The role of the prolactin/vasoinhibin axis in rheumatoid arthritis: An integrative overview
Open accessAbstract
Rheumatoid arthritis (RA) is a chronic, autoimmune, inflammatory disease destroying articular cartilage and bone. The female preponderance and the influence of reproductive states in RA have long linked this disease to sexually dimorphic, reproductive hormones such as prolactin (PRL). PRL has immune-enhancing properties and increases in the circulation of some patients with RA. However, PRL also suppresses the immune system, stimulates the formation and survival of joint tissues, acquires antiangiogenic properties upon its cleavage to vasoinhibins, and protects against joint destruction and inflammation in the adjuvant-induced model of RA. This review addresses risk factors for RA linked to PRL, the effects of PRL and vasoinhibins on joint tissues, blood vessels, and immune cells, and the clinical and experimental data associating PRL with RA. This information provides important insights into the pathophysiology of RA and highlights protective actions of the PRL/vasoinhibin axis that could lead to therapeutic benefits.
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Other inflammation-related genes dysregulated in hEDS/HSD include SPON2 up-regulated and PRLR decreased.
“Other inflammation-related genes dysregulated in hEDS/HSD include SPON2, up-regulated in patients’ cells, which encodes an ECM protein with multifunctional properties in the innate immune system and inflammatory cell recruitment [152,153,154], and PRLR, showing a decreased expression in hEDS/HSD cells, which encode the prolactin receptor implicated in inflammatory responses and immune cells”
From Cellular and Molecular Mechanisms in the Pathogenesis of Classical, Vascular, and Hypermobile Ehlers‒Danlos Syndromes (2019) · cites this paper as [155]
PRLR encodes the prolactin receptor implicated in inflammatory responses and immune cell regulation.
“Other inflammation-related genes dysregulated in hEDS/HSD include SPON2, up-regulated in patients’ cells, which encodes an ECM protein with multifunctional properties in the innate immune system and inflammatory cell recruitment [152,153,154], and PRLR, showing a decreased expression in hEDS/HSD cells, which encode the prolactin receptor implicated in inflammatory responses and immune cells”
From Cellular and Molecular Mechanisms in the Pathogenesis of Classical, Vascular, and Hypermobile Ehlers‒Danlos Syndromes (2019) · cites this paper as [155]
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Pope, J. E., Bellamy, N., & Stevens, A. (1999) · Seminars in Arthritis and Rheumatism · doi:10.1016/s0049-0172(99)80019-5 · Cited by 37 · see citing works
Stress in Autoimmune Disease Models
Harbuz, M. S., Richards, L. J., Chover-González, A. J., Martı́, O., & Jessop, D. (2006) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1351.005 · Cited by 37 · see citing works
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Overview of Rheumatoid Arthritis and Scientific Understanding of the Disease
Jahid, M., Khan, K., Rehan-Ul-Haq, & Ahmed, R. S. (2023) · Mediterranean Journal of Rheumatology · doi:10.31138/mjr.20230801.oo · Cited by 158 · see citing works
Samperi, I., Lithgow, K. C., & Karavitaki, N. (2019) · Journal of Clinical Medicine · doi:10.3390/jcm8122203 · Cited by 119 · see citing works
Prolactin Promotes Adipose Tissue Fitness and Insulin Sensitivity in Obese Males
Ruiz-Herrera, X., de los Ríos, E. A., Díaz, J. M., Lerma-Alvarado, R. M., de la Escalera, L. M., López-Barrera, F., Lemini, M., Arnold, E., de la Escalera, G. M., Clapp, C., et al. (2016) · Endocrinology · doi:10.1210/en.2016-1444 · Cited by 93 · see citing works
“PRL has been reported to exhibit both pro-and antiinflammatory actions in different cell types (43).”
BackgroundSelf-citationOsteoarthritis and the Complement Cascade
Silawal, S., Triebel, J., Bertsch, T., & Schulze-Tanzil, G. G. (2018) · Clinical Medicine Insights Arthritis and Musculoskeletal Disorders · doi:10.1177/1179544117751430 · Cited by 91 · see citing works
Self-citationChiarelli, N., Ritelli, M., Zoppi, N., & Colombi, M. (2019) · Genes · doi:10.3390/genes10080609 · Cited by 82 · see citing works
Tang, M. W., García, S., Gerlag, D. M., Tak, P. P., & Reedquist, K. A. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.00720 · Cited by 74 · see citing works
Ledesma-Colunga, M. G., Adán, N., Ortiz, G., Solís-Gutiérrez, M., López-Barrera, F., Martínez de la Escalera, G., & Clapp, C. (2017) · Arthritis Research & Therapy · doi:10.1186/s13075-017-1290-4 · Cited by 40 · see citing works
“In experimental inflammatory arthritis, PRL appears to be beneficial; however, the role of PRL in RA is controversial (as reviewed [58]).”
