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Open AccessArticle

Methylphenidate Promotes Premature Growth Plate Closure: In Vitro Evidence

by Andrés Pazos-Pérez, María Piñeiro-Ramil, Eloi Franco-Trepat, María Guillán-Fresco, Verónica López-López, Alberto Jorge-Mora, Ana Alonso-Pérez and Rodolfo Gómez

Int. J. Mol. Sci. 2023, 24(4), 4175; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24044175 - 20 Feb 2023

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Abstract

It is well known that patients with attention deficit hyperactivity disorder treated with stimulants, such as methylphenidate hydrochloride (MPH), have reduced height and weight. Even though MPH has an anorexigenic effect, an additional impact of this drug on the growth plate cannot be [...] Read more.

It is well known that patients with attention deficit hyperactivity disorder treated with stimulants, such as methylphenidate hydrochloride (MPH), have reduced height and weight. Even though MPH has an anorexigenic effect, an additional impact of this drug on the growth plate cannot be discarded. In this study, we aimed to determine the cellular effect of MPH on an in vitro growth plate model. We tested the effects of MPH on the viability and proliferation of a prechondrogenic cell line via an MTT assay. In vitro differentiation of this cell line was performed, and cell differentiation was evaluated through the expression of cartilage- and bone-related genes as measured via RT-PCR. MPH did not alter the viability or proliferation of prechondrogenic cells. However, it reduced the expression of cartilage extracellular matrix-related genes (type II collagen and aggrecan) and increased the expression of genes involved in growth plate calcification (Runx2, type I collagen, and osteocalcin) at different phases of their differentiation process. Our results evidence that MPH upregulates genes associated with growth plate hypertrophic differentiation. This may induce premature closure of the growth plate, which would contribute to the growth retardation that has been described to be induced by this drug. Full article

(This article belongs to the Special Issue Inflammation and the Musculoskeletal System)

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22 pages, 18237 KiB

Open AccessArticle

METTL3 Regulates Osteoclast Biological Behaviors via iNOS/NO-Mediated Mitochondrial Dysfunction in Inflammatory Conditions

by Di Li, Jinlin He, Caihong Fang, Yiwen Zhang, Mingli He, Zhanqi Zhang, Jinsong Hou and Qiong Xu

Int. J. Mol. Sci. 2023, 24(2), 1403; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24021403 - 11 Jan 2023

Cited by 6 | Viewed by 1922

Abstract

Excessive differentiation of osteoclasts contributes to the disruption of bone homeostasis in inflammatory bone diseases. Methyltransferase-like 3 (METTL3), the core methyltransferase that installs an N6-methyladenosine (m⁶A) modification on RNA, has been reported to participate in bone pathophysiology. However, whether METTL3-mediated m [...] Read more.

Excessive differentiation of osteoclasts contributes to the disruption of bone homeostasis in inflammatory bone diseases. Methyltransferase-like 3 (METTL3), the core methyltransferase that installs an N6-methyladenosine (m⁶A) modification on RNA, has been reported to participate in bone pathophysiology. However, whether METTL3-mediated m⁶A affects osteoclast differentiation in inflammatory conditions remains unelucidated. In this study, we observed that the total m⁶A content and METTL3 expression decreased during LPS-induced osteoclastogenesis. After knocking down METTL3, we found reduced levels of the number of osteoclasts, osteoclast-related gene expression and bone resorption area. A METTL3 deficiency increased osteoclast apoptosis and pro-apoptotic protein expression. RNA sequencing analysis showed that differentially expressed genes in METTL3-deficient cells were mainly associated with the mitochondrial function. The expression of the mitochondrial function-related genes, ATP production and mitochondrial membrane potential decreased after METTL3 knockdown. Moreover, the most obviously upregulated gene in RNA-Seq was Nos2, which encoded the iNOS protein to induce nitric oxide (NO) synthesis. METTL3 knockdown increased the levels of Nos2 mRNA, iNOS protein and NO content. NOS inhibitor L-NAME rescued the inhibited mitochondrial function and osteoclast formation while suppressing osteoclast apoptosis in METTL3-silenced cells. Mechanistically, a METTL3 deficiency promoted the stability and expression of Nos2 mRNA, and similar results were observed after m⁶A-binding protein YTHDF1 knockdown. Further in vivo evidence revealed that METTL3 knockdown attenuated the inflammatory osteolysis of the murine calvaria and suppressed osteoclast formation. In conclusion, these data suggested that METTL3 knockdown exacerbated iNOS/NO-mediated mitochondrial dysfunction by promoting a Nos2 mRNA stability in a YTHDF1-dependent manner and further inhibited osteoclast differentiation and increased osteoclast apoptosis in inflammatory conditions. Full article

