The cholinergic system in joint health and osteoarthritis: a narrative-review

Lauwers, Marianne; Sellam, Jérémie; Wen, Chunyi

doi:10.1016/j.joca.2021.02.005

Cited by 13 publications

(12 citation statements)

References 68 publications

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“…The nicotinic cholinergic system also plays an important role in joint pain and dysfunction, as observed in the OA pathology [ 99 ]. The classical cholinergic anti-inflammatory pathway was recently evaluated to reduce OA-related inflammation [ 100 ].…”

Section: New Approach In Treating Long-covid: the Role Of The Nicotinic Cholinergic Receptormentioning

confidence: 99%

“…The cholinergic system stimulates chondrocyte proliferation, early mineralization, and delays differentiation. It restores the subchondral bone structure through osteoblast proliferation and osteoclast apoptosis [ 99 ]. Therefore, attenuating COVID-19 through the nicotinic cholinergic system could also improve its associated OA-like phenotype.…”

Section: New Approach In Treating Long-covid: the Role Of The Nicotinic Cholinergic Receptormentioning

confidence: 99%

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COVID-19 in Joint Ageing and Osteoarthritis: Current Status and Perspectives

Lauwers

Yuan

et al. 2022

IJMS

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COVID-19 is a trending topic worldwide due to its immense impact on society. Recent trends have shifted from acute effects towards the long-term morbidity of COVID-19. In this review, we hypothesize that SARS-CoV-2 contributes to age-related perturbations in endothelial and adipose tissue, which are known to characterize the early aging process. This would explain the long-lasting symptoms of SARS-CoV-2 as the result of an accelerated aging process. Connective tissues such as adipose tissue and musculoskeletal tissue are the primary sites of aging. Therefore, current literature was analyzed focusing on the musculoskeletal symptoms in COVID-19 patients. Hypovitaminosis D, increased fragility, and calcium deficiency point towards bone aging, while joint and muscle pain are typical for joint and muscle aging, respectively. These characteristics could be classified as early osteoarthritis-like phenotype. Exploration of the impact of SARS-CoV-2 and osteoarthritis on endothelial and adipose tissue, as well as neuronal function, showed similar perturbations. At a molecular level, this could be attributed to the angiotensin-converting enzyme 2 expression, renin-angiotensin system dysfunction, and inflammation. Finally, the influence of the nicotinic cholinergic system is being evaluated as a new treatment strategy. This is combined with the current knowledge of musculoskeletal aging to pave the road towards the treatment of long-term COVID-19.

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Section: New Approach In Treating Long-covid: the Role Of The Nicotinic Cholinergic Receptormentioning

confidence: 99%

Section: New Approach In Treating Long-covid: the Role Of The Nicotinic Cholinergic Receptormentioning

confidence: 99%

COVID-19 in Joint Ageing and Osteoarthritis: Current Status and Perspectives

Lauwers

Yuan

et al. 2022

IJMS

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“…Nicotine, an exogenous stimulator of the cholinergic system, is also important component of cigarette smoke. Several studies reported the role of cholinergic system in the bone homeostasis in the context of osteoporosis and osteoarthritis 45 , 46 . Acetylcholine or exogenous activation via nicotine or muscarine, stimulates osteoblast proliferation and osteoclast apoptosis 45 .…”

Section: Discussionmentioning

confidence: 99%

“…Several studies reported the role of cholinergic system in the bone homeostasis in the context of osteoporosis and osteoarthritis 45 , 46 . Acetylcholine or exogenous activation via nicotine or muscarine, stimulates osteoblast proliferation and osteoclast apoptosis 45 . Acetylcholinesterase (AChE), an enzyme catalyzing the degradation of acetylcholine, plays an important role in the cholinergic regulation by terminating the action of acetylcholine.…”

Section: Discussionmentioning

confidence: 99%

Roles for B[a]P and FICZ in subchondral bone metabolism and experimental temporomandibular joint osteoarthritis via the AhR/Cyp1a1 signaling axis

