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Selected Papers of Workshop "Osteoarthritis: Novel Molecular Determinants Revolutionize Our Understanding of the Disease Pathology"

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (15 January 2021) | Viewed by 42781

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Prof. Dr. Susanne Grässel

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Department of Orthopedic Surgery, Exp. Orthopedics, ZMB/Biopark 1, University of Regensburg, 93053 Regensburg, Germany
Interests: osteoarthritis; chondrocytes; MSC; bone cells; cartilage regeneration; bone biology and regeneration; chondrogenic and osteogenic differentiation; sensory nervous system
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Prof. Dr. Henning Madry

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Center of Experimental Orthopaedics, Saarland University Medical Center, Kirrbergerstr. Bldg 37, D-66421 Homburg, Saar, Germany
Interests: human musculoskeletal disorders; clinical orthopaedics; animal models; human regenerative medicine
Special Issues, Collections and Topics in MDPI journals

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Dear Colleagues,

Clinical symptoms of OA appear in more than 10% of the world population and affect almost everyone over the age of 65. As a consequence of the increasing longevity and obesity within Western countries, the economic and social burden caused by OA is growing rapidly and substantially influencing the life quality of the affected individuals, with enormous costs to the health care system for diagnosis, treatment, sick leave, rehabilitation, and early retirement. For patients, the major problem is disability, resulting from joint tissue destruction and pain. OA is characterized by its extraordinary interpatient variability both clinically and structurally. This heterogeneity is considered as a major reason associated with the complexity of OA and the ongoing difficulties to identify one-size-fits-all therapies. The development of targeted therapies against the osteoarthritic processes in cartilage, synovium or bone will, therefore, require an understanding of the state of these joint tissues at the time of the intervention.

Here, we want to elucidate novel concepts and hypotheses regarding disease progression, which are relevant for understanding underlying molecular mechanisms as a prerequisite for future therapeutic approaches.

Prof. Dr. Susanne Grässel
Guest Editor

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Keywords

Osteoarthritis
Neuropeptides
Topographic modeling
Cytokines and proteases
Targeted therapy

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Published Papers (9 papers)

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19 pages, 6813 KiB

Open AccessArticle

Expression and Localization of Thrombospondins, Plastin 3, and STIM1 in Different Cartilage Compartments of the Osteoarthritic Varus Knee

by Daniela Mählich, Anne Glasmacher, Ilka Müller, Johannes Oppermann, David Grevenstein, Peer Eysel, Juliane Heilig, Brunhilde Wirth, Frank Zaucke and Anja Niehoff

Int. J. Mol. Sci. 2021, 22(6), 3073; https://doi.org/10.3390/ijms22063073 - 17 Mar 2021

Cited by 8 | Viewed by 3398

Abstract

Osteoarthritis (OA) is a multifactorial disease which is characterized by a change in the homeostasis of the extracellular matrix (ECM). The ECM is essential for the function of the articular cartilage and plays an important role in cartilage mechanotransduction. To provide a better understanding of the interaction between the ECM and the actin cytoskeleton, we investigated the localization and expression of the Ca²⁺-dependent proteins cartilage oligomeric matrix protein (COMP), thrombospondin-1 (TSP-1), plastin 3 (PLS3) and stromal interaction molecule 1 (STIM1). We investigated 16 patients who suffered from varus knee OA and performed a topographical analysis of the cartilage from the medial and lateral compartment of the proximal tibial plateau. In a varus knee, OA is more pronounced in the medial compared to the lateral compartment as a result of an overloading due to the malalignment. We detected a location-dependent staining of PLS3 and STIM1 in the articular cartilage tissue. The staining intensity for both proteins correlated with the degree of cartilage degeneration. The staining intensity of TSP-1 was clearly reduced in the cartilage of the more affected medial compartment, an observation that was confirmed in cartilage extracts by immunoblotting. The total amount of COMP was unchanged; however, slight changes were detected in the localization of the protein. Our results provide novel information on alterations in OA cartilage suggesting that Ca²⁺-dependent mechanotransduction between the ECM and the actin cytoskeleton might play an essential role in the pathomechanism of OA. Full article

