Anti-inflammatory and antiosteoclastogenesis properties of endogenous melanocortin receptor type 3 in experimental arthritis

Hetal B Patel; Michele Bombardieri; André L F Sampaio; Fulvio D'Acquisto; Mohini Gray; Paolo Grieco; Stephen J Getting; Costantino Pitzalis; Mauro Perretti

doi:10.1096/fj.10-167759

Anti-inflammatory and antiosteoclastogenesis properties of endogenous melanocortin receptor type 3 in experimental arthritis

Hetal B Patel, Michele Bombardieri, André L F Sampaio, Fulvio D'Acquisto, Mohini Gray, Paolo Grieco, Stephen J Getting, Costantino Pitzalis, Mauro Perretti

Research output: Contribution to journal › Article › peer-review

Abstract

The development of biological therapies has improved management of rheumatoid arthritis. However, costs and unresponsiveness to therapy in a sizeable proportion of patients limit their use, making it imperative to identify new targets for drug development programs. Here we investigated the melanocortin-receptor type 3 (MC(3)) pathway. Gene-deficient mice were subjected to a model of serum-transfer-induced arthritis and joints analyzed for gene expression (cytokines, MCs) and morphology. Pharmacological analyses were also conducted in this model. Osteoclastogenesis was studied from bone marrow cells. Mc(3)(-/-) mice displayed an exacerbated inflammatory arthritis, associated with prominent bone erosion and higher articular expression of Rankl. Osteoclastogenesis studied from Mc(3)(-/-) bone marrow cells revealed a higher degree of responsiveness to Rankl, linked to prolonged NF-κB activation compared to wild types. Up-regulation of a discrete set of inflammatory genes, including Il-1β, Il-6, and Nos2, was measured in Mc(3)(-/-) mice, and a marked up-regulation of joint Mc(3) accompanied arthritis resolution in wild-type mice. Administration of an MC(3) agonist, D[Trp8]-γ-MSH, attenuated disease incidence and severity in wild-type but not Mc(3)(-/-) mice. Overall, these findings identify MC(3)-mediated signaling as a beneficial pathway in experimental arthritis; hence this receptor is a novel target for the development of therapeutics for arthritis.

Original language	English
Pages (from-to)	4835-43
Number of pages	9
Journal	FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume	24
Issue number	12
DOIs	https://doi.org/10.1096/fj.10-167759
Publication status	Published - Dec 2010

Keywords

Animals
Arthritis, Experimental
Cell Differentiation
Electrophoretic Mobility Shift Assay
Flow Cytometry
Interleukin-1beta
Interleukin-6
Mice
Mice, Inbred C57BL
Mice, Knockout
Nitric Oxide Synthase Type II
Oligonucleotide Array Sequence Analysis
Osteoclasts
Osteogenesis
Polymerase Chain Reaction
Receptor, Melanocortin, Type 3
Journal Article
Research Support, Non-U.S. Gov't

Access to Document

10.1096/fj.10-167759

Cite this

Patel, H. B., Bombardieri, M., Sampaio, A. L. F., D'Acquisto, F., Gray, M., Grieco, P., Getting, S. J., Pitzalis, C., & Perretti, M. (2010). Anti-inflammatory and antiosteoclastogenesis properties of endogenous melanocortin receptor type 3 in experimental arthritis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 24(12), 4835-43. https://doi.org/10.1096/fj.10-167759

@article{651470f07d084910b4154b3d49f027b5,

title = "Anti-inflammatory and antiosteoclastogenesis properties of endogenous melanocortin receptor type 3 in experimental arthritis",

abstract = "The development of biological therapies has improved management of rheumatoid arthritis. However, costs and unresponsiveness to therapy in a sizeable proportion of patients limit their use, making it imperative to identify new targets for drug development programs. Here we investigated the melanocortin-receptor type 3 (MC(3)) pathway. Gene-deficient mice were subjected to a model of serum-transfer-induced arthritis and joints analyzed for gene expression (cytokines, MCs) and morphology. Pharmacological analyses were also conducted in this model. Osteoclastogenesis was studied from bone marrow cells. Mc(3)(-/-) mice displayed an exacerbated inflammatory arthritis, associated with prominent bone erosion and higher articular expression of Rankl. Osteoclastogenesis studied from Mc(3)(-/-) bone marrow cells revealed a higher degree of responsiveness to Rankl, linked to prolonged NF-κB activation compared to wild types. Up-regulation of a discrete set of inflammatory genes, including Il-1β, Il-6, and Nos2, was measured in Mc(3)(-/-) mice, and a marked up-regulation of joint Mc(3) accompanied arthritis resolution in wild-type mice. Administration of an MC(3) agonist, D[Trp8]-γ-MSH, attenuated disease incidence and severity in wild-type but not Mc(3)(-/-) mice. Overall, these findings identify MC(3)-mediated signaling as a beneficial pathway in experimental arthritis; hence this receptor is a novel target for the development of therapeutics for arthritis.",

keywords = "Animals, Arthritis, Experimental, Cell Differentiation, Electrophoretic Mobility Shift Assay, Flow Cytometry, Interleukin-1beta, Interleukin-6, Mice, Mice, Inbred C57BL, Mice, Knockout, Nitric Oxide Synthase Type II, Oligonucleotide Array Sequence Analysis, Osteoclasts, Osteogenesis, Polymerase Chain Reaction, Receptor, Melanocortin, Type 3, Journal Article, Research Support, Non-U.S. Gov't",

