From Low-Grade Inflammation in Osteoarthritis to Neuropsychiatric Sequelae: A Narrative Review

Abstract

Nowadays, osteoarthritis (OA), a common, multifactorial musculoskeletal disease, is considered to have a low-grade inflammatory pathogenetic component. Lately, neuropsychiatric sequelae of the disease have gained recognition. However, a link between the peripheral inflammatory process of OA and the development of neuropsychiatric pathology is not completely understood. In this review, we provide a narrative that explores the development of neuropsychiatric disease in the presence of chronic peripheral low-grade inflammation with a focus on its signaling to the brain. We describe the development of a pro-inflammatory environment in the OA-affected joint. We discuss inflammation-signaling pathways that link the affected joint to the central nervous system, mainly using primary sensory afferents and blood circulation via circumventricular organs and cerebral endothelium. The review describes molecular and cellular changes in the brain, recognized in the presence of chronic peripheral inflammation. In addition, changes in the volume of gray matter and alterations of connectivity important for the assessment of the efficacy of treatment in OA are discussed in the given review. Finally, the narrative considers the importance of the use of neuropsychiatric diagnostic tools for a disease with an inflammatory component in the clinical setting.

Keywords: central nervous system; cytokines; low-grade inflammation; neuropsychiatric disease; osteoarthritis; signaling.

Figure 1

A representative image that depicts the histopathological features of low-grade synovitis in OA. (a) The synovial lining layer is slightly thickened, and the stromal density is slightly increased; few perivascular lymphocytes are evident. (b) The lining cells form 3–4 layers, the cellular density within synovial stroma is increased, and inflammatory infiltrate is present (arrow). Hematoxylin and eosin staining. Scale bars: 50 μm.

Figure 2

A representative image that depicts the OA-associated changes in Safranin O/Fast green stained section of articular cartilage. (a) Degradation of cartilage and changes in the proteoglycan content, as indicated by the lack of orange–red staining, is evident. (b) Enlarged, hypertrophic chondrocytes contain abundant cytoplasmic inclusions (arrows). Deep vascular invasions (V) into the cartilage matrix and reactive chondroclasts (arrowheads) are evident. Safranin O/Fast green staining. Scale bars: 30 μm.

Figure 3

Signaling pathways and structural changes associated with the development of osteoarthritis.

Figure 4

An outline of the main pathways for signaling inflammatory mediators to the central nervous system and the sequelae of recognized routes.

Figure 5

An illustrative example of magnetic resonance imaging-based brain volumetry analyses of functional neuroimaging data in a patient with OA confirms the alteration of the structures in the left parietal lobule. Surface-based volumetry demonstrates precuneus (colored in green) and inferior parietal gyrus (colored in purple). (a) Axial plane; (b) Coronary plane; (c) Medial sagittal plane; (d) Lateral sagittal plane.

Figure 6

The structural appearance of the inferior parietal lobule of OA patient, post-mortem bran tissue. (a) An overview of the lobe as observed by the use of routine staining; (b) The interface of the gray and white matter presents with brown coloration in the cell bodies and moss-like processes of microglial cells (arrows), Iba1 immunohistochemistry; (c) Microglial cells (arrows) visualized by the presence of brown reaction products confirmed by the use of an anti-CD68 antibody, CD68 immunohistochemistry; (d) Astrocytes (arrows) that demonstrate strong expression of the glial fibrillary acidic protein (GFAP), GFAP immunohistochemistry. Scale bars: (a–c) 50 μm; (d) 30 μm.