(This article belongs to the Special Issue Selected Papers of Workshop "Osteoarthritis: Novel Molecular Determinants Revolutionize Our Understanding of the Disease Pathology")

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15 pages, 2933 KiB

Open AccessArticle

How miR-31-5p and miR-33a-5p Regulates SP1/CX43 Expression in Osteoarthritis Disease: Preliminary Insights

by Viviana Costa, Marcello De Fine, Valeria Carina, Alice Conigliaro, Lavinia Raimondi, Angela De Luca, Daniele Bellavia, Francesca Salamanna, Riccardo Alessandro, Giovanni Pignatti, Milena Fini and Gianluca Giavaresi

Int. J. Mol. Sci. 2021, 22(5), 2471; https://doi.org/10.3390/ijms22052471 - 28 Feb 2021

Cited by 15 | Viewed by 3070

Abstract

Osteoarthritis (OA) is a degenerative bone disease that involved micro and macro-environment of joints. To date, there are no radical curative treatments for OA and novel therapies are mandatory. Recent evidence suggests the role of miRNAs in OA progression. In our previous studies, we demonstrated the role of miR-31-5p and miR-33a families in different bone regeneration signaling. Here, we investigated the role of miR-31-5p and miR-33a-5p in OA progression. A different expression of miR-31-5p and miR-33a-5p into osteoblasts and chondrocytes isolated from joint tissues of OA patients classified in based on different Kellgren and Lawrence (KL) grading was highlighted; and through a bioinformatic approach the common miRNAs target Specificity proteins (Sp1) were identified. Sp1 regulates the expression of gap junction protein Connexin43 (Cx43), which in OA drives the modification of (i) osteoblasts and chondrocytes genes expression, (ii) joint inflammation cytokines releases and (iii) cell functions. Concerning this, thanks to gain and loss of function studies, the possible role of Sp1 as a modulator of CX43 expression through miR-31-5p and miR-33a-5p action was also evaluated. Finally, we hypothesize that both miRNAs cooperate to modulate the expression of SP1 in osteoblasts and chondrocytes and interfering, consequently, with CX43 expression, and they might be further investigated as new possible biomarkers for OA. Full article

(This article belongs to the Special Issue Selected Papers of Workshop "Osteoarthritis: Novel Molecular Determinants Revolutionize Our Understanding of the Disease Pathology")

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23 pages, 6104 KiB

Open AccessArticle

COMP and TSP-4: Functional Roles in Articular Cartilage and Relevance in Osteoarthritis

by Kathrin Maly, Enrique Andres Sastre, Eric Farrell, Andrea Meurer and Frank Zaucke

Int. J. Mol. Sci. 2021, 22(5), 2242; https://doi.org/10.3390/ijms22052242 - 24 Feb 2021

Cited by 35 | Viewed by 4399

Abstract

Osteoarthritis (OA) is a slow-progressing joint disease, leading to the degradation and remodeling of the cartilage extracellular matrix (ECM). The usually quiescent chondrocytes become reactivated and accumulate in cell clusters, become hypertrophic, and intensively produce not only degrading enzymes, but also ECM proteins, like the cartilage oligomeric matrix protein (COMP) and thrombospondin-4 (TSP-4). To date, the functional roles of these newly synthesized proteins in articular cartilage are still elusive. Therefore, we analyzed the involvement of both proteins in OA specific processes in in vitro studies, using porcine chondrocytes, isolated from femoral condyles. The effect of COMP and TSP-4 on chondrocyte migration was investigated in transwell assays and their potential to modulate the chondrocyte phenotype, protein synthesis and matrix formation by immunofluorescence staining and immunoblot. Our results demonstrate that COMP could attract chondrocytes and may contribute to a repopulation of damaged cartilage areas, while TSP-4 did not affect this process. In contrast, both proteins similarly promoted the synthesis and matrix formation of collagen II, IX, XII and proteoglycans, but inhibited that of collagen I and X, resulting in a stabilized chondrocyte phenotype. These data suggest that COMP and TSP-4 activate mechanisms to protect and repair the ECM in articular cartilage. Full article

