Development of novel osteoarthritis therapy by targeting AMPK-β-catenin-Runx2 signaling

Abstract

Osteoarthritis (OA) is a debilitating chronic joint disease affecting large populations of patients, especially the elderly. The pathological mechanisms of OA are currently unknown. Multiple risk factors are involved in OA development. Among these risk factors, alterations of mechanical loading in the joint leading to changes in biological signaling pathways have been known as a key event in OA development. The importance of AMPK-β-catenin-Runx2 signaling in the initiation and progression of OA has been recognized in recent years. In this review, we discuss the recent progress in understanding the role of this signaling pathway and the underlying interaction mechanisms during OA development. We also discuss the drug development aiming to target this signaling pathway for OA treatment.

Keywords: AMPK; Osteoarthritis; Runx2; Signaling pathway; β-catenin.

Figure 1

Schematic diagram of normal articular cartilage and OA cartilage. OA is a disease involving the whole joint, and its pathological changes include cartilage erosion, synovial inflammation and hyperplasia, osteophyte formation, abnormal vascular invasion, subchondral bone disorder, and reconstruction. The left side is normal articular cartilage tissue and cartilage local enlargement, and the right side is OA cartilage tissue. OA, osteoarthritis.

Figure 2

AMPK signaling in OA chondrocytes. AMPK is an important energy receptor with three subunits (α, β, and γ). LKB1, TAK1, CAMKK2 are key molecules that promote phosphorylation of AMPK, regulated by AMP/ADP, ATP, and Ca²⁺. The activity of AMPK in OA chondrocytes decreases, regulating the expression of its downstream target genes such as PGC1α, SIRT1, FOXO3, and CHOP, which ultimately leads to chondrocyte metabolic disorders, inflammatory response, oxidative stress, mitochondrial dysfunction, and chondrocyte autophagy. LKB1, liver kinase B1; TAK1, transforming growth factor-β-activated protein kinase-1; CAMKK2, calcium/calmodulin-dependent kinase; AMPK, AMP-activated protein kinase; PGC1α, peroxisome proliferator–activated receptor γ coactivator 1α; SIRT1, sirtuin 1; FOXO3, forkhead box O3; CHOP, C/EBP homologous protein; ROS, reactive oxygen species.

Figure 3

Activation and conduction of the Wnt/β-catenin signaling pathway in OA. Wnt/β-catenin signaling in healthy articular cartilage is tightly regulated. In the absence of Wnt binding to its ligand, β-catenin in the cytoplasm is phosphorylated by the destruction complex and is degraded by the proteasome after ubiquitination, and the Wnt/β-catenin signal is inhibited. In OA chondrocytes and synoviocytes, Wnt binds to its ligands Frizzled and LRP, resulting in the dissociation of the destruction complex in the cytoplasm, and β-catenin is freed from the destruction complex. β-catenin phosphorylation is reduced and β-catenin migrates into the nucleus. The Wnt/β-catenin signaling pathway activates the downstream target gene expression, including Runx2, MMPs, and ADAMTs, promoting the progression of OA. Axin, axis inhibition protein; CK1α, casein kinase 1α; GSK-3β, glycogen synthase kinase 3β; APC, adenomatous polyposis coli; Runx2, runt-associated transcription factor 2; MMPs, matrix metalloproteinase; ADAMTs, aggregate enzymes; Col10, collagen type X.

Figure 4

Conduction and crosstalk of AMPK-β-catenin-Runx2 signals in OA. AMPK, β-catenin, and Runx2 play unique roles in the disease development of OA, and the crosstalk between the three jointly regulates the pathological process of OA. AMPK acts as the upstream regulatory signal of β-catenin, and the conduction of AMPK signals can regulate the biological activity of β-catenin. Up-regulation of AMPK expression inhibits signaling of β-catenin by promoting its phosphorylation and degradation and blocking β-catenin nuclear translocation, ultimately inhibiting the downstream target gene Runx2 and reducing the expression of MMPs, ADAMTs, and Col-10. AICAR, 5-aminoimidazole-4-carboxamide 1-β-D-ribonucleoside; AMPK, AMP-activated protein kinase; Runx2, runt-associated transcription factor 2; MMPs, matrix metalloproteinase; ADAMTs, a disintegrin and metalloproteinase with thrombospondin motifs; Col10, collagen type X.