell cycle (108 genes) and Rho GTPases signaling (72 genes) in chondrocytes, while chondrocyte phenotypic shift was observed with histology, cell volume measurement, and MTT assay. IL-1β inhibited the spontaneous calcium signaling in chondrocytes, a fundamental signaling event in chondrocyte metabolic activities. The expression of 24 genes from 6 calcium-signaling related pathways were changed by IL-1β exposure. This study provided a comprehensive list of differentially expressed genes of healthy in situ chondrocytes in response to IL-1β attack, which represents a useful reference to verify and guide future cartilage studies related to the acute inflammation after joint trauma.

LDHA-mediated ROS generation in chondrocytes is a potential therapeutic target for osteoarthritis

“…IL-1β treatment caused metabolic reprogramming, mimicking the Warburg effect and expanding upon some previous reports studying chondrocyte metabolism 58 – 60 . Other gene expression sets from articular chondrocytes treated with IL-1β or OA chondrocytes also display similar alterations in metabolic enzyme expression 61 , 62 , confirming metabolic changes as a conserved aspect of OA. We highlight the metabolic shift is a potential target for treating OA and identify a non-metabolic function of LDHA that is critical for modulating the inflammatory response, independent of its canonical lactate-producing role.…”

Antibiotic Treatment Prior to Injury Improves Post-Traumatic Osteoarthritis Outcomes in Mice

“…We found 737 significantly downregulated genes in the AB uninjured group compared to the VEH uninjured group. These genes included regulators of skeletal development ( Alpl [ 37 ], Col6a1 [ 54 ], Col6a2 [ 55 ], Sox9 [ 37 ], Sox11 [ 56 ], and Wnt9a [ 57 ]), Hippo signaling ( Tead1 , Tead4 [ 58 ], and Yap1 [ 59 ]), muscle contraction ( Myh8 , Myh2 , and Myom2 ), and inflammatory response ( Tlr5 [ 60 ], Ccl8 [ 61 ], Cxcl13 [ 37 ], C5ar1 [ 62 ], Cxcr1 [ 63 ], and Foxo6 [ 64 ]). Inflammatory gene comparison between AB injured and uninjured groups compared to the corresponding VEH groups are shown in Figure 5 A and Table 1 .…”

Articular Chondrocyte Phenotype Regulation through the Cytoskeleton and the Signaling Processes That Originate from or Converge on the Cytoskeleton: Towards a Novel Understanding of the Intersection between Actin Dynamics and Chondrogenic Function

“…This is believed to initiate and perpetuate a cascade of events that leads to permanent tissue damage [ 13 ] and disability [ 14 , 15 , 16 ]. Thus, many studies have focused on CH phenotype regulation in the context of hypertrophic differentiation [ 13 , 17 ], acute joint inflammation [ 18 ], aging and OA [ 19 ], mechanical/biophysical stimulation [ 20 , 21 , 22 ], inter-tissue communication [ 23 ], epigenetic regulation [ 24 ], in vitro chondrogenesis [ 25 , 26 ], therapeutic redifferentiation [ 27 , 28 ], and post-traumatic phenotype stabilization [ 29 ]. Collectively, these and many other studies have assembled a complex picture of how various extracellular stimuli and intracellular signaling pathways modulate the CH phenotype.…”