(This article belongs to the Special Issue Selected Papers of Workshop "Osteoarthritis: Novel Molecular Determinants Revolutionize Our Understanding of the Disease Pathology")

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26 pages, 2561 KiB

Open AccessArticle

Cartilage Targets of Knee Osteoarthritis Shared by Both Genders

by Chenshuang Li and Zhong Zheng

Int. J. Mol. Sci. 2021, 22(2), 569; https://doi.org/10.3390/ijms22020569 - 8 Jan 2021

Cited by 9 | Viewed by 3482

Abstract

As the leading cause of disability, osteoarthritis (OA) affects people of all ages, sexes, and races. With the increasing understanding of OA, the sex differences have attracted specific attention as the burden of OA is greater in women. There is no doubt that gender-specific OA management has great potential for precision treatment. On the other hand, from the marketing aspect, a medication targeting the OA-responsive biomarker(s) shared by both genders is more favorable for drug development. Thus, in the current study, a published transcriptome dataset of knee articular cartilage was used to compare OA and healthy samples for identifying the genes with the same significantly different expression trend in both males and females. With 128 genes upregulated and 143 genes downregulated in both OA males and females, 9 KEGG pathways have been enriched based on the current knowledge, including ‘renal cell carcinoma,’ ‘ECM-receptor interaction,’ ‘HIF-1 signaling pathway,’ ‘MicroRNAs in cancer,’ ‘focal adhesion,’ ‘Relaxin signaling pathway,’ ‘breast cancer,’ ‘PI3K-Akt signaling pathway,’ and ‘human papillomavirus infection.’ Here, we explore the potential impacts of these clusters in OA. We also analyze the identified ‘cell plasma membrane related genes’ in-depth to identify the potential chondrocyte cell surface target(s) of OA management. Full article

(This article belongs to the Special Issue Selected Papers of Workshop "Osteoarthritis: Novel Molecular Determinants Revolutionize Our Understanding of the Disease Pathology")

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17 pages, 5814 KiB

Open AccessArticle

Identification and Characterization of the Intra-Articular Microbiome in the Osteoarthritic Knee

by Joseph C. Tsai, Grant Casteneda, Abby Lee, Kypros Dereschuk, Wei Tse Li, Jaideep Chakladar, Alecio F. Lombardi, Weg M. Ongkeko and Eric Y. Chang

Int. J. Mol. Sci. 2020, 21(22), 8618; https://doi.org/10.3390/ijms21228618 - 16 Nov 2020

Cited by 26 | Viewed by 3380

Abstract

Osteoarthritis (OA) is the most common joint disorder in the United States, and the gut microbiome has recently emerged as a potential etiologic factor in OA development. Recent studies have shown that a microbiome is present at joint synovia. Therefore, we aimed to characterize the intra-articular microbiome within osteoarthritic synovia and to illustrate its role in OA disease progression. RNA-sequencing data from OA patient synovial tissue was aligned to a library of microbial reference genomes to identify microbial reads indicative of microbial abundance. Microbial abundance data of OA and normal samples was compared to identify differentially abundant microbes. We computationally explored the correlation of differentially abundant microbes to immunological gene signatures, immune signaling pathways, and immune cell infiltration. We found that microbes correlated to OA are related to dysregulation of two main functional pathways: increased inflammation-induced extracellular matrix remodeling and decreased cell signaling pathways crucial for joint and immune function. We also confirmed that the differentially abundant and biologically relevant microbes we had identified were not contaminants. Collectively, our findings contribute to the understanding of the human microbiome, well-known OA risk factors, and the role microbes play in OA pathogenesis. In conclusion, we present previously undiscovered microbes implicated in the OA disease progression that may be useful for future treatment purposes. Full article

(This article belongs to the Special Issue Selected Papers of Workshop "Osteoarthritis: Novel Molecular Determinants Revolutionize Our Understanding of the Disease Pathology")

