The Organ-Joint Axes in Osteoarthritis: Significant Pathogenesis and Therapeutic Targets

Abstract

Osteoarthritis (OA), a prevalent age-related disease, is increasingly recognized as a multifactorial condition. This comprehensive review provides a multifaceted perspective on the organ-joint crosstalk contributing to OA, transcending the traditional focus on local joint pathology. Based on current research, we discussed the brain-joint, gut-joint, muscle-joint interactions in the etiology and progression of OA. In brain-joint axis, the neuroendocrine regulation, circadian rhythms, and leptin signaling influence joint tissues. We also discussed the role of prostaglandin E2 in skeletal interoception and its potential as a therapeutic target. The gut-joint axis is underscored by the impact of gut microbiota dysbiosis on systemic inflammation and metabolic disorders, both of which are implicated in OA pathogenesis. Furthermore, age-related sarcopenia, characterized by muscle mass and strength loss, is identified as a significant risk factor. Sarcopenia may contribute to OA progression through compromised mechanical support, systemic inflammation, and muscle-derived myokines. Finally, we synthesize the evidence supporting the modulation of circadian rhythm, skeletal interoception, gut microbiome, and muscle mass as innovative strategies for OA management. The organ-joint crosstalk is integral to the complex pathogenesis of OA, highlighting the multifactorial nature of OA and the potential for targeted therapeutic interventions. By integrating these multidimensional perspectives, we aim to enhance our understanding of OA pathogenesis and explore potential pharmacological targets.

Figure 1.

The brain-joint crosstalk in OA progression. (A) The neuroendocrine regulation of OA. Neurotransmitters and neuropeptides derived from the central and autonomic nervous systems exert effects on articular tissues, contributing to cartilage degeneration, synovial inflammation, and aberrant remodeling of the subchondral bone. (B) The circadian rhythm and OA. The SCN master clock impacts the local circadian rhythms of joint through the modulation of neural distribution, hormonal secretion, body temperature, feeding-fasting cycles, and physical activity. (C) Leptin: a potential mediator of crosstalk between joint and brain. Leptin, secreted by adipose tissue, can directly influence joint tissues and is implicated in the modulation of subchondral bone remodeling through its actions on the ARC, PVN, and VMH. (D) Skeletal interoception in OA. OBs within the subchondral bone, upon sensing mechanical load signals, produce PGE2. This molecule, upon interaction with the EP4 of the DRG, conveys interoceptive signals to the hypothalamic VMH and ARC, leading to a dampening of SNS activity. Consequently, this promotes the differentiation of BMSCs into OBs in subchondral bone and stimulates lipolysis to provide energy for osteogenesis. SCN, suprachiasmatic nucleus, ARC, hypothalamic arcuate nucleus, PVN, paraventricular nucleus, VMH, ventromedial hypothalamus, OB, osteoblast, PGE2, prostaglandin E2, EP4, prostaglandin E receptor 4, DRG, dorsal root ganglion, SNS, sympathetic nervous system, BMSC, bone marrow mesenchymal stem cell.

Figure 2.

The gut microbiota dysbiosis in the pathogenesis of OA. Gut microbiota dysbiosis promotes the progression of OA through two primary mechanisms. Initially, the perturbation results in an elevated ratio of pro-inflammatory bacterial species, thereby triggering a systemic inflammation that fosters OA. Concurrently, metabolites derived from the gut microbiota facilitate the development of metabolic syndrome and obesity, which are established contributors to the pathogenesis of OA. Among these metabolites, there are also pro-inflammatory substances such as tryptophan and s SCFAs, which are instrumental in amplifying systemic inflammatory responses. SCFA, short-chain fatty acid.

Figure 3.

The potential role of sarcopenia in the etiology of OA. The risk of sarcopenia rises with aging and muscle disuse. Decreased strength in the periarticular muscles can lead to joint instability, subjecting the joints to increased mechanical stress. Furthermore, the secretion of inflammatory cytokines by atrophied muscle tissue enters systemic circulation, potentially propagating systemic or local inflammation. Myokines released from the muscle may also exert paracrine effects, diffusing to the adjacent cartilage or subchondral bone and influencing their metabolic homeostatic and remodeling processes. Above mechanisms may increase the risk of OA associated with sarcopenia.