(This article belongs to the Special Issue Inflammation and the Musculoskeletal System)

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Review

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21 pages, 1738 KiB

Open AccessReview

The Ying and Yang of Sphingosine-1-Phosphate Signalling within the Bone

by Kathryn Frost, Amy J. Naylor and Helen M. McGettrick

Int. J. Mol. Sci. 2023, 24(8), 6935; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24086935 - 08 Apr 2023

Viewed by 1437

Abstract

Bone remodelling is a highly active and dynamic process that involves the tight regulation of osteoblasts, osteoclasts, and their progenitors to allow for a balance of bone resorption and formation to be maintained. Ageing and inflammation are risk factors for the dysregulation of [...] Read more.

Bone remodelling is a highly active and dynamic process that involves the tight regulation of osteoblasts, osteoclasts, and their progenitors to allow for a balance of bone resorption and formation to be maintained. Ageing and inflammation are risk factors for the dysregulation of bone remodelling. Once the balance between bone formation and resorption is lost, bone mass becomes compromised, resulting in disorders such as osteoporosis and Paget’s disease. Key molecules in the sphingosine-1-phosphate signalling pathway have been identified for their role in regulating bone remodelling, in addition to its more recognised role in inflammatory responses. This review discusses the accumulating evidence for the different, and, in certain circumstances, opposing, roles of S1P in bone homeostasis and disease, including osteoporosis, Paget’s disease, and inflammatory bone loss. Specifically, we describe the current, often conflicting, evidence surrounding S1P function in osteoblasts, osteoclasts, and their precursors in health and disease, concluding that S1P may be an effective biomarker of bone disease and also an attractive therapeutic target for disease. Full article

(This article belongs to the Special Issue Inflammation and the Musculoskeletal System)

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18 pages, 1303 KiB

Open AccessReview

Macrophage-Driven Inflammation in Metabolic Osteoarthritis: Implications for Biomarker and Therapy Development

by Kelly Warmink, Prateeksha Vinod, Nicoline M. Korthagen, Harrie Weinans and Jaqueline L. Rios

Int. J. Mol. Sci. 2023, 24(7), 6112; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24076112 - 24 Mar 2023

Cited by 5 | Viewed by 2517

Abstract

Osteoarthritis (OA) is a common and debilitating joint disorder that leads to progressive joint breakdown and loss of articular cartilage. Accompanied by a state of low-grade inflammation, its etiology extends beyond that of a wear-and-tear disease, and the immune system might have a [...] Read more.

Osteoarthritis (OA) is a common and debilitating joint disorder that leads to progressive joint breakdown and loss of articular cartilage. Accompanied by a state of low-grade inflammation, its etiology extends beyond that of a wear-and-tear disease, and the immune system might have a role in its initiation and progression. Obesity, which is directly associated with an increased incidence of OA, alters adipokine release, increases pro-inflammatory macrophage activity, and affects joint immune regulation. Studying inflammatory macrophage expression and strategies to inhibit inflammatory macrophage phenotype polarization might provide insights into disease pathogenesis and therapeutic applications. In pre-clinical studies, the detection of OA in its initial stages was shown to be possible using imaging techniques such as SPECT-CT, and advances are made to detect OA through blood-based biomarker analysis. In this review, obesity-induced osteoarthritis and its mechanisms in inducing joint degeneration are summarized, along with an analysis of the current developments in patient imaging and biomarker use for diagnostic and therapeutic strategies. Full article

(This article belongs to the Special Issue Inflammation and the Musculoskeletal System)

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12 pages, 1050 KiB

Open AccessReview

SOXC Transcription Factors as Diagnostic Biomarkers and Therapeutic Targets for Arthritis

by Emad A. Ahmed and Abdullah M. Alzahrani

Int. J. Mol. Sci. 2023, 24(4), 4215; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24044215 - 20 Feb 2023

Cited by 5 | Viewed by 1769

Abstract

Osteoarthritis (OA) and rheumatoid arthritis (RA) are two common disorders that disrupt the quality of life of millions of people. These two chronic diseases cause damage to the joint cartilage and surrounding tissues of more than 220 million people worldwide. Sex-determining region Y-related [...] Read more.

