Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Arthritis Research & Therapy
Published in: Arthritis Research & Therapy 1/2017

Open Access 01-12-2017 | Research article

Prolactin blocks the expression of receptor activator of nuclear factor κB ligand and reduces osteoclastogenesis and bone loss in murine inflammatory arthritis

Authors: Maria G. Ledesma-Colunga, Norma Adán, Georgina Ortiz, Mariana Solís-Gutiérrez, Fernando López-Barrera, Gonzalo Martínez de la Escalera, Carmen Clapp

Published in: Arthritis Research & Therapy | Issue 1/2017

Login to get access

Abstract

Background

Prolactin (PRL) reduces joint inflammation, pannus formation, and bone destruction in rats with polyarticular adjuvant-induced arthritis (AIA). Here, we investigate the mechanism of PRL protection against bone loss in AIA and in monoarticular AIA (MAIA).

Methods

Joint inflammation, trabecular bone loss, and osteoclastogenesis were evaluated in rats with AIA treated with PRL (via osmotic minipumps) and in mice with MAIA that were null (Prlr-/-) or not (Prlr+/+) for the PRL receptor. To help define target cells, synovial fibroblasts from Prlr+/+ mice were treated or not with proinflammatory cytokines ((Cyt), including TNFα, IL-1β, and interferon (IFN)γ) with or without PRL, and these synovial cells were co-cultured or not with bone marrow osteoclast progenitors from Prlr+/+ or Prlr-/- mice.

Results

In AIA, PRL treatment reduced joint swelling, increased trabecular bone area, lowered osteoclast density, and reduced mRNA levels of osteoclast-associated genes (tartrate-resistant acid phosphatase (Trap)), cathepsin K (Ctsk), matrix metalloproteinase 9 (Mmp9), and receptor activator of nuclear factor κB or RANK (Tnfrsf11a)), of genes encoding cytokines with osteoclastogenic activity (Tnfa, Il1b, Il6, and receptor activator of nuclear factor κB ligand or RANKL (Tnfrsf11)), and of genes encoding for transcription factors and cytokines related to T helper (Th)17 cells (Rora, Rorc, Il17a, Il21, Il22) and to regulatory T cells (Foxp3, Ebi3, Il12a, Tgfb1, Il10). Prlr-/- mice with MAIA showed enhanced joint swelling, reduced trabecular bone area, increased osteoclast density, and elevated expression of Tnfa, Il1b, Il6, Trap, Tnfrsf11a, Tnfrsf11, Il17a, Il21, Il22, 1 l23, Foxp3, and Il10. The expression of the long PRL receptor form increased in arthritic joints, and in synovial membranes and cultured synovial fibroblasts treated with Cyt. PRL induced the phosphorylation/activation of signal transducer and activator of transcription-3 (STAT3) and inhibited the Cyt-induced expression of Il1b, Il6, and Tnfrsf11 in synovial fibroblast cultures. The STAT3 inhibitor S31-201 blocked inhibition of Tnfrsf11 by PRL. Finally, PRL acted on both synovial fibroblasts and osteoclast precursor cells to downregulate Cyt-induced osteoclast differentiation.