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17 pages, 3437 KiB

Open AccessArticle

Norepinephrine Inhibits the Proliferation of Human Bone Marrow-Derived Mesenchymal Stem Cells via β2-Adrenoceptor-Mediated ERK1/2 and PKA Phosphorylation

by Jessica Hedderich, Karima El Bagdadi, Peter Angele, Susanne Grässel, Andrea Meurer, Rainer H. Straub, Frank Zaucke and Zsuzsa Jenei-Lanzl

Int. J. Mol. Sci. 2020, 21(11), 3924; https://doi.org/10.3390/ijms21113924 - 30 May 2020

Cited by 19 | Viewed by 3827

Abstract

Bone marrow-derived mesenchymal stem cells (BMSCs) represent an alternative to chondrocytes to support cartilage regeneration in osteoarthritis (OA). The sympathetic neurotransmitter norepinephrine (NE) has been shown to inhibit their chondrogenic potential; however, their proliferation capacity under NE influence has not been studied yet. Therefore, we used BMSCs obtained from trauma and OA donors and compared the expression of adrenergic receptors (AR). Then, BMSCs from both donor groups were treated with NE, as well as with combinations of NE and α1-, α2- or β1/2-AR antagonists (doxazosin, yohimbine or propranolol). Activation of AR-coupled signaling was investigated by analyzing ERK1/2 and protein kinase A (PKA) phosphorylation. A similar but not identical subset of ARs was expressed in trauma (α2B-, α2C- and β2-AR) and OA BMSCs (α2A-, α2B-, and β2-AR). NE in high concentrations inhibited the proliferation of both trauma and OA BMCSs significantly. NE in low concentrations did not influence proliferation. ERK1/2 as well as PKA were activated after NE treatment in both BMSC types. These effects were abolished only by propranolol. Our results demonstrate that NE inhibits the proliferation and accordingly lowers the regenerative capacity of human BMSCs likely via β2-AR-mediated ERK1/2 and PKA phosphorylation. Therefore, targeting β2-AR-signaling might provide novel OA therapeutic options. Full article

(This article belongs to the Special Issue Selected Papers of Workshop "Osteoarthritis: Novel Molecular Determinants Revolutionize Our Understanding of the Disease Pathology")

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15 pages, 1496 KiB

Open AccessArticle

Early OA Stage Like Response Occurs after Dynamic Stretching of Human Synovial Fibroblasts

by Ute Nazet, Susanne Grässel, Jonathan Jantsch, Peter Proff, Agnes Schröder and Christian Kirschneck

Int. J. Mol. Sci. 2020, 21(11), 3874; https://doi.org/10.3390/ijms21113874 - 29 May 2020

Cited by 8 | Viewed by 2852

Abstract

As events triggering early osteoarthritis onset can be related to mechanical stress and proinflammatory signaling, we investigated the effect of different mechanical strain protocols on the expression of proinflammatory genes, as well as extracellular matrix remodelling in human synovial fibroblasts. Three distinct models of tensile stretching were applied: static isotropic tensile strain at 0 Hz, 16% tension for 48 h; short-term high-frequency cyclic tension at 1 Hz, 10% tension for 4 h; and dynamic tensile stretching for 48 h, consisting of two blocks of moderate stretching at 0.2 Hz, 2%, advanced stretching at 0.5 Hz, 15%, or a combination of both. General signs of inflammation were present after static isotropic tension, whereas short-term high-frequency cyclic tension showed increased levels of IL-6 paired with diminished levels of IL-1β. Reduced inflammatory effects of TNF-α, IL-6, and IL-1β were observed when exposed to advanced stretching. Long-term tensile strain induced extracellular matrix remodelling at the gene and protein levels. While hyaluronan acid synthesis was increased with static tensile strain, dynamic tensile stretching had a reducing effect. Our study revealed that proinflammatory markers were activated by mechanical strain as seen in static isotropic tension and short-term high-frequency tensile strain, whereas long-term exposure induced extracellular matrix remodelling processes. Full article

(This article belongs to the Special Issue Selected Papers of Workshop "Osteoarthritis: Novel Molecular Determinants Revolutionize Our Understanding of the Disease Pathology")

