Interplay of Glucose Metabolism and Hippo Pathway in Chondrocytes: Pathophysiology and Therapeutic Targets

Abstract

In this review, we explore the intricate relationship between glucose metabolism and mechanotransduction pathways, with a specific focus on the role of the Hippo signaling pathway in chondrocyte pathophysiology. Glucose metabolism is a vital element in maintaining proper chondrocyte function, but it has also been implicated in the pathogenesis of osteoarthritis (OA) via the induction of pro-inflammatory signaling pathways and the establishment of an intracellular environment conducive to OA. Alternatively, mechanotransduction pathways such as the Hippo pathway possess the capacity to respond to mechanical stimuli and have an integral role in maintaining chondrocyte homeostasis. However, these mechanotransduction pathways can be dysregulated and potentially contribute to the progression of OA. We discussed how alterations in glucose levels may modulate the Hippo pathway components via a variety of mechanisms. Characterizing the interaction between glucose metabolism and the Hippo pathway highlights the necessity of balancing both metabolic and mechanical signaling to maintain chondrocyte health and optimal functionality. Furthermore, this review demonstrates the scarcity of the literature on the relationship between glucose metabolism and mechanotransduction and provides a summary of current research dedicated to this specific area of study. Ultimately, increased research into this topic may elucidate novel mechanisms and relationships integrating mechanotransduction and glucose metabolism. Through this review we hope to inspire future research into this topic to develop innovative treatments for addressing the clinical challenges of OA.

Keywords: OA therapeutics; chondrocyte; glucose; mechanotransduction; metabolism; osteoarthritis.

Figure 1

The mechanotransduction pathway in chondrocytes mediated by the HIPPO signaling cascade.

Figure 2

The schematic of the proposed mechanism of increased sensitivity to inflammatory responses in hyperglycemic conditions. Hyperglycemia results in higher concentrations of AGEs, leading to increased RAGE binding on macrophages and chondrocytes. Meanwhile, chronic hyperglycemia leads to synovial insulin resistance. Both sequences induce polarization of macrophages and fibroblasts into catabolic phenotypes, which increase inflammatory mediators and cytokines. The inflammatory response from macrophages and fibroblasts, in combination with a chondrocyte response, activates NF-κB and MAPK, increases oxidative stress, and creates a positive inflammatory feedback loop leading to cartilage degradation and OA progression.

Figure 3

The schematic of the proposed biochemical mechanism by which hyperglycemia may contribute to OA progression. Hyperglycemic conditions lead to the activation of PI3K, AKT, mTOR, NF-κB, and MAPK pathways, which have various intracellular effects, most of which lead to OA progression (as indicated by red arrows/inhibitors). Conversely, hypoglycemic conditions activate the AMPK pathway, also leading to OA progression. Increased blood glucose also leads to increased glycolysis, which alters the mechanosensitivity of chondrocytes by changing ion channels and integrin activity. Finally, hyperglycemia also leads to increased ROS and RAGE binding, leading to a pro-inflammatory state.