Conclusion

PRL protects against osteoclastogenesis and bone loss in inflammatory arthritis by inhibiting cytokine-induced expression of RANKL in joints and synovial fibroblasts via its canonical STAT3 signaling pathway.
Appendix
Available only for authorised users
Literature
1.
Cohen SB, Dore RK, Lane NE, Ory PA, Peterfy CG, Sharp JT, van der Heijde D, Zhou L, Tsuji W, Newmark R, et al. Denosumab treatment effects on structural damage, bone mineral density, and bone turnover in rheumatoid arthritis: a twelve-month, multicenter, randomized, double-blind, placebo-controlled, phase II clinical trial. Arthritis Rheum. 2008;58(5):1299–309.CrossRefPubMed
2.
3.
4.
Kong YY, Feige U, Sarosi I, Bolon B, Tafuri A, Morony S, Capparelli C, Li J, Elliott R, McCabe S, et al. Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand. Nature. 1999;402(6759):304–9.CrossRefPubMed
5.
Gravallese EM, Manning C, Tsay A, Naito A, Pan C, Amento E, Goldring SR. Synovial tissue in rheumatoid arthritis is a source of osteoclast differentiation factor. Arthritis Rheum. 2000;43(2):250–8.CrossRefPubMed
6.
Tunyogi-Csapo M, Kis-Toth K, Radacs M, Farkas B, Jacobs JJ, Finnegan A, Mikecz K, Glant TT. Cytokine-controlled RANKL and osteoprotegerin expression by human and mouse synovial fibroblasts: fibroblast-mediated pathologic bone resorption. Arthritis Rheum. 2008;58(8):2397–408.CrossRefPubMed
7.
Hofbauer LC, Heufelder AE. Role of receptor activator of nuclear factor-kappaB ligand and osteoprotegerin in bone cell biology. J Mol Med (Berl). 2001;79(5-6):243–53.CrossRef
8.
9.
Brennan P, Ollier B, Worthington J, Hajeer A, Silman A. Are both genetic and reproductive associations with rheumatoid arthritis linked to prolactin? Lancet. 1996;348(9020):106–9.CrossRefPubMed
10.
Neidhart M, Gay RE, Gay S. Prolactin and prolactin-like polypeptides in rheumatoid arthritis. Biomed Pharmacother. 1999;53(5-6):218–22.CrossRefPubMed
11.
Costanza M, Binart N, Steinman L, Pedotti R. Prolactin: a versatile regulator of inflammation and autoimmune pathology. Autoimmun Rev. 2015;14(3):223–30.CrossRefPubMed
12.
Matera L, Cesano A, Bellone G, Oberholtzer E. Modulatory effect of prolactin on the resting and mitogen-induced activity of T, B, and NK lymphocytes. Brain Behav Immun. 1992;6(4):409–17.CrossRefPubMed
13.
Dugan AL, Thellin O, Buckley DJ, Buckley AR, Ogle CK, Horseman ND. Effects of prolactin deficiency on myelopoiesis and splenic T lymphocyte proliferation in thermally injured mice. Endocrinology. 2002;143(10):4147–51.CrossRefPubMed
14.
Oberbeck R, Schmitz D, Wilsenack K, Schuler M, Biskup C, Schedlowski M, Nast-Kolb D, Exton MS. Prolactin modulates survival and cellular immune functions in septic mice. J Surg Res. 2003;113(2):248–56.CrossRefPubMed
15.
de Man YA, Dolhain RJ, van de Geijn FE, Willemsen SP, Hazes JM. Disease activity of rheumatoid arthritis during pregnancy: results from a nationwide prospective study. Arthritis Rheum. 2008;59(9):1241–8.CrossRefPubMed
16.
Pikwer M, Bergstrom U, Nilsson JA, Jacobsson L, Berglund G, Turesson C. Breast feeding, but not use of oral contraceptives, is associated with a reduced risk of rheumatoid arthritis. Ann Rheum Dis. 2009;68(4):526–30.CrossRefPubMed
17.
Grimaldi MG. Long-term low dose haloperidol treatment in rheumatoid patients: effects on serum sulphydryl levels, technetium index, ESR, and clinical response. Br J Clin Pharmacol. 1981;12(4):579–81.CrossRefPubMedPubMedCentral
18.
Adan N, Guzman-Morales J, Ledesma-Colunga MG, Perales-Canales SI, Quintanar-Stephano A, Lopez-Barrera F, Mendez I, Moreno-Carranza B, Triebel J, Binart N, et al. Prolactin promotes cartilage survival and attenuates inflammation in inflammatory arthritis. J Clin Invest. 2013;123(9):3902–13.CrossRefPubMedPubMedCentral
19.
Clement-Lacroix P, Ormandy C, Lepescheux L, Ammann P, Damotte D, Goffin V, Bouchard B, Amling M, Gaillard-Kelly M, Binart N, et al. Osteoblasts are a new target for prolactin: analysis of bone formation in prolactin receptor knockout mice. Endocrinology. 1999;140(1):96–105.CrossRefPubMed
