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Cholesterol metabolism regulates cartilage metabolic-inflammatory crosstalk by triggering osteocyte mitochondria transfer as a therapeutic target for osteoarthritis

ABSTRACT: Osteoarthritis (OA) is considered as a metabolic related inflammatory disease in the joint affecting both cartilage and subchondral bone. Cholesterol metabolism has been implicated in the pathogenesis of OA, yet the underlying mechanism still remains elusive. Understanding the role of cholesterol metabolism in the joint inflammation will provide treatment alternatives of OA. Here, we found that the disordered cholesterol metabolism in joint do not directly target cartilage and synovium but target subchondral bone by transferring osteocyte mitochondria to amplify inflammatory phenotype in the cartilage. In detail, Nudt8 in osteocyte mitochondria serves as a metabolic-inflammatory switch point to alter cholesterol metabolism by degrading coenzyme A (CoA) and further increase the cytosolic mitochondrial DNA (mtDNA) stress to activate cGAS-STING pathway in chondrocytes, resulting in exacerbated inflammation and OA severity. Inhibiting the transfer of osteocyte mitochondria ameliorated joint inflammation and OA progression. Pharmacological targeting osteocyte mitochondria regulated cholesterol metabolism by supplementation of pantethine - an important precursor metabolite of CoA - ameliorated osteocyte mitochondria activated cGAS-STING pathway and OA phenotype in chondrocytes, and subsequent improved the joint damage and reduced painful behavior in OA mice. Targeting cholesterol-mitochondria regulated metabolic-inflammatory crosstalk represents a promising treatment strategy for OA.

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

PROVIDER: MTBLS11733 | MetaboLights | 2025-09-28

REPOSITORIES: MetaboLights

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Project description:Osteoarthritis (OA) is the most common joint disease and this is a major cause of joint pain and disability in the aging population. Its etiology is multifactorial (i.e., age, obesity, joint injury, genetic predisposition), and the pathophysiologic process affects the entirety of the joint (Martel-Pelletier J et al. Osteoarthritis. Nature reviews Disease primers. 2016;2:16072). Although it is not yet clear if it precedes or occurs subsequently to cartilage damage, subchondral bone sclerosis is an important feature in OA pathophysiology (Goldring SR et al. Changes in the osteochondral unit during osteoarthritis: structure, function and cartilage-bone crosstalk. Nat Rev Rheumatol. 2016;12:632-44). It is characterized by local bone resorption and the accumulation of weakly mineralized osteoid substance (Bailey AJ et al. Phenotypic expression of osteoblast collagen in osteoarthritic bone: production of type I homotrimer. Int J Biochem Cell Biol. 2002;34:176-82). Subchondral bone sclerosis is suspected to be linked to cartilage degradation, not only by modifying the mechanical stresses transmitted to the cartilage, but also by releasing biochemical factors with an activity on cartilage metabolism (Sanchez C et al. Osteoblasts from the sclerotic subchondral bone downregulate aggrecan but upregulate metalloproteinases expression by chondrocytes. This effect is mimicked by interleukin-6, -1beta and oncostatin M pre-treated non-sclerotic osteoblasts. Osteoarthritis Cartilage. 2005;13:979-87; Sanchez C et al. Subchondral bone osteoblasts induce phenotypic changes in human osteoarthritic chondrocytes. Osteoarthritis Cartilage. 2005;13:988-97; Westacott CI et al J. Alteration of cartilage metabolism by cells from osteoarthritic bone. Arthritis Rheum. 1997;40:1282-91. We have previously demonstrated that osteoblasts isolated from subchondral OA bone exhibited an altered phenotype. More precisely, we showed that osteoblasts coming from the thickening (called sclerotic, SC) of subchondral bone located just below a cartilage lesion produced higher levels of alkaline phosphatase, interleukin (IL)-6, IL-8, prostaglandinE2, vascular endothelial growth factor (VEGF), matrix metalloproteinase (MMP)-9 and transforming growth factor(TGF)-β1 and type I collagen than osteoblasts coming from the non-thickening neighboring area (called non-sclerotic area, NSC) (Sanchez C et al. Phenotypic characterization of osteoblasts from the sclerotic zones of osteoarthritic subchondral bone. Arthritis Rheum. 2008;58:442-55; Sanchez C et al. Regulation of subchondral bone osteoblast metabolism by cyclic compression. Arthritis Rheum. 2012;64:1193-203.) To compare secretome of cells living in different in vivo conditions is useful, not only to better understand the pathological mechanisms underlying changes in OA subchondral bone, but also to identify soluble biomarkers potentially reflecting these changes. Using our well-characterised human subchondral osteoblast culture model, we compared the secretome of osteoblasts coming from sclerotic and non sclerotic OA subchondral bone. This approach allowed to identify changes in secretome that contribute to explain some subchondral bone abnormalities in OA and to propose osteomodulin and fibulin-3 as potential biomarkers of OA subchondral bone remodelling.

Project description:Baker2017 - The role of cytokines, MMPs and fibronectin fragments osteoarthritis This model is described in the article: Mathematical modelling of cytokines, MMPs and fibronectin fragments in osteoarthritic cartilage. Baker M, Brook BS, Owen MR. J Math Biol 2017 Feb; : Abstract: Osteoarthritis (OA) is a degenerative disease which causes pain and stiffness in joints. OA progresses through excessive degradation of joint cartilage, eventually leading to significant joint degeneration and loss of function. Cytokines, a group of cell signalling proteins, present in raised concentrations in OA joints, can be classified into pro-inflammatory and anti-inflammatory groups. They mediate cartilage degradation through several mechanisms, primarily the up-regulation of matrix metalloproteinases (MMPs), a group of collagen-degrading enzymes. In this paper we show that the interactions of cytokines within cartilage have a crucial role to play in OA progression and treatment. We develop a four-variable ordinary differential equation model for the interactions between pro- and anti-inflammatory cytokines, MMPs and fibronectin fragments (Fn-fs), a by-product of cartilage degradation and up-regulator of cytokines. We show that the model has four classes of dynamic behaviour: homoeostasis, bistable inflammation, tristable inflammation and persistent inflammation. We show that positive and negative feedbacks controlling cytokine production rates can determine either a pre-disposition to OA or initiation of OA. Further, we show that manipulation of cytokine, MMP and Fn-fs levels can be used to treat OA, but we suggest that multiple treatment targets may be essential to halt or slow disease progression. This model is hosted on BioModels Database and identified by: MODEL1704120000. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

			Action	DRS
	HFX3_1368586_CN_QC1.raw	Raw
	HFX3_1368586_CN_QC2.raw	Raw
	HFX3_1368586_CN_QC3.raw	Raw
	HFX3_1368586_CP_QC1.raw	Raw
	HFX3_1368586_CP_QC2.raw	Raw

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Cholesterol metabolism regulates cartilage metabolic-inflammatory crosstalk by triggering osteocyte mitochondria transfer as a therapeutic target for osteoarthritis

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