BackgroundSelf-citationThe Emerging Roles of Endocrine Hormones in Different Arthritic Disorders
Bertoldo, E., Adami, G., Rossini, M., Giollo, A., Orsolini, G., Viapiana, O., Gatti, D., & Fassio, A. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.620920 · Cited by 34 · see citing works
Prolactin: structure, receptors, and functions
Chasseloup, F., Bernard, V., & Chanson, P. (2024) · Reviews in Endocrine and Metabolic Disorders · doi:10.1007/s11154-024-09915-8 · Cited by 34 · see citing works
“The female prevalence and negative effects of lactation and stress on the disease severity of rheumatoid arthritis suggest a potential role of PRL in the pathophysiology of this disease [ 119 , 120].”
Ortiz, G., Ledesma-Colunga, M. G., Wu, Z., García-Rodrigo, J. F., Adán, N., de la Escalera, G. M., & Clapp, C. (2020) · Laboratory Investigation · doi:10.1038/s41374-020-0432-5 · Cited by 21 · see citing works
Self-citationFrom Bench to Bedside: Translating the Prolactin/Vasoinhibin Axis
Triebel, J., Robles-Osorio, M. L., García-Franco, R., de la Escalera, G. M., Clapp, C., & Bertsch, T. (2017) · Frontiers in Endocrinology · doi:10.3389/fendo.2017.00342 · Cited by 19 · see citing works
“Of note, there are more clinical entities in which studies reported that a dysregulation of PRL and of the PRL/vasoinhibin axis might play a role, for example, breast and prostate cancer (71–75), preeclampsia and eclampsia (67, 76, 77), pregnancyinduced hypertension (78), pulmonary artery hypertension (79), retinopath…”
BackgroundSelf-citationLing, Y., Xu, H. Z., Ren, N., Chen, C., Zeng, P., Lu, D., Yao, X., & Ma, W. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.639382 · Cited by 19 · see citing works
“Rheumatoid arthritis (RA) is an autoimmune disease characterized with chronic synovitis and proliferation of synovial cells (Weyand and Goronzy, 2017) accompanied with the release of inflammatory factors, which destroy the bone and the cartilage and eventually lead to the loss of joint function (Clapp et al., 2016; St…”
BackgroundGlobal Deletion of the Prolactin Receptor Aggravates Streptozotocin-Induced Diabetes in Mice
Ramírez‐Hernández, G., Adán‐Castro, E., Díaz‐Lezama, N., Ruíz‐Herrera, X., de la Escalera, G. M., Macotela, Y., & Clapp, C. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.619696 · Cited by 17 · see citing works
Self-citationProlactin mitigates deficiencies of retinal function associated with aging
Arnold, E., Thébault, S. C., Aroña, R. M., de la Escalera, G. M., & Clapp, C. (2019) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2019.10.002 · Cited by 17 · see citing works
Self-citationEndocrine Regulation of Epimorphic Regeneration
Easterling, M. R., Engbrecht, K. M., & Crespi, E. J. (2019) · Endocrinology · doi:10.1210/en.2019-00321 · Cited by 15 · see citing works
Dual Roles of Prolactin and Vasoinhibin in Inflammatory Arthritis
Clapp, C., Ortiz, G., García-Rodrigo, J. F., Ledesma-Colunga, M. G., Martínez-Díaz, O., Adán, N., & de la Escalera, G. M. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.905756 · Cited by 14 · see citing works
Self-citationThe role of prolactin/vasoinhibins in cardiovascular diseases
Zhao, H. Z., Gong, S., Shi, Y., Luo, C., Qiu, H., He, J., Sun, Y., Huang, Y., Wang, S., Miao, Y., et al. (2022) · Animal Models and Experimental Medicine · doi:10.1002/ame2.12264 · Cited by 13 · see citing works
Huo, X., Peng, Y., Li, H., Li, C., Liao, F., Miao, C., & Huang, Y. (2025) · Frontiers in Pharmacology · doi:10.3389/fphar.2025.1481089 · Cited by 12 · see citing works
“…suggesting that gender differences in angiogenic responses were mainly related to the endothelial genotype, sex-speci fi c differences in VEC function — potentially linked to hormonal in fl uences — may partially explain the higher RA prevalence in women (Baggio et al., 2022; Clapp et al., 2016).”