20.
Seriwatanachai D, Charoenphandhu N, Suthiphongchai T, Krishnamra N. Prolactin decreases the expression ratio of receptor activator of nuclear factor kappaB ligand/osteoprotegerin in human fetal osteoblast cells. Cell Biol Int. 2008;32(9):1126–35.CrossRefPubMed
21.
Kondegowda NG, Fenutria R, Pollack IR, Orthofer M, Garcia-Ocana A, Penninger JM, Vasavada RC. Osteoprotegerin and denosumab stimulate human beta cell proliferation through inhibition of the receptor activator of NF-kappaB ligand pathway. Cell Metab. 2015;22(1):77–85.CrossRefPubMedPubMedCentral
22.
Srivastava S, Matsuda M, Hou Z, Bailey JP, Kitazawa R, Herbst MP, Horseman ND. Receptor activator of NF-kappaB ligand induction via Jak2 and Stat5a in mammary epithelial cells. J Biol Chem. 2003;278(46):46171–8.CrossRefPubMed
23.
Gauldie SD, McQueen DS, Clarke CJ, Chessell IP. A robust model of adjuvant-induced chronic unilateral arthritis in two mouse strains. J Neurosci Methods. 2004;139(2):281–91.CrossRefPubMed
24.
Armaka M, Gkretsi V, Kontoyiannis D, Kollias G. A standardized protocol for the isolation and culture of normal and arthritogenic murine synovial fibroblasts. Protocol Exch. 2009. doi:10.​1038/​nprot.​2009.​1102.
25.
Zermeno C, Guzman-Morales J, Macotela Y, Nava G, Lopez-Barrera F, Kouri JB, Lavalle C, de la Escalera GM, Clapp C. Prolactin inhibits the apoptosis of chondrocytes induced by serum starvation. J Endocrinol. 2006;189(2):R1–8.CrossRefPubMed
26.
Rauner M, Foger-Samwald U, Kurz MF, Brunner-Kubath C, Schamall D, Kapfenberger A, Varga P, Kudlacek S, Wutzl A, Hoger H, et al. Cathepsin S controls adipocytic and osteoblastic differentiation, bone turnover, and bone microarchitecture. Bone. 2014;64:281–7.CrossRefPubMed
27.
28.
Shakibaei M, De Souza P, Merker HJ. Integrin expression and collagen type II implicated in maintenance of chondrocyte shape in monolayer culture: an immunomorphological study. Cell Biol Int. 1997;21(2):115–25.CrossRefPubMed
29.
Rauner M, Winzer M, Stupphann D, Krenbek D, Pietschmann P. RANKL and OPG gene expression bone marrow stromal cells and calvarial osteoblasts in mouse and rat. Osteologie. 2007;16:19–28.CrossRef
30.
Alunno A, Manetti M, Caterbi S, Ibba-Manneschi L, Bistoni O, Bartoloni E, Valentini V, Terenzi R, Gerli R. Altered immunoregulation in rheumatoid arthritis: the role of regulatory T cells and proinflammatory Th17 cells and therapeutic implications. Mediat Inflamm. 2015;2015:751793.
31.
32.
Sato K, Suematsu A, Okamoto K, Yamaguchi A, Morishita Y, Kadono Y, Tanaka S, Kodama T, Akira S, Iwakura Y, et al. Th17 functions as an osteoclastogenic helper T cell subset that links T cell activation and bone destruction. J Exp Med. 2006;203(12):2673–82.CrossRefPubMedPubMedCentral
33.
34.
Siddiquee K, Zhang S, Guida WC, Blaskovich MA, Greedy B, Lawrence HR, Yip ML, Jove R, McLaughlin MM, Lawrence NJ, et al. Selective chemical probe inhibitor of Stat3, identified through structure-based virtual screening, induces antitumor activity. Proc Natl Acad Sci USA. 2007;104(18):7391–6.CrossRefPubMedPubMedCentral
35.
Ghule S, Dhotre A, Gupta M, Dharme P, Vaidya S. Serum prolactin levels in women with rheumatoid arthritis. Biomed Res. 2009;20(2):2009–5. 2009-2008.
36.
Hamed EA, Hamed EA, Hamed SA, Gamal H-A. Synovial fluid and serum levels of sE-selectin, IL-1β and TNF-α in rheumatoid arthritis. JKAU Med Sci. 2007;14(1):19–34.CrossRef
37.
38.
Sakaguchi S, Miyara M, Costantino CM, Hafler DA. FOXP3+ regulatory T cells in the human immune system. Nat Rev Immunol. 2010;10(7):490–500.CrossRefPubMed
39.
Deknuydt F, Bioley G, Valmori D, Ayyoub M. IL-1beta and IL-2 convert human Treg into T(H)17 cells. Clin Immunol. 2009;131(2):298–307.CrossRefPubMed
40.
Diller ML, Kudchadkar RR, Delman KA, Lawson DH, Ford ML. Balancing inflammation: the link between Th17 and regulatory T cells. Mediat Inflamm. 2016;2016:6309219.CrossRef
