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1. Nanoscale insight into the degradation mechanisms of the cartilage articulating surface preceding OA

   https://doi.org/10.1039/d0bm00496k  

   Shoaib, Tooba; Yuh, Catherine; Wimmer, Markus A.; Schmid, Thomas M.; Espinosa-Marzal, Rosa M. (July 2020, Biomaterials Science)

   null (Ed.)

   Osteoarthritis (OA) is a degenerative joint disease and a leading cause of disability globally. In OA, the articulating surface of cartilage is compromised by fissures and cracks, and sometimes even worn away completely. Due to its avascular nature, articular cartilage has a poor self-healing ability, and therefore, understanding the mechanisms underlying degradation is key for OA prevention and for optimal design of replacements. In this work, the articulating surface of bovine cartilage was investigated in an environment with enhanced calcium concentration -as often found in cartilage in relation to OA- by combining atomic force microscopy, spectroscopy and an extended surface forces apparatus for the first time. The experimental results reveal that increased calcium concentration irreversibly weakens the cartilage's surface layer, and promotes stiction and high friction. The synergistic effect of calcium on altering the cartilage surface's structural, mechanical and frictional properties is proposed to compromise cartilage integrity at the onset of OA. Furthermore, two mechanisms at the molecular level based on the influence of calcium on lubricin and on the aggregation of the cartilage's matrix, respectively, are identified. The results of this work might not only help prevent OA but also help design better cartilage replacements. 

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2. Advancements in Cartilage Tissue Engineering: A Focused Review

   https://doi.org/10.1002/jbm.b.35520  

   Welsh, Breanne_L; Sikder, Prabaha (January 2025, Journal of Biomedical Materials Research Part B: Applied Biomaterials)

   ABSTRACT Osteoarthritis (OA) is a prevalent joint disorder that is characterized by the degeneration of articular cartilage in synovial joints. Most of the current treatment options for this disorder tend to focus on symptom management rather than addressing the underlying progression of the disease. Cartilage tissue engineering has emerged as a promising approach to address the limitations of current OA treatments, aiming to regenerate cartilage and restore the natural function of affected joints. Like any other tissue engineering field, cartilage tissue engineering uses different fabrication techniques and biomaterials to develop the constructs. Numerous studies over the last few years have demonstrated the preclinical efficacy of tissue‐engineered constructs in promoting cartilage regeneration and highlight the potential of tissue‐engineered constructs as a viable therapeutic approach for OA. This paper aims to provide a focused review of advancements in tissue‐engineered constructs over the past decade. Specifically, we highlight the constructs based on natural, synthetic, and composite biomaterials and the varying conventional and advanced fabrication techniques. We also highlight the challenges instate‐of‐the‐artcartilage tissue engineering that must be overcome in the upcoming years to fully replicate the complex anatomy of the native cartilage. We believe that continued collaborative research efforts among researchers from various facets of engineering and clinicians are required to advance the field of cartilage tissue engineering and become a viable OA therapy. 

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3. Quantification of Cartilage Poroelastic Material Properties Via Analysis of Loading-Induced Cell Death

   https://doi.org/10.1115/1.4065194  

   Kotelsky, Alexander; Carrier, Joseph S; Buckley, Mark R (August 2024, Journal of Biomechanical Engineering)

   Abstract Articular cartilage (AC) is a load-bearing tissue that covers long bones in synovial joints. The biphasic/poroelastic mechanical properties of AC help it to protect joints by distributing loads, absorbing impact forces, and reducing friction. Unfortunately, alterations in these mechanical properties adversely impact cartilage function and precede joint degeneration in the form of osteoarthritis (OA). Thus, understanding what factors regulate the poroelastic mechanical properties of cartilage is of great scientific and clinical interest. Transgenic mouse models provide a valuable platform to delineate how specific genes contribute to cartilage mechanical properties. However, the poroelastic mechanical properties of murine articular cartilage are challenging to measure due to its small size (thickness ∼ 50 microns). In the current study, our objective was to test whether the poroelastic mechanical properties of murine articular cartilage can be determined based solely on time-dependent cell death measurements under constant loading conditions. We hypothesized that in murine articular cartilage subjected to constant, sub-impact loading from an incongruent surface, cell death area and tissue strain are closely correlated. We further hypothesized that the relationship between cell death area and tissue strain can be used—in combination with inverse finite element modeling—to compute poroelastic mechanical properties. To test these hypotheses, murine cartilage-on-bone explants from different anatomical locations were subjected to constant loading conditions by an incongruent surface in a custom device. Cell death area increased over time and scaled linearly with strain, which rose in magnitude over time due to poroelastic creep. Thus, we were able to infer tissue strain from cell death area measurements. Moreover, using tissue strain values inferred from cell death area measurements, we applied an inverse finite element modeling procedure to compute poroelastic material properties and acquired data consistent with previous studies. Collectively, our findings demonstrate in the key role poroelastic creep plays in mediating cell survival in mechanically loaded cartilage and verify that cell death area can be used as a surrogate measure of tissue strain that enables determination of murine cartilage mechanical properties. 