Osteoarthritis (OA) and rheumatoid arthritis (RA) are two common disorders that disrupt the quality of life of millions of people. These two chronic diseases cause damage to the joint cartilage and surrounding tissues of more than 220 million people worldwide. Sex-determining region Y-related (SRY) high-mobility group (HMG) box C, SOXC, is a superfamily of transcription factors that have been recently shown to be involved in various physiological and pathological processes. These include embryonic development, cell differentiation, fate determination, and autoimmune diseases, as well as carcinogenesis and tumor progression. The SOXC superfamily includes SOX4, SOX11, and SOX12, all have a similar DNA-binding domain, i.e., HMG. Herein, we summarize the current knowledge about the role of SOXC transcription factors during arthritis progression and their potential utilization as diagnostic biomarkers and therapeutic targets. The involved mechanistic processes and signaling molecules are discussed. SOX12 appears to have no role in arthritis, however SOX11 is dysregulated and promotes arthritic progression according to some studies but supports joint maintenance and protects cartilage and bone cells according to others. On the other hand, SOX4 upregulation during OA and RA was documented in almost all studies including preclinical and clinical models. Molecular details have indicated that SOX4 can autoregulate its own expression besides regulating the expression of SOX11, a characteristic associated with the transcription factors that protects their abundance and activity. From analyzing the currently available data, SOX4 seems to be a potential diagnostic biomarker and therapeutic target of arthritis. Full article

(This article belongs to the Special Issue Inflammation and the Musculoskeletal System)

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31 pages, 4642 KiB

Open AccessReview

Healthy and Osteoarthritis-Affected Joints Facing the Cellular Crosstalk

by Sofija Semenistaja, Sandra Skuja, Anda Kadisa and Valerija Groma

Int. J. Mol. Sci. 2023, 24(4), 4120; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24044120 - 18 Feb 2023

Cited by 2 | Viewed by 2392

Abstract

Osteoarthritis (OA) is a chronic, progressive, severely debilitating, and multifactorial joint disease that is recognized as the most common type of arthritis. During the last decade, it shows an incremental global rise in prevalence and incidence. The interaction between etiologic factors that mediate [...] Read more.

Osteoarthritis (OA) is a chronic, progressive, severely debilitating, and multifactorial joint disease that is recognized as the most common type of arthritis. During the last decade, it shows an incremental global rise in prevalence and incidence. The interaction between etiologic factors that mediate joint degradation has been explored in numerous studies. However, the underlying processes that induce OA remain obscure, largely due to the variety and complexity of these mechanisms. During synovial joint dysfunction, the osteochondral unit undergoes cellular phenotypic and functional alterations. At the cellular level, the synovial membrane is influenced by cartilage and subchondral bone cleavage fragments and extracellular matrix (ECM) degradation products from apoptotic and necrotic cells. These “foreign bodies” serve as danger-associated molecular patterns (DAMPs) that trigger innate immunity, eliciting and sustaining low-grade inflammation in the synovium. In this review, we explore the cellular and molecular communication networks established between the major joint compartments—the synovial membrane, cartilage, and subchondral bone of normal and OA-affected joints. Full article

(This article belongs to the Special Issue Inflammation and the Musculoskeletal System)

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21 pages, 1053 KiB

Open AccessReview

Mechanisms Underlying Anti-Inflammatory and Anti-Cancer Properties of Stretching—A Review

by Małgorzata Król, Patrycja Kupnicka, Mateusz Bosiacki and Dariusz Chlubek

Int. J. Mol. Sci. 2022, 23(17), 10127; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231710127 - 04 Sep 2022

Cited by 6 | Viewed by 5003

Abstract

Stretching is one of the popular elements in physiotherapy and rehabilitation. When correctly guided, it can help minimize or slow down the disabling effects of chronic health conditions. Most likely, the benefits are associated with reducing inflammation; recent studies demonstrate that this effect [...] Read more.

Stretching is one of the popular elements in physiotherapy and rehabilitation. When correctly guided, it can help minimize or slow down the disabling effects of chronic health conditions. Most likely, the benefits are associated with reducing inflammation; recent studies demonstrate that this effect from stretching is not just systemic but also local. In this review, we present the current body of knowledge on the anti-inflammatory properties of stretching at a molecular level. A total of 22 papers, focusing on anti-inflammatory and anti-cancer properties of stretching, have been selected and reviewed. We show the regulation of oxidative stress, the expression of pro- and anti-inflammatory genes and mediators, and remodeling of the extracellular matrix, expressed by changes in collagen and matrix metalloproteinases levels, in tissues subjected to stretching. We point out that a better understanding of the anti-inflammatory properties of stretching may result in increasing its importance in treatment and recovery from diseases such as osteoarthritis, systemic sclerosis, and cancer. Full article

