How does multi-axial loading affect the biosynthetic response and mechanical quality of cartilage in early osteo-arthritis?

Articular cartilage covers the end of the long bones in joints and is constantly susceptible to mechanical stresses during joint loading. These forces have a direct effect on the chondrocyte within the cartilage tissue. Due to cell-matrix interactions, chondrocytes are able to sense these effects and alter their biosynthetic activity in order to maintain their extracellular matrix (ECM) components, mainly including collagen and proteoglycans, to provide cartilage homeostasis.

However, the exact biomechanical and biological processes that control mechanotransduction in chondrocytes are not well understood. A better knowledge on this matter will provide insight into the normal regulatory processes that maintain cartilage homeostasis during mechanical loading in healthy cartilage, as well as into the pathological processes ongoing in degenerative diseases, such as osteoarthritis (OA).

Current research regarding the mechanoresponsiveness of chondrocytes has shown that the type and magnitude of mechanical load will determine whether the chondrocytes turn on anabolic or catabolic pathways. In vivo  and in vitro studies generally conclude that static high-magnitude compression leads to a decreased gene expression and synthesis of ECM proteins, while a dynamic low magnitude and frequency compression will lead to increased chondrocyte proliferation and ECM synthesis.

However, there are several limitations to the studies conducted earlier. Firstly, current evidence concerning mechanotransduction in chondrocytes is often derived from studies that load chondrocytes in monolayer. It is known that chondrocytes lose their specific molecular phenotype when cultured in monolayer which therefore is not representative for the 3D environment of the chondrocytes in vivo. Secondly, most  studies in present literature use non-human chondrocytes, such as primary bovine or murine cells. Another crucial gap in current literature is the lack of studies using loading conditions representative for the dynamic in vivo joint situation. Up till now, we are not aware of specific information regarding the biological response of chondrocytes to multi-axial loading. Since most of the present studies are using a loading device that is only capable of providing uni- or biaxial loading, it is necessary to study mechano-responsiveness of chondrocytes under multi-axial loading conditions i.e. a combination of compression, tension and torsional force.

The general aim of this project is to further understand the mechanoresponsiveness of healthy and OA-affected human chondrocytes in 3D culture under multi-axial loading conditions, representative for the in vivo joint environment. Like this, critical mechanical stimuli associated with the switch between anabolic and catabolic molecular responses can be identified in constructs using cells from healthy and diseased cartilage.

By using cell-embedded hydrogels in combination with a unique multi-axial bioreactor, we will mimic the in vivo joint situation and measure how chondrocytes respond to loading by analyzing the transcriptome and metabolome.  Furthermore, we will quantify the local biological responses of human articular chondrocytes subjected to multi-axial loading by using mechanosensitive reporter constructs.

By acquiring knowledge on which amount of impact leads to the activation of either an anabolic or catabolic pathway, we can implement this into a prevention rehabilitation program, or even extrapolate this to diseased cartilage for finding new treatment modalities in the context of OA.