author = "Patel, {Hetal B} and Michele Bombardieri and Sampaio, {Andr{\'e} L F} and Fulvio D'Acquisto and Mohini Gray and Paolo Grieco and Getting, {Stephen J} and Costantino Pitzalis and Mauro Perretti",

year = "2010",

month = dec,

doi = "10.1096/fj.10-167759",

language = "English",

volume = "24",

pages = "4835--43",

journal = "FASEB journal : official publication of the Federation of American Societies for Experimental Biology",

issn = "0892-6638",

publisher = "FASEB",

number = "12",

}

Patel, HB, Bombardieri, M, Sampaio, ALF, D'Acquisto, F, Gray, M, Grieco, P, Getting, SJ, Pitzalis, C & Perretti, M 2010, 'Anti-inflammatory and antiosteoclastogenesis properties of endogenous melanocortin receptor type 3 in experimental arthritis', FASEB journal : official publication of the Federation of American Societies for Experimental Biology, vol. 24, no. 12, pp. 4835-43. https://doi.org/10.1096/fj.10-167759

Anti-inflammatory and antiosteoclastogenesis properties of endogenous melanocortin receptor type 3 in experimental arthritis. / Patel, Hetal B; Bombardieri, Michele; Sampaio, André L F et al.
In: FASEB journal : official publication of the Federation of American Societies for Experimental Biology, Vol. 24, No. 12, 12.2010, p. 4835-43.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Anti-inflammatory and antiosteoclastogenesis properties of endogenous melanocortin receptor type 3 in experimental arthritis

AU - Patel, Hetal B

AU - Bombardieri, Michele

AU - Sampaio, André L F

AU - D'Acquisto, Fulvio

AU - Gray, Mohini

AU - Grieco, Paolo

AU - Getting, Stephen J

AU - Pitzalis, Costantino

AU - Perretti, Mauro

PY - 2010/12

Y1 - 2010/12

N2 - The development of biological therapies has improved management of rheumatoid arthritis. However, costs and unresponsiveness to therapy in a sizeable proportion of patients limit their use, making it imperative to identify new targets for drug development programs. Here we investigated the melanocortin-receptor type 3 (MC(3)) pathway. Gene-deficient mice were subjected to a model of serum-transfer-induced arthritis and joints analyzed for gene expression (cytokines, MCs) and morphology. Pharmacological analyses were also conducted in this model. Osteoclastogenesis was studied from bone marrow cells. Mc(3)(-/-) mice displayed an exacerbated inflammatory arthritis, associated with prominent bone erosion and higher articular expression of Rankl. Osteoclastogenesis studied from Mc(3)(-/-) bone marrow cells revealed a higher degree of responsiveness to Rankl, linked to prolonged NF-κB activation compared to wild types. Up-regulation of a discrete set of inflammatory genes, including Il-1β, Il-6, and Nos2, was measured in Mc(3)(-/-) mice, and a marked up-regulation of joint Mc(3) accompanied arthritis resolution in wild-type mice. Administration of an MC(3) agonist, D[Trp8]-γ-MSH, attenuated disease incidence and severity in wild-type but not Mc(3)(-/-) mice. Overall, these findings identify MC(3)-mediated signaling as a beneficial pathway in experimental arthritis; hence this receptor is a novel target for the development of therapeutics for arthritis.

AB - The development of biological therapies has improved management of rheumatoid arthritis. However, costs and unresponsiveness to therapy in a sizeable proportion of patients limit their use, making it imperative to identify new targets for drug development programs. Here we investigated the melanocortin-receptor type 3 (MC(3)) pathway. Gene-deficient mice were subjected to a model of serum-transfer-induced arthritis and joints analyzed for gene expression (cytokines, MCs) and morphology. Pharmacological analyses were also conducted in this model. Osteoclastogenesis was studied from bone marrow cells. Mc(3)(-/-) mice displayed an exacerbated inflammatory arthritis, associated with prominent bone erosion and higher articular expression of Rankl. Osteoclastogenesis studied from Mc(3)(-/-) bone marrow cells revealed a higher degree of responsiveness to Rankl, linked to prolonged NF-κB activation compared to wild types. Up-regulation of a discrete set of inflammatory genes, including Il-1β, Il-6, and Nos2, was measured in Mc(3)(-/-) mice, and a marked up-regulation of joint Mc(3) accompanied arthritis resolution in wild-type mice. Administration of an MC(3) agonist, D[Trp8]-γ-MSH, attenuated disease incidence and severity in wild-type but not Mc(3)(-/-) mice. Overall, these findings identify MC(3)-mediated signaling as a beneficial pathway in experimental arthritis; hence this receptor is a novel target for the development of therapeutics for arthritis.

KW - Animals

KW - Arthritis, Experimental

KW - Cell Differentiation

KW - Electrophoretic Mobility Shift Assay

KW - Flow Cytometry

KW - Interleukin-1beta

KW - Interleukin-6

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Knockout

KW - Nitric Oxide Synthase Type II

KW - Oligonucleotide Array Sequence Analysis

KW - Osteoclasts

KW - Osteogenesis

KW - Polymerase Chain Reaction

KW - Receptor, Melanocortin, Type 3

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1096/fj.10-167759

DO - 10.1096/fj.10-167759

M3 - Article

C2 - 20702773

SN - 0892-6638

VL - 24

SP - 4835

EP - 4843

JO - FASEB journal : official publication of the Federation of American Societies for Experimental Biology

JF - FASEB journal : official publication of the Federation of American Societies for Experimental Biology

IS - 12

ER -