Mechanotransduction and Stiffness-Sensing: Mechanisms and Opportunities to Control Multiple Molecular Aspects of Cell Phenotype as a Design Cornerstone of Cell-Instructive Biomaterials for Articular Cartilage Repair

Abstract

Since material stiffness controls many cell functions, we reviewed the currently available knowledge on stiffness sensing and elucidated what is known in the context of clinical and experimental articular cartilage (AC) repair. Remarkably, no stiffness information on the various biomaterials for clinical AC repair was accessible. Using mRNA expression profiles and morphology as surrogate markers of stiffness-related effects, we deduced that the various clinically available biomaterials control chondrocyte (CH) phenotype well, but not to equal extents, and only in non-degenerative settings. Ample evidence demonstrates that multiple molecular aspects of CH and mesenchymal stromal cell (MSC) phenotype are susceptible to material stiffness, because proliferation, migration, lineage determination, shape, cytoskeletal properties, expression profiles, cell surface receptor composition, integrin subunit expression, and nuclear shape and composition of CHs and/or MSCs are stiffness-regulated. Moreover, material stiffness modulates MSC immuno-modulatory and angiogenic properties, transforming growth factor beta 1 (TGF-β1)-induced lineage determination, and CH re-differentiation/de-differentiation, collagen type II fragment production, and TGF-β1- and interleukin 1 beta (IL-1β)-induced changes in cell stiffness and traction force. We then integrated the available molecular signaling data into a stiffness-regulated CH phenotype model. Overall, we recommend using material stiffness for controlling cell phenotype, as this would be a promising design cornerstone for novel future-oriented, cell-instructive biomaterials for clinical high-quality AC repair tissue.

An Evidence-Based Systematic Review of Human Knee Post-Traumatic Osteoarthritis (PTOA): Timeline of Clinical Presentation and Disease Markers, Comparison of Knee Joint PTOA Models and Early Disease Implications

“…Therefore, theoretically, TGF-β would also be subjected to IL-17 modulation. For other effects of TGF-β on chondrocytes and/or MSCs, we refer the interested reader to our recent reviews [ 13 , 183 ].…”

Articular Chondrocyte Phenotype Regulation through the Cytoskeleton and the Signaling Processes That Originate from or Converge on the Cytoskeleton: Towards a Novel Understanding of the Intersection between Actin Dynamics and Chondrogenic Function

“…In contrast, complex formation with Smad1 (ALK1) induces CH terminal differentiation [ 246 ]. In the context of this review, TGF-β-induced SF formation appears to be mediated by Rho GTPases and Smad proteins ( Figure 1 ), as demonstrated in Swiss 3T3 fibroblasts [ 22 , 247 ]. In those cells, TGF-β1 and/or Smad2/3 trigger the activation of the Rho GTPase RhoA and, to a lesser extent, RhoB [ 247 ], explaining mechanistically how TGF-β signaling leads to SF formation.…”

“…Altered TGF-β family signaling has been associated with aging, mechanical stress, inflammation, and OA [ 241 , 243 , 244 ]. For example, altered TGF-β signaling in ageing and OA onset has been traced back to a change in the balance of the expression of the ALK1 vs. ALK5 TGF-βRI family members [ 245 ], which has been described as a “receptor switch” from the classical ALK5/TGF-βRI-activated Smad2/3 signaling to TGF-βRI family member ALK1/ACVRL1-induced Smad1/5/8 signaling [ 22 ] ( Figure 8 ). These findings are based on murine AC models for aging and OA and were supported by data on a range of human OA ACs, which demonstrated that the measured levels of ALK5 and ALK1 mRNA expression varied across samples, and that ALK5 expression levels correlate with COL2 levels, whereas the ALK1 expression levels correlate with MMP-13 expression [ 245 ].…”

“…A recent study provided a mechanical model at the nanoscale that quantitatively relates physiologically relevant intracellular forces such as cytoskeletal tension and pre-stress to cell stiffness [ 252 ], illustrating the quantitative interconnectivity between cytoskeletal structures and forces. We refer the interested reader to [ 253 ] for a condensed overview on cytoskeletal building blocks, network architecture and mechanics, cytoskeletal epigenetics, and mechanosensing, which we recently have reviewed in the context of CHs and MSCs in [ 22 ]. Generally, the main determinants of cytoskeletal stiffness are the actin and myosin fiber assemblies.…”

“…This is believed to initiate and perpetuate a cascade of events that leads to permanent tissue damage [ 13 ] and disability [ 14 , 15 , 16 ]. Thus, many studies have focused on CH phenotype regulation in the context of hypertrophic differentiation [ 13 , 17 ], acute joint inflammation [ 18 ], aging and OA [ 19 ], mechanical/biophysical stimulation [ 20 , 21 , 22 ], inter-tissue communication [ 23 ], epigenetic regulation [ 24 ], in vitro chondrogenesis [ 25 , 26 ], therapeutic redifferentiation [ 27 , 28 ], and post-traumatic phenotype stabilization [ 29 ]. Collectively, these and many other studies have assembled a complex picture of how various extracellular stimuli and intracellular signaling pathways modulate the CH phenotype.…”