New insights into human prolactin pathophysiology: genomics and beyond
Chang, S., & Copperman, A. B. (2019) · Current Opinion in Obstetrics & Gynecology · doi:10.1097/gco.0000000000000545 · Cited by 12 · see citing works
Regulator of Angiogenesis and Vascular Function: A 2019 Update of the Vasoinhibin Nomenclature
Triebel, J., Robles, J. P., Zamora, M., de la Escalera, G. M., Bertsch, T., & Clapp, C. (2019) · Frontiers in Endocrinology · doi:10.3389/fendo.2019.00214 · Cited by 11 · see citing works
Self-citationImmunometric and functional measurement of endogenous vasoinhibin in human sera
Zamora, M., Harris, D., Davies, N., Ebnet, J., Radermacher, P., Brucker, C. V. M., Waller, C., Robles, J. P., Bertsch, T., Clapp, C., et al. (2024) · Frontiers in Endocrinology · doi:10.3389/fendo.2024.1345996 · Cited by 9 · see citing works
Self-citationShen, P., Zhang, D., Abdelrehem, A., Jin, S., Luo, Y., & Yang, C. (2022) · Clinical Oral Investigations · doi:10.1007/s00784-022-04667-8 · Cited by 7 · see citing works
Vasoinhibin is Generated and Promotes Inflammation in Mild Antigen-induced Arthritis
Ortiz, G., Ledesma-Colunga, M. G., Wu, Z., García-Rodrigo, J. F., Adán, N., Martínez-Díaz, O., Ríos, E. A. D. L., López-Barrera, F., de la Escalera, G. M., & Clapp, C. (2022) · Endocrinology · doi:10.1210/endocr/bqac036 · Cited by 7 · see citing works
Self-citationMolecular evolutionary insights from PRLR in mammals
Paré, P., Reales, G., Paixão‐Côrtes, V. R., Vargas‐Pinilla, P., Viscardi, L. H., Fam, B. S. D. O., Pissinatti, A., dos Santos, F. R., & Bortolini, M. C. (2021) · General and Comparative Endocrinology · doi:10.1016/j.ygcen.2021.113791 · Cited by 7 · see citing works
García-Rodrigo, J. F., Ortiz, G., Martínez-Díaz, O., Furuzawa‐Carballeda, J., Ruíz‐Herrera, X., Macías, F., Ledesma-Colunga, M. G., de la Escalera, G. M., & Clapp, C. (2023) · Endocrinology · doi:10.1210/endocr/bqad156 · Cited by 6 · see citing works
Self-citationWang, Y., Shen, G., Chan, D. S., Wu, L., Wong, C.-Y., Wang, J., Leung, C., & Wang, W. (2026) · Analytical Chemistry · doi:10.1021/acs.analchem.5c06894 · Cited by 5 · see citing works
Vasoinhibin generation and effect on neuronal apoptosis in the hippocampus of late mouse embryos
Aroña, R. M., Arnold, E., Macías, F., López‐Casillas, F., Clapp, C., & de la Escalera, G. M. (2020) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00286.2019 · Cited by 5 · see citing works
“Dysregulation of this axis has been shown to contribute to the pathogenesis and progression of diabetic retinopathy (5), retinopathy of prematurity (58), rheumatoid arthritis (16), peripartum cardiomyopathy (35), and preeclampsia (33).”
BackgroundSelf-citationCastillo, X., Ortiz, G., Arnold, E., Wu, Z., Tovar‐y‐Romo, L. B., Clapp, C., & de la Escalera, G. M. (2024) · Journal of Neuroendocrinology · doi:10.1111/jne.13415 · Cited by 4 · see citing works
Self-citationVasoinhibin is Generated by the Renin-angiotensin System
Núñez, F. F., Siqueiros‐Márquez, L., Adán‐Castro, E., Zamora, M., Robles, J. P., Ruíz‐Herrera, X., Bertsch, T., Triebel, J., de la Escalera, G. M., & Clapp, C. (2025) · Endocrinology · doi:10.1210/endocr/bqaf023 · Cited by 3 · see citing works
Self-citationLu, M., Xu, M., Tang, X., Qiao, L., Chen, H., & Yang, B. (2026) · Frontiers in Medicine · doi:10.3389/fmed.2026.1737904 · Cited by 2 · see citing works
de Santana, L. B., Lima, T. A. D. S., Costa, A. R., Sandoval, L., de Souza, T. Y., da Mota, L. M. H., & Naves, L. A. (2024) · Revista Brasileira de Reumatologia · doi:10.1186/s42358-024-00394-8 · Cited by 2 · see citing works
“Several small-scale clinical studies have linked serum PRL levels with RA disease activity, but results have been conflicting [12, 22].”