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27 pages, 11526 KiB

Open AccessArticle

Mice Lacking the Matrilin Family of Extracellular Matrix Proteins Develop Mild Skeletal Abnormalities and Are Susceptible to Age-Associated Osteoarthritis

by Ping Li, Lutz Fleischhauer, Claudia Nicolae, Carina Prein, Zsuzsanna Farkas, Maximilian Michael Saller, Wolf Christian Prall, Raimund Wagener, Juliane Heilig, Anja Niehoff, Hauke Clausen-Schaumann, Paolo Alberton and Attila Aszodi

Int. J. Mol. Sci. 2020, 21(2), 666; https://doi.org/10.3390/ijms21020666 - 19 Jan 2020

Cited by 30 | Viewed by 7433

Abstract

Matrilins (MATN1, MATN2, MATN3 and MATN4) are adaptor proteins of the cartilage extracellular matrix (ECM), which bridge the collagen II and proteoglycan networks. In humans, dominant-negative mutations in MATN3 lead to various forms of mild chondrodysplasias. However, single or double matrilin knockout mice generated previously in our laboratory do not show an overt skeletal phenotype, suggesting compensation among the matrilin family members. The aim of our study was to establish a mouse line, which lacks all four matrilins and analyze the consequence of matrilin deficiency on endochondral bone formation and cartilage function. Matn1-4^−/− mice were viable and fertile, and showed a lumbosacral transition phenotype characterized by the sacralization of the sixth lumbar vertebra. The development of the appendicular skeleton, the structure of the growth plate, chondrocyte differentiation, proliferation, and survival were normal in mutant mice. Biochemical analysis of knee cartilage demonstrated moderate alterations in the extractability of the binding partners of matrilins in Matn1-4^−/− mice. Atomic force microscopy (AFM) revealed comparable compressive stiffness but higher collagen fiber diameters in the growth plate cartilage of quadruple mutant compared to wild-type mice. Importantly, Matn1-4^−/− mice developed more severe spontaneous osteoarthritis at the age of 18 months, which was accompanied by changes in the biomechanical properties of the articular cartilage. Interestingly, Matn4^−/− mice also developed age-associated osteoarthritis suggesting a crucial role of MATN4 in maintaining the stability of the articular cartilage. Collectively, our data provide evidence that matrilins are important to protect articular cartilage from deterioration and are involved in the specification of the vertebral column. Full article

(This article belongs to the Special Issue Selected Papers of Workshop "Osteoarthritis: Novel Molecular Determinants Revolutionize Our Understanding of the Disease Pathology")

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Review

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19 pages, 2663 KiB

Open AccessReview

Physiological and Pathophysiological Aspects of Primary Cilia—A Literature Review with View on Functional and Structural Relationships in Cartilage

by Friedrich Barsch, Tanja Niedermair, Andreas Mamilos, Volker H. Schmitt, David Grevenstein, Maximilian Babel, Thomas Burgoyne, Amelia Shoemark and Christoph Brochhausen

Int. J. Mol. Sci. 2020, 21(14), 4959; https://doi.org/10.3390/ijms21144959 - 14 Jul 2020

Cited by 9 | Viewed by 10078

Abstract

Cilia are cellular organelles that project from the cell. They occur in nearly all non-hematopoietic tissues and have different functions in different tissues. In mesenchymal tissues primary cilia play a crucial role in the adequate morphogenesis during embryological development. In mature articular cartilage, primary cilia fulfil chemo- and mechanosensitive functions to adapt the cellular mechanisms on extracellular changes and thus, maintain tissue homeostasis and morphometry. Ciliary abnormalities in osteoarthritic cartilage could represent pathophysiological relationships between ciliary dysfunction and tissue deformation. Nevertheless, the molecular and pathophysiological relationships of ‘Primary Cilia’ (PC) in the context of osteoarthritis is not yet fully understood. The present review focuses on the current knowledge about PC and provide a short but not exhaustive overview of their role in cartilage. Full article

(This article belongs to the Special Issue Selected Papers of Workshop "Osteoarthritis: Novel Molecular Determinants Revolutionize Our Understanding of the Disease Pathology")

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