Yoshikawa

Izawa

Hamada

et al. 2021

Sci Rep

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Bone loss due to smoking represents a major risk factor for fractures and bone osteoporosis. Signaling through the aryl hydrocarbon receptor (AhR) and its ligands contributes to both bone homeostasis and inflammatory diseases. It remains unclear whether the same AhR signaling axis affects the temporomandibular joint (TMJ). The aim of this study was to investigate possible mechanisms which mediate bone loss in the TMJ due to smoking. In particular, whether benzo[a]pyrene (B[a]P), a carcinogen of tobacco smoke, induces expression of the AhR target gene, Cyp1a1, in mandibular condyles. Possible functions of an endogenous ligand of FICZ, were also investigated in a TMJ-osteoarthritis (OA) mouse model. B[a]P was administered orally to wild-type and AhR−/− mice and bone metabolism was subsequently examined. TMJ-OA was induced in wild-type mice with forceful opening of the mouth. Therapeutic functions of FICZ were detected with μCT and histology. Exposure to B[a]P accelerated bone loss in the mandibular subchondral bone. This bone loss manifested with osteoclastic bone resorption and upregulated expression of Cyp1a1 in an AhR-dependent manner. In a mouse model of TMJ-OA, FICZ exhibited a dose-dependent rescue of mandibular subchondral bone loss by repressing osteoclast activity. Meanwhile, in vitro, pre-treatment with FICZ reduced RANKL-mediated osteoclastogenesis. B[a]P regulates mandibular subchondral bone metabolism via the Cyp1a1. The AhR ligand, FICZ, can prevent TMJ-OA by regulating osteoclast differentiation.

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“…Beyond the neuronal cholinergic systems, a range of non-neuronal cells are also able to produce and interact with Ach defining the non-neuronal cholinergic system ( 14 ). For example, chondrocytes belong to the non-neuronal cholinergic system since they express the molecular components to produce, transport, and degrade Ach as well as several nicotinic receptors including α7nAchR ( 15 ). α7nAchR activation can dampen inflammatory, degradative, and apoptotic responses of chondrocytes and could protect animals from OA ( 16 – 18 ).…”

Section: Introductionmentioning

confidence: 99%

Alpha-7 Nicotinic Receptor Dampens Murine Osteoblastic Response to Inflammation and Age-Related Osteoarthritis

Petit

Legris

et al. 2022

Front. Immunol.

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IntroductionOsteoarthritis (OA) is a whole-joint disease characterized by a low-grade inflammation that is involved in both cartilage degradation and subchondral bone remodeling. Since subchondral bone has a cholinergic innervation and that acetylcholine (Ach) might have an anti-inflammatory effect through the α7 nicotinic Ach receptor (α7nAchR), we aimed (i) to determine the expression of non-neuronal cholinergic system and nicotinic receptor subunits by murine and human osteoblasts, (ii) to address the role of α7nAchR in osteoblastic response to inflammation, and (iii) to study the role of α7nAchR in a spontaneous aging OA model.MethodsPrimary cultures of WT and α7nAchR knock-out mice (Chrna7-/-) murine osteoblasts and of subchondral bone human OA osteoblasts were performed. The expressions of the non-neuronal cholinergic system and of the nAchR subunits were assessed by PCR. In vitro, IL1β-stimulated WT, Chrna7-/-, and human osteoblasts were pretreated with nicotine. At 24 h, expressions of interleukin-6 (IL6) and metalloproteinase-3 and -13 (MMP), RANK-ligand (RANKL), and osteoprotegerin (OPG) were quantified by qPCR and ELISA. Spontaneous aging OA was evaluated and compared between male WT and Chrna7-/- mice of 9 and 12 months.ResultsMurine WT osteoblasts express the main components of the cholinergic system and α7 subunit composing α7nAchR. Nicotine partially prevented the IL1β-induced expression and production of IL6, MMP3, and RANKL in WT osteoblasts. The effect for IL6 and MMP was mediated by α7nAchR since nicotine had no effect on Chrna7-/- osteoblasts while the RANKL decrease persisted. Chrna7-/- mice displayed significantly higher cartilage lesions than their WT counterparts at 9 and 12 months, without difference in subchondral bone remodeling. Human OA osteoblasts also expressed the non-neuronal cholinergic system and α7 subunit as well as CHRFAM7A, the dominant negative duplicate of Chrna7. Nicotine pretreatment did not significantly reduce IL6 and MMP3 production in IL-1β-stimulated human osteoarthritic osteoblasts (n = 4), possibly due to CHRFAM7A.ConclusionCholinergic system counteracts murine osteoblastic response to IL-1β through α7nAchR. Since α7nAchR deletion may limit cartilage degradation during murine age-related OA, enhancing cholinergic system could be a new therapeutic target in OA but may depend on CHRFAM7A expression.

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The cholinergic system in joint health and osteoarthritis: a narrative-review

Cited by 13 publications

References 68 publications

COVID-19 in Joint Ageing and Osteoarthritis: Current Status and Perspectives

COVID-19 in Joint Ageing and Osteoarthritis: Current Status and Perspectives

Roles for B[a]P and FICZ in subchondral bone metabolism and experimental temporomandibular joint osteoarthritis via the AhR/Cyp1a1 signaling axis

Alpha-7 Nicotinic Receptor Dampens Murine Osteoblastic Response to Inflammation and Age-Related Osteoarthritis

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