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4. Osteocyte dysfunction promotes osteoarthritis through MMP13-dependent suppression of subchondral bone homeostasis

   https://doi.org/10.1038/s41413-019-0070-y  

   Mazur, Courtney M.; Woo, Jonathon J.; Yee, Cristal S.; Fields, Aaron J.; Acevedo, Claire; Bailey, Karsyn N.; Kaya, Serra; Fowler, Tristan W.; Lotz, Jeffrey C.; Dang, Alexis; et al (December 2019, Bone Research)

   null (Ed.)

   Abstract Osteoarthritis (OA), long considered a primary disorder of articular cartilage, is commonly associated with subchondral bone sclerosis. However, the cellular mechanisms responsible for changes to subchondral bone in OA, and the extent to which these changes are drivers of or a secondary reaction to cartilage degeneration, remain unclear. In knee joints from human patients with end-stage OA, we found evidence of profound defects in osteocyte function. Suppression of osteocyte perilacunar/canalicular remodeling (PLR) was most severe in the medial compartment of OA subchondral bone, with lower protease expression, diminished canalicular networks, and disorganized and hypermineralized extracellular matrix. As a step toward evaluating the causality of PLR suppression in OA, we ablated the PLR enzyme MMP13 in osteocytes while leaving chondrocytic MMP13 intact, using Cre recombinase driven by the 9.6-kb DMP1 promoter. Not only did osteocytic MMP13 deficiency suppress PLR in cortical and subchondral bone, but it also compromised cartilage. Even in the absence of injury, osteocytic MMP13 deficiency was sufficient to reduce cartilage proteoglycan content, change chondrocyte production of collagen II, aggrecan, and MMP13, and increase the incidence of cartilage lesions, consistent with early OA. Thus, in humans and mice, defects in PLR coincide with cartilage defects. Osteocyte-derived MMP13 emerges as a critical regulator of cartilage homeostasis, likely via its effects on PLR. Together, these findings implicate osteocytes in bone-cartilage crosstalk in the joint and suggest a causal role for suppressed perilacunar/canalicular remodeling in osteoarthritis. 

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5. Assessing Human Articular Cartilage Transcriptome Layers with RNA Sequencing

   Pondipornnont, P; Van_Wie, BJ; Driskell, R; Driskell, I; Bonassar, LJ; Gozen, A; Dong, W; Scalise, D; Wildung, M; Matan, S; et al (October 2024, American Institute of Chemical Engineering)

   Osteoarthritis, a chronic disease, remains an issue for adults that causes cartilage degradation within a joint . According to the Centers forDisease Control and Prevention (2023), over 32.5 million adults in the US are affected by osteoarthritis (OA). In this study we seek tounderstand the connection between tissue engineering and genetics to regenerate human articular cartilage (hAC). We purpose to validatea protocol for RNA isolation and characterize the transcriptome of hAC in a tri-layer fashion via bulk RNA sequencing (bulk-RNA-seq).Additionally, we aim to analyze the transcriptome of normal articular cartilage in comparison to the hAC chemical composition and physicalproperties. We are relating these properties to the tri-layers of hAC through histological staining with Safranin O—Fast green and imagingwith differential interference contrast (DIC) microscopy. We are relating these properties to superfic ial, middle, and deep zone with acryotome procedure, RNA extracted, and qualified by Bioanalyzer. Next, we generate bulk RNA sequencing of hAC layer-by-layer andcompare results to early passaging of Mesenchymal Stromal Cells (MSC) and tissues intended for Matrix-Induced Autologous ChondrocyteImplantation (MACI). We will use differential gene expression (DE) analysis by DESeq2 R package software for bulk-RNA-seq. The resultwill be interpreted in terms of differentiation from MSCs to gene expression patterns of tri-layer hAC. We will report on development andvalidation of protocols for isolating cells and their subsequent characterization with application in regenerating the tri-layered hACtranscriptome stimulatory bioreactors used in our laboratory and corresponding properties of the extracellular matrix (ECM) 

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