Prolactin promotes cartilage survival and attenuates inflammation in inflammatory arthritis
Norma Adán, Jessica Guzmán-Morales, Maria G. Ledesma-Colunga, Sonia I. Perales-Canales, Andrés Quintanar-Stéphano, Fernando López-Barrera, Isabel Méndez, Bibiana Moreno-Carranza, Jakob Triebel, Nadine Binart, Gonzalo Martínez de la Escalera, Stéphanie Thebault, Carmen Clapp
Norma Adán, Jessica Guzmán-Morales, Maria G. Ledesma-Colunga, Sonia I. Perales-Canales, Andrés Quintanar-Stéphano, Fernando López-Barrera, Isabel Méndez, Bibiana Moreno-Carranza, Jakob Triebel, Nadine Binart, Gonzalo Martínez de la Escalera, Stéphanie Thebault, Carmen Clapp
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Research Article Inflammation

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.

Authors

Norma Adán, Jessica Guzmán-Morales, Maria G. Ledesma-Colunga, Sonia I. Perales-Canales, Andrés Quintanar-Stéphano, Fernando López-Barrera, Isabel Méndez, Bibiana Moreno-Carranza, Jakob Triebel, Nadine Binart, Gonzalo Martínez de la Escalera, Stéphanie Thebault, Carmen Clapp

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Figure 7

PRL and Hal prevent joint inflammation in adjuvant-induced arthritis.

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PRL and Hal prevent joint inflammation in adjuvant-induced arthritis. (A...
(A) Experimental design diagram: osmotic minipumps delivering PRL or subcutaneous tablets releasing Hal were implanted 3 days before the injection of CFA in rats. (B) Representative photographs of hind paws from groups injected or not with CFA. (C and F) Time course of ankle circumference in groups infused with PRL (n = 10) or treated with Hal (n = 16) under control and CFA-injected conditions. (C) Days 15, 18, and 21, P < 0.001, CFA vs. control. Days 18 and 21, P < 0.001, PRL vs. PRL plus CFA. (F) Days 15 and 18, P < 0.001, CFA vs. control. Days 12, 15, 18, and 21, P < 0.001, CFA vs. Hal plus CFA. (D and G) Nociceptive threshold in groups infused with PRL (n = 5–9) or treated with Hal (n = 5–9). (E and H) qRT-PCR–based quantification of Infg, Il6, iNos, Il1b, and Tnfa mRNA levels in ankle joints from rats treated with PRL (n = 3–10) or with Hal (n = 3–10) under control and CFA-injected conditions on day 21 after CFA. Bars are mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001.