Mechanics of chondrocyte hypertrophy

Abstract

Chondrocyte hypertrophy is a characteristic of osteoarthritis and dominates bone growth. Intra-and extracellular changes that are known to be induced by metabolically active hypertrophic chondrocytes are known to contribute to hypertrophy. However, it is unknown to which extent these mechanical conditions together can be held responsible for the total magnitude of hypertrophy. The present paper aims to provide a quantitative, mechanically sound answer to that question. To address this aim requires a quantitative tool that captures the mechanical effects of collagen and proteoglycans, allows temporal changes in tissue composition, and can compute cell and tissue deformations. These requirements are met in our numerical model that is validated for articular cartilage mechanics, which we apply to quantitatively explain a range of experimental observations related to hypertrophy. After validating the numerical approach for studying hypertrophy, the model is applied to evaluate the direct mechanical effects of axial tension and compression on hypertrophy (Hueter-Volkmann principle) and to explore why hypertrophy is reduced in case of partially or fully compromised proteoglycan expression. Finally, a mechanical explanation is provided for the observation that chondrocytes do not hypertrophy when enzymatical collagen degradation is prohibited (S1Pcko knock-out mouse model). This paper shows that matrix turnover by metabolically active chondrocytes, together with externally applied mechanical conditions, can explain quantitatively the volumetric change of chondrocytes during hypertrophy. It provides a mechanistic explanation for the observation that collagen degradation results in chondrocyte hypertrophy, both under physiological and pathological conditions.

A tissue adaptation model based on strain-dependent collagen degradation and contact-guided cell traction

“…This unnatural response may be solved by combining the present model with a tissue growth approach in which newly synthesized collagen assembles to form an unstrained fibril within the present geometry, i.e. within the deformed matrix (Van Donkelaar and Wilson, 2007Wilson, , 2012Khoshgoftar et al, 2014). Fourth, because cells attach to the ECM, cell deformation is assumed to follow ECM strain.…”

Signaling Pathways in Cartilage Repair

“…Smad 2 and 3 exert an inhibitory effect on chondrocyte hypertrophy [30,43], which represents the phenotypic hallmark of terminal differentiated chondrocytes. A similar phenotypic modification occurs in OA and also in ageing chondrocytes [13,44,45] and it has been shown to be associated with a reduced expression of ALK5 leading to a break of the chondrocyte quiescent state and the induction of the terminal differentiation of chondrocytes [13]. …”

The effect of tissue-engineered cartilage biomechanical and biochemical properties on its post-implantation mechanical behavior

“…In addition, we may speculate that unstrained fibers may be degraded after implantation, because of their enhanced susceptibility to enzymatic degradation (Huang and Yannas 1977;Nabeshima et al 1996;Ruberti and Hallab 2005). Such effects have not been reported before, and it may be worthwhile to explore this experimentally, or using models that include effects of transient development of cartilage matrix (Klisch et al 2003;van Donkelaar and Wilson 2011). Hence, we postulate that a mismatch between collagen and PG synthesis rates in cartilage TE may lead to adverse mechanical conditions in the collagen fiber network.…”