41.
Zhou L, Lopes JE, Chong MM, Ivanov II, Min R, Victora GD, Shen Y, Du J, Rubtsov YP, Rudensky AY, et al. TGF-beta-induced Foxp3 inhibits T(H)17 cell differentiation by antagonizing RORgammat function. Nature. 2008;453(7192):236–40.CrossRefPubMedPubMedCentral
42.
Voo KS, Wang YH, Santori FR, Boggiano C, Wang YH, Arima K, Bover L, Hanabuchi S, Khalili J, Marinova E, et al. Identification of IL-17-producing FOXP3+ regulatory T cells in humans. Proc Natl Acad Sci USA. 2009;106(12):4793–8.CrossRefPubMedPubMedCentral
43.
Komatsu N, Okamoto K, Sawa S, Nakashima T, Oh-hora M, Kodama T, Tanaka S, Bluestone JA, Takayanagi H. Pathogenic conversion of Foxp3+ T cells into TH17 cells in autoimmune arthritis. Nat Med. 2014;20(1):62–8.CrossRefPubMed
44.
Panayi GS, Lanchbury JS, Kingsley GH. The importance of the T cell in initiating and maintaining the chronic synovitis of rheumatoid arthritis. Arthritis Rheum. 1992;35(7):729–35.CrossRefPubMed
45.
Bole-Feysot C, Goffin V, Edery M, Binart N, Kelly PA. Prolactin (PRL) and its receptor: actions, signal transduction pathways and phenotypes observed in PRL receptor knockout mice. Endocr Rev. 1998;19(3):225–68.CrossRefPubMed
46.
Ben-Jonathan N, LaPensee CR, LaPensee EW. What can we learn from rodents about prolactin in humans? Endocr Rev. 2008;29(1):1–41.CrossRefPubMed
47.
Nagafuchi H, Suzuki N, Kaneko A, Asai T, Sakane T. Prolactin locally produced by synovium infiltrating T lymphocytes induces excessive synovial cell functions in patients with rheumatoid arthritis. J Rheumatol. 1999;26(9):1890–900.PubMed
48.
Corbacho AM, Macotela Y, Nava G, Eiserich JP, Cross CE, Martinez de la Escalera G, Clapp C. Cytokine induction of prolactin receptors mediates prolactin inhibition of nitric oxide synthesis in pulmonary fibroblasts. FEBS Lett. 2003;544(1-3):171–5.CrossRefPubMed
49.
Moreno-Carranza B, Goya-Arce M, Vega C, Adan N, Triebel J, Lopez-Barrera F, Quintanar-Stephano A, Binart N, Martinez de la Escalera G, Clapp C. Prolactin promotes normal liver growth, survival, and regeneration in rodents: effects on hepatic IL-6, suppressor of cytokine signaling-3, and angiogenesis. Am J Physiol Regul Integr Comp Physiol. 2013;305(7):R720–6.CrossRefPubMed
50.
Fadda S, Hamdy A, Abulkhair E, Mahmoud Elsify H, Mostafa A. Serum levels of osteoprotegerin and RANKL in patients with rheumatoid arthritis and their relation to bone mineral density and disease activity. Egyptian Rheumatologist. 2015;37:1–6.CrossRef
51.
Martinez-Calatrava MJ, Prieto-Potin I, Roman-Blas JA, Tardio L, Largo R, Herrero-Beaumont G. RANKL synthesized by articular chondrocytes contributes to juxta-articular bone loss in chronic arthritis. Arthritis Res Ther. 2012;14(3):R149.CrossRefPubMedPubMedCentral
52.
DaSilva L, Rui H, Erwin RA, Howard OM, Kirken RA, Malabarba MG, Hackett RH, Larner AC, Farrar WL. Prolactin recruits STAT1, STAT3 and STAT5 independent of conserved receptor tyrosines TYR402, TYR479, TYR515 and TYR580. Mol Cell Endocrinol. 1996;117(2):131–40.CrossRefPubMed
53.
Holland SM, DeLeo FR, Elloumi HZ, Hsu AP, Uzel G, Brodsky N, Freeman AF, Demidowich A, Davis J, Turner ML, et al. STAT3 mutations in the hyper-IgE syndrome. N Engl J Med. 2007;357(16):1608–19.CrossRefPubMed
54.
Minegishi Y, Saito M, Tsuchiya S, Tsuge I, Takada H, Hara T, Kawamura N, Ariga T, Pasic S, Stojkovic O, et al. Dominant-negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome. Nature. 2007;448(7157):1058–62.CrossRefPubMed
55.
Hashizume M, Hayakawa N, Mihara M. IL-6 trans-signalling directly induces RANKL on fibroblast-like synovial cells and is involved in RANKL induction by TNF-alpha and IL-17. Rheumatology. 2008;47(11):1635–40.CrossRefPubMed
56.
O’Brien CA, Gubrij I, Lin SC, Saylors RL, Manolagas SC. STAT3 activation in stromal/osteoblastic cells is required for induction of the receptor activator of NF-kappaB ligand and stimulation of osteoclastogenesis by gp130-utilizing cytokines or interleukin-1 but not 1,25-dihydroxyvitamin D3 or parathyroid hormone. J Biol Chem. 1999;274(27):19301–8.CrossRefPubMed