(This article belongs to the Special Issue Inflammation and the Musculoskeletal System)

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25 pages, 13228 KiB

Open AccessReview

Interplay of Environmental, Individual and Genetic Factors in Rheumatoid Arthritis Provocation

by Marina Arleevskaya, Elena Takha, Sergey Petrov, Gevorg Kazarian, Yves Renaudineau, Wesley Brooks, Regina Larionova, Marina Korovina, Anna Valeeva, Eduard Shuralev, Malik Mukminov, Olga Kravtsova and Andrey Novikov

Int. J. Mol. Sci. 2022, 23(15), 8140; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23158140 - 23 Jul 2022

Cited by 10 | Viewed by 2837

Abstract

In this review, we explore systemization of knowledge about the triggering effects of non-genetic factors in pathogenic mechanisms that contribute to the development of rheumatoid arthritis (RA). Possible mechanisms involving environmental and individual factors in RA pathogenesis were analyzed, namely, infections, mental stress, [...] Read more.

In this review, we explore systemization of knowledge about the triggering effects of non-genetic factors in pathogenic mechanisms that contribute to the development of rheumatoid arthritis (RA). Possible mechanisms involving environmental and individual factors in RA pathogenesis were analyzed, namely, infections, mental stress, sleep deprivation ecology, age, perinatal and gender factors, eating habits, obesity and smoking. The non-genetic factors modulate basic processes in the body with the impact of these factors being non-specific, but these common challenges may be decisive for advancement of the disease in the predisposed body at risk for RA. The provocation of this particular disease is associated with the presence of congenital loci minoris resistentia. The more frequent non-genetic factors form tangles of interdependent relationships and, thereby, several interdependent external factors hit one vulnerable basic process at once, either provoking or reinforcing each other. Understanding the specific mechanisms by which environmental and individual factors impact an individual under RA risk in the preclinical stages can contribute to early disease diagnosis and, if the factor is modifiable, might be useful for the prevention or delay of its development. Full article

(This article belongs to the Special Issue Inflammation and the Musculoskeletal System)

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20 pages, 4099 KiB

Open AccessReview

Structural Analysis of Mitochondrial Dynamics—From Cardiomyocytes to Osteoblasts: A Critical Review

by Daniel H. Mendelsohn, Katja Schnabel, Andreas Mamilos, Samuel Sossalla, Steffen Pabel, Georg Daniel Duerr, Karsten Keller, Volker H. Schmitt, Friedrich Barsch, Nike Walter, Ronald Man Yeung Wong, Thaqif El Khassawna, Tanja Niedermair, Volker Alt, Markus Rupp and Christoph Brochhausen

Int. J. Mol. Sci. 2022, 23(9), 4571; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23094571 - 20 Apr 2022

Cited by 3 | Viewed by 2848

Abstract

Mitochondria play a crucial role in cell physiology and pathophysiology. In this context, mitochondrial dynamics and, subsequently, mitochondrial ultrastructure have increasingly become hot topics in modern research, with a focus on mitochondrial fission and fusion. Thus, the dynamics of mitochondria in several diseases [...] Read more.

Mitochondria play a crucial role in cell physiology and pathophysiology. In this context, mitochondrial dynamics and, subsequently, mitochondrial ultrastructure have increasingly become hot topics in modern research, with a focus on mitochondrial fission and fusion. Thus, the dynamics of mitochondria in several diseases have been intensively investigated, especially with a view to developing new promising treatment options. However, the majority of recent studies are performed in highly energy-dependent tissues, such as cardiac, hepatic, and neuronal tissues. In contrast, publications on mitochondrial dynamics from the orthopedic or trauma fields are quite rare, even if there are common cellular mechanisms in cardiovascular and bone tissue, especially regarding bone infection. The present report summarizes the spectrum of mitochondrial alterations in the cardiovascular system and compares it to the state of knowledge in the musculoskeletal system. The present paper summarizes recent knowledge regarding mitochondrial dynamics and gives a short, but not exhaustive, overview of its regulation via fission and fusion. Furthermore, the article highlights hypoxia and its accompanying increased mitochondrial fission as a possible link between cardiac ischemia and inflammatory diseases of the bone, such as osteomyelitis. This opens new innovative perspectives not only for the understanding of cellular pathomechanisms in osteomyelitis but also for potential new treatment options. Full article

(This article belongs to the Special Issue Inflammation and the Musculoskeletal System)

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