Effects of Age and Mechanical Loading on Articular Cartilage Metabolism and Corresponding Consequences for Tissue Health

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Abstract

Articular cartilage poses a major clinical challenge. Beyond skeletal adolescence, cartilage loses regenerative functionality, rendering this tissue vulnerable to accumulation of damage over time. Thus, age and mechanical overloading are predisposing factors for development of osteoarthritis (OA), a globally burdensome condition. Metabolic dysregulation has also been identified as a key feature of cartilage degeneration. Therapeutic OA treatments are lacking, due in large part to an incomplete understanding of the complex interplay between these predisposing factors. This knowledge gap can be addressed by studying the interactive effects of tissue age, mechanical loading, and metabolic activity in cartilage. The aims of this thesis were: (1) determine the consequences of maturation on chondrocyte identity and activity, (2) develop a method of observing the real-time effects of loading on cartilage metabolism and analyze loading rate- and age-dependent sensitivity to compression with respect to metabolism, gene expression, and progenitor functionality, and (3) identify the downstream implications of metabolic activity for tissue health. Maturation and loading effects were analyzed with respect to progenitor cells and gene expression, identifying age-dependent expression of chondroprogenitor markers and anabolic genes and revealing maturation-dependent sensitivity to mechanical loading and tissue culture. A metabolic imaging technique, optical metabolic imaging (OMI), was adapted for use in articular cartilage, and was employed to analyze the effects of physiological and superphysiological compression on metabolism. This work demonstrated transient metabolic flux following compression, with differential pathway-specific and time-dependent effects following physiological and superphysiological loading. Metabolic consequences of maturation were studied by mapping metabolic activity as a function of age in samples spanning pre- and post-adolescence. Maturation-dependent metabolic activity was observed in both the glycolytic and oxphos fluorescence channels, showing a pattern of nonlinearity in optical redox ratio across age groups. The consequences of metabolism were probed via chemical inhibition; glycolytic inhibition suppressed expression of both anabolic and catabolic genes pertinent to tissue maintenance while oxphos inhibition did not. Finally, an association between tissue metabolism and degree of degeneration was revealed in mature cartilage. This interdisciplinary approach to understanding cartilage mechanobiology provides novel insights into cartilage function and has meaningful implications for future research.

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