Modulation of Dopamine Receptors on Osteoblasts as a Possible Therapeutic Strategy for Inducing Bone Formation in Arthritis

Abstract

Rheumatoid arthritis (RA) is associated with systemic osteoporosis, which leads to severe disability and low quality of life. Current therapies target osteoclasts to reduce bone degradation, but more treatment options would be required to promote bone protection by acting directly on osteoblasts (OB). Recently, the local production of dopamine in inflamed joints of RA has been observed. Thus, in this project, we aimed to determine the implication of the neurotransmitter dopamine in the bone formation process in RA. Dopamine receptors (DR) in the human bone tissue of RA or osteoarthritis (OA) patients were examined by immunohistochemistry. DR in isolated human osteoblasts (OB) was analyzed by flow cytometry, and dopamine content was evaluated by ELISA. Osteoclasts (OC) were differentiated from the PBMCs of healthy controls (HC) and RA patients. Isolated cells were treated with specific dopamine agonists. The effect of dopamine on mineralization was evaluated by Alizarin red staining. Cytokine release in supernatants was measured by ELISA. Osteoclastogenesis was evaluated with TRAP staining. OC markers were analyzed via real-time PCR and bone resorption via staining of resorption pits with toluidine blue. All DR were observed in bone tissue, especially in the bone remodeling area. Isolated OB maintained DR expression, which allowed their study in vitro. Isolated OB expressed tyrosine hydroxylase, the rate-limiting enzyme for dopamine production, and contained dopamine. The activation of D2-like DR significantly increased bone mineralization in RA osteoblasts and increased osteoclastogenesis but did not alter the expression of OC markers nor bone resorption. DR were found in the bone remodeling area of human bone tissue and dopamine can be produced by osteoblasts themselves, thus suggesting a local autocrine/paracrine pathway of dopamine in the bone. D2-like DRs are responsible for bone mineralization in osteoblasts from RA patients without an increase in bone resorption, thus suggesting the D2-like DR pathway as a possible future therapeutic target to counteract bone resorption in arthritis.

Dopamine is involved in reparative dentin formation through odontoblastic differentiation of dental pulp stem cells

“…Moreover, these factors are expressed in non-neural cells such as those in the heart and pancreas 24,25 . Even in osteoblasts and pre-odontoblasts, these factors are expressed and promote their differentiation 20,26 . Taken together, we demonstrated that TH and DA were involved in odontoblastic differentiation of DPSCs during reparative dentin formation.…”

Circulating serotonin and dopamine concentrations in osteoarthritis patients: a pilot study on the effect of pelotherapy

“…The reported anti-inflammatory effects of dopamine (Lu et al 2015 ) have been the basis for investigations assessing the potential role of dopamine in inflammatory rheumatic diseases treatment, such as RA and OA. Recent studies focus on the inhibition of inflammatory responses by targeting dopamine receptors to treat inflammatory diseases (Feng and Lu 2021 ; Schwendich et al 2022 ). Capellino et al ( 2014 ) demonstrated that exogenous dopamine strongly inhibited the production of IL-8 in RA patients, suggesting that dopaminergic agents lead to a reduction of inflammation.…”

Antiangiogenic Effect of Dopamine and Dopaminergic Agonists as an Adjuvant Therapeutic Option in the Treatment of Cancer, Endometriosis, and Osteoarthritis

“…Healthy articular cartilage lacks nerve endings and blood vessels, which form simultaneously with bone formation during OA [ 137 , 138 ]. Because of the formation of these nerve endings, OA is a chronic pain condition; however, the role of neurotransmitters during OA is just beginning to be understood [ 139 , 140 , 141 , 142 , 143 , 144 ]. Although cartilage lacks nerve endings, chondrocytes have been found to express some catecholamine receptors, and the role of DA during bone formation has been studied in vitro and also in fracture models in adult individuals [ 140 , 145 , 146 ].…”

“…Because of the formation of these nerve endings, OA is a chronic pain condition; however, the role of neurotransmitters during OA is just beginning to be understood [ 139 , 140 , 141 , 142 , 143 , 144 ]. Although cartilage lacks nerve endings, chondrocytes have been found to express some catecholamine receptors, and the role of DA during bone formation has been studied in vitro and also in fracture models in adult individuals [ 140 , 145 , 146 ]. Another important aspect in the pathogenesis of OA is inflammation, which is exacerbated in the initial phase of OA, mainly by cytokines such as interleukin-1β (IL-1β) and tumor necrosis factor alpha (TNFα), which can also contribute to the damage of articular chondrocytes and ultimately to the dedifferentiation of chondrocytes to a fibrocartilaginous phenotype and finally to bone formation [ 144 , 147 , 148 , 149 ].…”

“…It is possible that during OA, DA may act on stem cells that contribute to osteophyte formation during OA, as several papers show how DA inhibits mesenchymal stem cell migration through its D2R [ 176 ] and may contribute to bone mass loss and inhibit osteogenesis [ 97 ], as it has also been shown to suppress rat bone marrow stem cell differentiation through the protein kinase B/Glycogen synthase kinase-3 beta/β-catenin (AKT/GSK-3β/β-catenin) pathway. Thus, the modulation of DA receptors in osteoblasts has also been proposed as a possible therapy to induce healing in those with rheumatoid arthritis [ 140 ] and possibly osteoporosis. We think that, in contrast, the activation or application of DA can regulate the wear and deterioration of articular cartilage in different mechanisms, such as by regulating inflammation, controlling chondrocyte maturation toward hypertrophy, and consequently inhibiting osteoblast formation on the articular surface, where osteophytes are usually formed from fibrochondrocytes or bone marrow stem cells; additionally, we think that DA can reduce angiogenesis through D2R, which suggests that using DA can be an important antiangiogenic strategy to treat OA, but further studies are needed to clarify this issue.…”