57.
Shin HI, Divieti P, Sims NA, Kobayashi T, Miao D, Karaplis AC, Baron R, Bringhurst R, Kronenberg HM. Gp130-mediated signaling is necessary for normal osteoblastic function in vivo and in vitro. Endocrinology. 2004;145(3):1376–85.CrossRefPubMed
58.
Clapp C, Adan N, Ledesma-Colunga MG, Solís-Gutiérrez M, Triebel J, Martinez de la Escalera G. The role of the prolactin/vasoinhibin axis in rheumatoid arthritis: an integrative overview. Cell Mol Life Sci. 2016;73(15):2929–48.
59.
Lotinun S, Limlomwongse LC, Sirikulchayanonta V, Krishnamra N. Bone calcium turnover, formation, and resorption in bromocriptine- and prolactin-treated lactating rats. Endocrine. 2003;20(1-2):163–70.CrossRefPubMed
60.
Seriwatanachai D, Thongchote K, Charoenphandhu N, Pandaranandaka J, Tudpor K, Teerapornpuntakit J, Suthiphongchai T, Krishnamra N. Prolactin directly enhances bone turnover by raising osteoblast-expressed receptor activator of nuclear factor kappaB ligand/osteoprotegerin ratio. Bone. 2008;42(3):535–46.CrossRefPubMed
61.
Macotela Y, Aguilar MB, Guzman-Morales J, Rivera JC, Zermeno C, Lopez-Barrera F, Nava G, Lavalle C, Martinez de la Escalera G, Clapp C. Matrix metalloproteases from chondrocytes generate an antiangiogenic 16 kDa prolactin. J Cell Sci. 2006;119(Pt 9):1790–800.CrossRefPubMed
62.
Corbacho AM, Macotela Y, Nava G, Torner L, Duenas Z, Noris G, Morales MA, Martinez De La Escalera G, Clapp C. Human umbilical vein endothelial cells express multiple prolactin isoforms. J Endocrinol. 2000;166(1):53–62.CrossRefPubMed
63.
Mazziotti G, Porcelli T, Mormando M, De Menis E, Bianchi A, Mejia C, Mancini T, De Marinis L, Giustina A. Vertebral fractures in males with prolactinoma. Endocrine. 2011;39(3):288–93.CrossRefPubMed
64.
Jacobi AM, Rohde W, Volk HD, Dorner T, Burmester GR, Hiepe F. Prolactin enhances the in vitro production of IgG in peripheral blood mononuclear cells from patients with systemic lupus erythematosus but not from healthy controls. Ann Rheum Dis. 2001;60(3):242–7.CrossRefPubMedPubMedCentral
Metadata
Title
Prolactin blocks the expression of receptor activator of nuclear factor κB ligand and reduces osteoclastogenesis and bone loss in murine inflammatory arthritis
Authors
Maria G. Ledesma-Colunga
Norma Adán
Georgina Ortiz
Mariana Solís-Gutiérrez
Fernando López-Barrera
Gonzalo Martínez de la Escalera
Carmen Clapp
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Arthritis Research & Therapy / Issue 1/2017
Electronic ISSN: 1478-6362
DOI
https://doi.org/10.1186/s13075-017-1290-4

Other articles of this Issue 1/2017

Arthritis Research & Therapy 1/2017 Go to the issue

Research article

Pathogenic roles of CXCL10 signaling through CXCR3 and TLR4 in macrophages and T cells: relevance for arthritis

Research article

Assessing risk of liver enzyme elevation in patients with immune-mediated diseases and different hepatitis B virus serostatus receiving anti-TNF agents: a nested case-control study

Research article

RANK/RANKL/OPG system in the intervertebral disc

Research article

Osteoarthritis-associated basic calcium phosphate crystals activate membrane proximal kinases in human innate immune cells

Research article

Interleukin-10-producing LAG3+ regulatory T cells are associated with disease activity and abatacept treatment in rheumatoid arthritis

Research article

Advanced Knee Structure Analysis (AKSA): a comparison of bone mineral density and trabecular texture measurements using computed tomography and high-resolution peripheral quantitative computed tomography of human knee cadavers

ACC 2024 Congress Coverage

Heart Failure Video

Year in Review: Heart failure and cardiomyopathies

Watch now

Watch this official video from ACC.24. Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits