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Therapeutic Effect of Modified Meridian-Guided Acupoint Pressing on Lumbar Facet Joint Osteoarthritis: An Integrated Microbiomics and Metabolomics Analysis

ABSTRACT: Lumbar facet joint osteoarthritis (LFJ OA) is a leading cause of chronic low back pain, with limited effective long-term treatments due to the side effects of pharmacological interventions. Modified Meridian-Guided Acupoint Pressing (MMGAP), a Traditional Chinese Medicine (TCM) physical therapy, has shown potential in musculoskeletal pain management, but its therapeutic efficacy and mechanisms in LFJ OA remain unclear. This study aimed to investigate the effects of MMGAP on LFJ OA and explore the underlying mechanisms using integrated microbiomics and metabolomics analyses. Our results showed that MMGAP significantly alleviated histopathological lesions and inflammatory cell infiltration in lumbar muscles and facet joints, reduced serum levels of IL-1β and TNF-α, and downregulated TRPV1 expression in LFJ OA rats. MMGAP also reshaped gut microbiota composition (altered α/β-diversity and differential taxa) and modulated serum metabolomic profiles, with enrichment of the mTOR signaling pathway. Fecal microbiota transplantation (FMT) from MMGAP-treated rats recapitulated the therapeutic effects, confirming gut microbiota as a key mediator. Furthermore, the mTORC1 inhibitor rapamycin mimicked MMGAP’s anti-inflammatory and analgesic effects. Collectively, our findings demonstrate that MMGAP alleviates LFJ OA through a novel mechanism involving gut microbiota reshaping, serum metabolomic reprogramming, and mTORC1 pathway inhibition. This study provides a scientific basis for the clinical application of MMGAP in LFJ OA and highlights the potential of TCM physical therapies as targeted non-invasive alternatives for degenerative joint diseases

INSTRUMENT(S): Liquid Chromatography MS - positive - hilic, Liquid Chromatography MS - negative - hilic

PROVIDER: MTBLS14816 | MetaboLights | 2026-06-22

REPOSITORIES: MetaboLights

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			Action	DRS
	a_MTBLS14816_LC-MS_negative_hilic.txt	Txt
	a_MTBLS14816_LC-MS_positive_hilic.txt	Txt
	i_Investigation.txt	Txt
	m_MTBLS14816_LC-MS_negative_hilic_v2_maf.tsv	Tabular
	m_MTBLS14816_LC-MS_positive_hilic_v2_maf.tsv	Tabular

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Project description:Abstract Objective: Osteoarthritis (OA) is accompanied by severe and debilitating pain that current analgesics are unable to fully alleviate. A multitude of signaling molecules, pathways, and cells have been identified as regulators of OA pain. Fatty acid binding protein 5 (FABP5) regulates pain in other disease states and we hypothesized that it is involved in the regulation of OA pain. Design: This was a combined clinical and pre-clinical study. Human synovial and osteochondral tissues collected during total knee arthroplasty were subjected to immunohistochemical analyses to identify the spatial expression patterns of FAB5, COX1, COX2, and macrophages. In addition, synovial specimens were cultured the presence and absence of SBFI-103, a selective FABP5 inhibitor, and cytokines and chemokines levels were measured. The rat monoiodoacetate (MIA) model of OA was then enlisted to evaluate the efficacy of SBFI-103 in alleviating OA pain. Finally, RNAseq was performed to identify alterations in synovial gene expression in vehicle and SBFI-103 treated MIA rats. Results: FABP5 expression was present in clinical OA tissues, with higher expression seen higher grade OA and no apparent differences between genders. Furthermore, FABP5 staining colocalized with CD14+ cells, indicating a macrophage origin of FABP5. Synovial specimens secreted CCL2, IL6, IL8, CXCL1, MIF, and Serpin E1 in vitro and treatment with SBFI-103 attenuated CCL2, IL6, IL8, and CXCL1, but not MIF and Serpin E1. Twenty-eight days after MIA injection, rats exhibited histological joint degradation and significant incapacitance. Ketoprofen treatment partially reduced incapacitance and naproxen had no effect; however, SBFI-103 showed a dose dependent alleviation of incapacitance that was independent of cannabinoid or PPARα receptor activity. RNAseq analyses identified differential expression of >6,000 transcripts compared to contralateral controls in vehicle treated rats and only 513 after SBFI-103 treatment. Notably, CCL2, CCL7, CCL9, and CXCL1were upregulated in vehicle treated rats, but not those treated with SBFI-103, and this was confirmed with qPCR. Conclusions: Our results show that FABP5 is upregulated in clinical and preclinical OA tissues and that its inhibition lowers pronociceptive signaling and reduces OA pain, indicating that FABP5 inhibitors may constitute a novel class of analgesics to treat OA.

Project description:Enhancer of zeste homolog 2 (EZH2), a histone methyltransferase, has gained attention as a promising therapeutic target in osteoarthritis (OA) due to its central role in modulating inflammation, catabolism, and hypertrophy within chondrocytes. Previous studies have further demonstrated that EZH2 inhibition can slow OA progression in surgically induced mouse models, highlighting its potential in reducing joint degradation. However, the precise mechanisms by which EZH2 influences other key cell types in OA pathology remain poorly understood. In this study, we aimed to evaluate the effects of EZH2 inhibition in an alternative OA model and investigate its broader impact on cellular and molecular pathways across various tissues involved in OA progression and joint pain. OA was induced in mice via intra-articular injection of monosodium iodoacetate (MIA), with disease progression evaluated by histological and behavioral assessments. In parallel, human synoviocytes and bone marrow-derived cells were isolated from OA patients. Synoviocytes were stimulated with interleukin-1β (IL-1β) in the presence or absence of the EZH2 inhibitor EPZ-6438 (Tazemetostat), and ChIP-Seq and proteomic analyses were conducted to identify genomic and proteomic targets of EZH2. Additionally, the effects of EZH2 inhibition on M1 macrophage polarization and osteoclast differentiation were analyzed. Results revealed that EZH2 inhibition attenuated both OA progression and joint pain in the MIA-induced mouse model. IL-1β stimulation significantly upregulated EZH2 expression in synoviocytes, and treatment with the EZH2 inhibitor reduced the expression of genes linked to inflammation, pain, and catabolism while promoting autophagy. Proteomic analysis highlighted significant alterations in pathways related to IL-1β signaling, matrix metalloproteinase (MMP) activation, and autophagy, as well as changes in proteins associated with metabolic regulation and axon guidance. Importantly, EZH2 inhibition decreased M1 macrophage polarization and osteoclast formation, cellular processes that contribute to OA pain and inflammation. In conclusion, this study underscores the pivotal role of the histone methyltransferase EZH2 in the pathophysiology of osteoarthritis and associated joint pain. Our findings reveal that EZH2 inhibition not only attenuates inflammation in synovial cells and macrophages but also modulates axon guidance and osteoclastogenesis, both critical in OA progression and pain. These insights position EZH2 inhibition as a promising, multi-targeted therapeutic approach for addressing the complex cellular interactions underlying osteoarthritis, offering new hope for effective treatment strategies in this debilitating condition.

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Therapeutic Effect of Modified Meridian-Guided Acupoint Pressing on Lumbar Facet Joint Osteoarthritis: An Integrated Microbiomics and Metabolomics Analysis

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