BackgroundDhilip, A., & Parameswari, R. P. (2024) · Journal of Pharmacy And Bioallied Sciences · doi:10.4103/jpbs.jpbs_539_23 · Cited by 2 · see citing works
“[21] Our study aligns with Xia H’s research, which found higher levels of Cathepsin D in OA patients’ blood serum compared to healthy individuals.”
do Nascimento, A. F., Thompsom, B., Rocha, P. R. D., Kirychuk, S., Bernardi, M. M., & Felício, L. F. (2019) · NeuroImmunoModulation · doi:10.1159/000505096 · Cited by 2 · see citing works
Navarro‐Zarza, J. E., Muñóz-Valle, J. F., Baños‐Hernández, C. J., Parra‐Rojas, I., Reyes-Castillo, Z., Rangel‐Villalobos, H., & Hernández‐Bello, J. (2019) · Clinical Rheumatology · doi:10.1007/s10067-019-04517-1
Bandeira de Santana, L., de Souza Lima, T. A., Costa, A. R., Sandoval, L. A. M., de Souza, T. Y., da Mota, L. M. H., & Naves, L. A. (2024) · Figshare · doi:10.6084/m9.figshare.26758670
Macotela, Y., de la Escalera, G. M., & Clapp, C. (2026) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2026.01.016
Self-citationPrasad, S., Friedman, M., Speisman, M., Hassan, R. S., Omatsone, C., Patel, A., Shahrara, S., Hanson, H. A., & Sweiss, N. (2026) · Elsevier eBooks · doi:10.1016/b978-0-443-45863-7.00079-2
Tenascin X and Tenascin C Serum Levels in Relation to Age and Cardiometabolic Risk Parameters
Baumgartner-Parzer, S. M., Fuhrberg, K., Wagenlechner, C., Schnait, F., Schmid, N., Bayerle‐Eder, M., Grimm, G., Vila, G., & Schernthaner-Reiter, M. H. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27209180
“Alternatively, the association of TNX with prolactin may reflect the less well-known roles of prolactin in cartilage survival, such as bone turnover and immune modulation [24–29].”
- Authors
- Clapp, C., Adán, N., Ledesma-Colunga, M. G., Solís-Gutiérrez, M., Triebel, J., & Martínez de la Escalera, G.
- Affiliations
- Universidad Nacional Autónoma de México (MX)
- Paracelsus Medizinische Privatuniversität (DE)
- Corresponding author
- Clapp, Carmen
- Venue
- Cellular and Molecular Life Sciences
- Published
- 2016-03-29
- Volume
- 73
- Issue
- 15
- Pages
- 2929-2948
- ISSN
- 1420-682X (ISSN-L)
- 1420-9071
- PMC
- PMC11108309
- OpenAlex
- W2321665593
- Cited by
- 38
- References
- 272
- Citations by year
- 2026: 5 · 2025: 2 · 2024: 6 · 2023: 2 · 2022: 4 · 2021: 4 · 2020: 2 · 2019: 8 · 2018: 1 · 2017: 3 · 2016: 1
- FWCI
- 0.68
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Cellular and Molecular Life Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Dirección General Asuntos del Personal Académico, Universidad Nacional Autónoma de México (MX) (IN201315)
- Topics
- Health Sciences › Medicine › Rheumatology › Rheumatoid Arthritis Research and Therapies
- Health Sciences › Medicine › Complementary and alternative medicine › Natural Compounds in Disease Treatment
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Keywords
- rheumatoid arthritis, prolactin, vasoinhibin, sex differences, reproductive hormones, immune regulation, antiangiogenic activity, joint destruction, risk factors, therapeutic target
- MeSH terms
- Animals, Arthritis, Rheumatoid, Cartilage, Articular, Female, Humans, Immune Tolerance, Immunity, Cellular, Inflammation, Joints, Male, Prolactin, Reproduction, Sex Factors, Stress, Physiological, Stress, Psychological, Angiogenesis Inhibitors
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