Systems approaches in osteoarthritis: Identifying routes to novel diagnostic and therapeutic strategies

Mueller, Alan; Peffers, Mandy J.; Proctor, Carole J.; Clegg, Peter

doi:10.1002/jor.23563

Cited by 12 publications

(6 citation statements)

References 128 publications

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“… 6 Unfortunately, no drugs are currently available to reverse OA and clinical analgesic strategies for managing OA pain have been constrained by suboptimal effectiveness and significant adverse effects, which leaves end-stage patients with limited treatment options, such as joint replacement surgery. 146 Nevertheless, skeletal interoception revealing the role of PGE2 in subchondral bone and bone metabolism offers promising therapeutic prospects for counteracting the progression of OA and mitigating associated pain. In this section, we discuss the critical role of inhibiting PGE2 in subchondral bone, emphasizing its potential for attenuating OA progression and pain.…”

Section: Targeting Skeletal Interoception Is a Promising Therapy For ...mentioning

confidence: 99%

Skeletal interoception in osteoarthritis

Yang,

Xu,

et al. 2024

Bone Res

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The interoception maintains proper physiological conditions and metabolic homeostasis by releasing regulatory signals after perceving changes in the internal state of the organism. Among its various forms, skeletal interoception specifically regulates the metabolic homeostasis of bones. Osteoarthritis (OA) is a complex joint disorder involving cartilage, subchondral bone, and synovium. The subchondral bone undergoes continuous remodeling to adapt to dynamic joint loads. Recent findings highlight that skeletal interoception mediated by aberrant mechanical loads contributes to pathological remodeling of the subchondral bone, resulting in subchondral bone sclerosis in OA. The skeletal interoception is also a potential mechanism for chronic synovial inflammation in OA. In this review, we offer a general overview of interoception, specifically skeletal interoception, subchondral bone microenviroment and the aberrant subchondral remedeling. We also discuss the role of skeletal interoception in abnormal subchondral bone remodeling and synovial inflammation in OA, as well as the potential prospects and challenges in exploring novel OA therapies that target skeletal interoception.

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Section: Targeting Skeletal Interoception Is a Promising Therapy For ...mentioning

confidence: 99%

Skeletal interoception in osteoarthritis

Yang,

Xu,

et al. 2024

Bone Res

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“…Reductionism is important in breaking a system into its constituent parts; however, it does not do away with the system. A whole body systems-based approach to OA research may help to develop new disease-modifying drugs and bioelectronic therapies 43 . Moving from a 'whole joint-centric' view to a "whole bodycentric" view involving the CNS, may redefine the OA patient but only time will tell.…”

Section: P 89mentioning

confidence: 99%

Defining the osteoarthritis patient: back to the future

Dobson

Letson

Grant

et al. 2018

Osteoarthritis and Cartilage

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The history of osteoarthritis (OA) is important because it can help broaden our perspective on past and present controversies. The naming of OA, beginning with Heberden's nodes, is itself a fascinating story. According to Albert Hoffa, R. Llewellyn Jones and Archibald Edward Garrod, the name OA was introduced in the mid-nineteenth century by surgeon Richard von Volkmann who distinguished it from rheumatoid arthritis and gout. Others preferred the terms 'chronical rheumatism', 'senile arthritis', 'hypertrophic arthritis' or 'arthritis deformans'. A similar narrative applies to the concept of OA affecting the whole joint vs the 'wear-and-tear' hypothesis, inflammation and the role of the central nervous system (CNS). In the late nineteenth and early twentieth centuries, the Garrods (father and son) and Hermann Senator argued that OA was a whole joint disease, and that inflammation played a major role in its progression. Garrod Jnr and John Spender also linked OA to a neurogenic lesion 'outside the joint'. The remaining twentieth century was no less dynamic, with major advances in basic science, diagnostics, treatments, surgical interventions and technologies. Today, OA is characterized as a multi-disease with inflammation, immune and CNS dysfunction playing central roles in whole joint damage, injury progression, pain and disability. In the current 'omics' era (genomics, proteomics and metabolomics), we owe a great debt to past physicians and surgeons who dared to think 'outside-the-box' to explain and treat OA. Over 130 years later, despite these developments, we still don't fully understand the underlying complexities of OA, and we still don't have a cure.

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“…The application of quantitative and mechanistic systems biology models has been instrumental in modern translational research, in terms of generating and testing new hypotheses, uncovering novel mechanisms and features that are otherwise hidden in the complex cellular regulations, and expediting drug discovery at various stages such as target identification and preclinical as well as clinical development [19,20,21,22,23,24]. The same concept and methodology when applied to miR research have greatly advanced our understanding of how miRs regulate cellular phenotypes and disease pathways, as demonstrated by a series of kinetic computational models developed over the past decade for various disease contexts.…”

Section: Introductionmentioning

confidence: 99%

Mechanistic Computational Models of MicroRNA-Mediated Signaling Networks in Human Diseases

Zhao

Zhang

Popel

2019

IJMS

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MicroRNAs (miRs) are endogenous non-coding RNA molecules that play important roles in human health and disease by regulating gene expression and cellular processes. In recent years, with the increasing scientific knowledge and new discovery of miRs and their gene targets, as well as the plentiful experimental evidence that shows dysregulation of miRs in a wide variety of human diseases, the computational modeling approach has emerged as an effective tool to help researchers identify novel functional associations between differential miR expression and diseases, dissect the phenotypic expression patterns of miRs in gene regulatory networks, and elucidate the critical roles of miRs in the modulation of disease pathways from mechanistic and quantitative perspectives. Here we will review the recent systems biology studies that employed different kinetic modeling techniques to provide mechanistic insights relating to the regulatory function and therapeutic potential of miRs in human diseases. Some of the key computational aspects to be discussed in detail in this review include (i) models of miR-mediated network motifs in the regulation of gene expression, (ii) models of miR biogenesis and miR–target interactions, and (iii) the incorporation of such models into complex disease pathways in order to generate mechanistic, molecular- and systems-level understanding of pathophysiology. Other related bioinformatics tools such as computational platforms that predict miR-disease associations will also be discussed, and we will provide perspectives on the challenges and opportunities in the future development and translational application of data-driven systems biology models that involve miRs and their regulatory pathways in human diseases.

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Systems approaches in osteoarthritis: Identifying routes to novel diagnostic and therapeutic strategies

Cited by 12 publications

References 128 publications

Skeletal interoception in osteoarthritis

Skeletal interoception in osteoarthritis

Defining the osteoarthritis patient: back to the future

Mechanistic Computational Models of MicroRNA-Mediated Signaling Networks in Human Diseases

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