Prolactin promotes cartilage survival and attenuates inflammation in inflammatory arthritis

Abstract

Chondrocytes are the only cells in cartilage, and their death by apoptosis contributes to cartilage loss in inflammatory joint diseases, such as rheumatoid arthritis (RA). A putative therapeutic intervention for RA is the inhibition of apoptosis-mediated cartilage degradation. The hormone prolactin (PRL) frequently increases in the circulation of patients with RA, but the role of hyperprolactinemia in disease activity is unclear. Here, we demonstrate that PRL inhibits the apoptosis of cultured chondrocytes in response to a mixture of proinflammatory cytokines (TNF-α, IL-1β, and IFN-γ) by preventing the induction of p53 and decreasing the BAX/BCL-2 ratio through a NO-independent, JAK2/STAT3-dependent pathway. Local treatment with PRL or increasing PRL circulating levels also prevented chondrocyte apoptosis evoked by injecting cytokines into the knee joints of rats, whereas the proapoptotic effect of cytokines was enhanced in PRL receptor-null (Prlr -/-) mice. Moreover, eliciting hyperprolactinemia in rats before or after inducing the adjuvant model of inflammatory arthritis reduced chondrocyte apoptosis, proinflammatory cytokine expression, pannus formation, bone erosion, joint swelling, and pain. These results reveal the protective effect of PRL against inflammation-induced chondrocyte apoptosis and the therapeutic potential of hyperprolactinemia to reduce permanent joint damage and inflammation in RA.

Prolactin: A versatile regulator of inflammation and autoimmune pathology

“…PRL has been shown to inhibit in vitro chondrocyte apoptosis induced by serum starvation [111], to augment the proliferation of bone marrow-derived mesenchymal stem cells undergoing chondrogenic differentiation and to increase their synthesis of proteoglycans and type II collagen [6]. In accordance with these previous observations, and contrarily to the hypothesis of a pathogenic role of PRL in RA, a recent study has demonstrated that, surprisingly, high levels of circulating PRL protect against permanent joint damage and inflammation in experimental arthritis in rats [112]. In this study PRL was shown to counteract the apoptosis of rat chondrocytes induced by a mixture of cytokines (i.e.…”

“…TNF-, IL-1, IFN-) both in vitro and in vivo via JAK2/STAT3-dependent pathway. Interestingly, PRLR-deficient mice injected with the same cytokine cocktail display higher chondrocyte apoptosis than wild-type mice, suggesting that, under inflammatory conditions, endogenous PRL at physiological concentrations contributes to chondrocyte survival [112].…”

Prolactin regulates TRPV1, TRPA1, and TRPM8 in sensory neurons in a sex-dependent manner: Contribution of prolactin receptor to inflammatory pain

“…The data presented here mostly cover short-term actions (Ͻ5 days) of PRL and PRL-R and demonstrate that the disruption of PRL and PRL-R significantly decreases inflammatory hyperalgesia at 1-24 h post-CFA. Interestingly, shortterm hyperprolactinemia increased inflammatory edema in male animals, whereas long-term 30-day hyperprolactinemia had anti-inflammatory effects (1,55). Fifth, it has been shown that PRL produces antihyperalgesic effects in lactating females (60,63).…”

“…These findings imply that the physiological levels of PRL are mildly antinociceptive, and inflammation-induced PRL levels have hyperalgesic effects. Interestingly, systemic and prolonged treatments with supraphysiological concentrations of PRL, which are observed during lactation in females, could provide a protective effect for certain cell types (1,50). This dual-effect phenomenon is reported for many trophic factors, and PRL could play such a role.…”

Artesunate Ameliorates Functional Limitations in Freund’s Complete Adjuvant-Induced Monoarthritis in Rat by Maintaining Oxidative Homeostasis and Inhibiting COX-2 Expression

“…The peak inflammatory response in this model occurs on day 3 where the level of myeloperoxidase, the number of infiltrating cells, and TUNEL-positive cells were higher in FCA control rats as compared to normal rats. Treatment of arthritic rats with artesunate suppressed cell apoptosis that has been related to attenuation of inflammatory arthritis [43]. The protection afforded by artesunate was also evident from the histological analysis of the arthritic joints.…”