Osmolarity‐Induced Altered Intracellular Molecular Crowding Drives Osteoarthritis Pathology

TL;DR

Changes in joint osmolarity affect chondrocyte behavior through intracellular crowding, offering a new understanding of osteoarthritis.

Contribution

Reveals osmolarity-induced intracellular molecular crowding as a novel mechanism in osteoarthritis pathology.

Findings

Lowered intracellular crowding increases sensitivity to inflammation and decreases anabolic response.

Higher extracellular osmolarity can reverse OA-related chondrocyte behavior and metabolism.

Osmolarity regulates OA pathophysiology via intracellular molecular crowding.

Abstract

Osteoarthritis (OA) is a multifactorial degenerative joint disease of which the underlying mechanisms are yet to be fully understood. At the molecular level, multiple factors including altered signaling pathways, epigenetics, metabolic imbalance, extracellular matrix degradation, production of matrix metalloproteinases, and inflammatory cytokines, are known to play a detrimental role in OA. However, these factors do not initiate OA, but are mediators or consequences of the disease, while many other factors causing the etiology of OA are still unknown. Here, it is revealed that microenvironmental osmolarity can induce and reverse osteoarthritis‐related behavior of chondrocytes via altered intracellular molecular crowding, which represents a previously unknown mechanism underlying OA pathophysiology. Decreased intracellular crowding is associated with increased sensitivity to proinflammatory triggers and decreased responsiveness to anabolic stimuli. OA‐induced lowered intracellular molecular crowding could be renormalized via exposure to higher extracellular osmolarity such as those found in healthy joints, which reverse OA chondrocyte's sensitivity to catabolic stimuli as well as its glycolytic metabolism.

Osteoarthritis alteration of joint osmolarity is known as consequence of this joint disease, but its role has remained largely unknown. It is demonstrated that healthy osmotic levels sensitize chondrocyte to regeneration and desensitize to inflammation, while an osteoarthritic osmotic level has the opposite effect. Osmolarity regulates pathophysiological effects by altering intracellular molecular crowding, which represents a novel mechanism for therapeutic targeting.

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