Preventive CCL2/CCR2 Axis Blockade Suppresses Osteoclast Activity in a Mouse Model of Rheumatoid Arthritis by Reducing Homing of CCR2hi Osteoclast Progenitors to the Affected Bone
Detailed characterization of medullary and extramedullary reservoirs of osteoclast progenitors (OCPs) is required to understand the pathophysiology of increased periarticular and systemic bone resorption in arthritis. In this study, we focused on identifying the OCP population specifically induced b...
Guardado en:
| Autores principales: | , , , , , , , , , , , |
|---|---|
| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
Frontiers Media S.A.
2021
|
| Materias: | |
| Acceso en línea: | https://doaj.org/article/19b1ea8888ac4196b38ea6e603c61165 |
| Etiquetas: |
Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
|
| id |
oai:doaj.org-article:19b1ea8888ac4196b38ea6e603c61165 |
|---|---|
| record_format |
dspace |
| spelling |
oai:doaj.org-article:19b1ea8888ac4196b38ea6e603c611652021-12-03T04:51:34ZPreventive CCL2/CCR2 Axis Blockade Suppresses Osteoclast Activity in a Mouse Model of Rheumatoid Arthritis by Reducing Homing of CCR2hi Osteoclast Progenitors to the Affected Bone1664-322410.3389/fimmu.2021.767231https://doaj.org/article/19b1ea8888ac4196b38ea6e603c611652021-12-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fimmu.2021.767231/fullhttps://doaj.org/toc/1664-3224Detailed characterization of medullary and extramedullary reservoirs of osteoclast progenitors (OCPs) is required to understand the pathophysiology of increased periarticular and systemic bone resorption in arthritis. In this study, we focused on identifying the OCP population specifically induced by arthritis and the role of circulatory OCPs in inflammatory bone loss. In addition, we determined the relevant chemokine axis responsible for their migration, and targeted the attraction signal to reduce bone resorption in murine collagen-induced arthritis (CIA). OCPs were expanded in periarticular as well as circulatory compartment of arthritic mice, particularly the CCR2hi subset. This subset demonstrated enhanced osteoclastogenic activity in arthritis, whereas its migratory potential was susceptible to CCR2 blockade in vitro. Intravascular compartment of the periarticular area contained increased frequency of OCPs with the ability to home to the arthritic bone, as demonstrated in vivo by intravascular staining and adoptive transfer of splenic LysMcre/Ai9 tdTomato-expressing cells. Simultaneously, CCL2 levels were increased locally and systemically in arthritic mice. Mouse cohorts were treated with the small-molecule inhibitor (SMI) of CCR2 alone or in combination with methotrexate (MTX). Preventive CCR2/CCL2 axis blockade in vivo reduced bone resorption and OCP frequency, whereas combining with MTX treatment also decreased disease clinical score, number of active osteoclasts, and OCP differentiation potential. In conclusion, our study characterized the functional properties of two distinct OCP subsets in CIA, based on their CCR2 expression levels, implying that the CCR2hi circulatory-like subset is specifically induced by arthritis. Signaling through the CCL2/CCR2 axis contributes to OCP homing in the inflamed joints and to their increased osteoclastogenic potential. Therefore, addition of CCL2/CCR2 blockade early in the course of arthritis is a promising approach to reduce bone pathology.Darja FlegarDarja FlegarMaša FilipovićMaša FilipovićAlan ŠućurAlan ŠućurAntonio MarkotićAntonio MarkotićNina LukačNina LukačDino ŠislDino ŠislMarina Ikić MatijaševićZrinka JajićTomislav KelavaTomislav KelavaVedran KatavićVedran KatavićNataša KovačićNataša KovačićDanka GrčevićDanka GrčevićFrontiers Media S.A.articleinflammationmyeloid cellsosteoclastschemokinesmouse arthritishuman arthritisImmunologic diseases. AllergyRC581-607ENFrontiers in Immunology, Vol 12 (2021) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
inflammation myeloid cells osteoclasts chemokines mouse arthritis human arthritis Immunologic diseases. Allergy RC581-607 |
| spellingShingle |
inflammation myeloid cells osteoclasts chemokines mouse arthritis human arthritis Immunologic diseases. Allergy RC581-607 Darja Flegar Darja Flegar Maša Filipović Maša Filipović Alan Šućur Alan Šućur Antonio Markotić Antonio Markotić Nina Lukač Nina Lukač Dino Šisl Dino Šisl Marina Ikić Matijašević Zrinka Jajić Tomislav Kelava Tomislav Kelava Vedran Katavić Vedran Katavić Nataša Kovačić Nataša Kovačić Danka Grčević Danka Grčević Preventive CCL2/CCR2 Axis Blockade Suppresses Osteoclast Activity in a Mouse Model of Rheumatoid Arthritis by Reducing Homing of CCR2hi Osteoclast Progenitors to the Affected Bone |
| description |
Detailed characterization of medullary and extramedullary reservoirs of osteoclast progenitors (OCPs) is required to understand the pathophysiology of increased periarticular and systemic bone resorption in arthritis. In this study, we focused on identifying the OCP population specifically induced by arthritis and the role of circulatory OCPs in inflammatory bone loss. In addition, we determined the relevant chemokine axis responsible for their migration, and targeted the attraction signal to reduce bone resorption in murine collagen-induced arthritis (CIA). OCPs were expanded in periarticular as well as circulatory compartment of arthritic mice, particularly the CCR2hi subset. This subset demonstrated enhanced osteoclastogenic activity in arthritis, whereas its migratory potential was susceptible to CCR2 blockade in vitro. Intravascular compartment of the periarticular area contained increased frequency of OCPs with the ability to home to the arthritic bone, as demonstrated in vivo by intravascular staining and adoptive transfer of splenic LysMcre/Ai9 tdTomato-expressing cells. Simultaneously, CCL2 levels were increased locally and systemically in arthritic mice. Mouse cohorts were treated with the small-molecule inhibitor (SMI) of CCR2 alone or in combination with methotrexate (MTX). Preventive CCR2/CCL2 axis blockade in vivo reduced bone resorption and OCP frequency, whereas combining with MTX treatment also decreased disease clinical score, number of active osteoclasts, and OCP differentiation potential. In conclusion, our study characterized the functional properties of two distinct OCP subsets in CIA, based on their CCR2 expression levels, implying that the CCR2hi circulatory-like subset is specifically induced by arthritis. Signaling through the CCL2/CCR2 axis contributes to OCP homing in the inflamed joints and to their increased osteoclastogenic potential. Therefore, addition of CCL2/CCR2 blockade early in the course of arthritis is a promising approach to reduce bone pathology. |
| format |
article |
| author |
Darja Flegar Darja Flegar Maša Filipović Maša Filipović Alan Šućur Alan Šućur Antonio Markotić Antonio Markotić Nina Lukač Nina Lukač Dino Šisl Dino Šisl Marina Ikić Matijašević Zrinka Jajić Tomislav Kelava Tomislav Kelava Vedran Katavić Vedran Katavić Nataša Kovačić Nataša Kovačić Danka Grčević Danka Grčević |
| author_facet |
Darja Flegar Darja Flegar Maša Filipović Maša Filipović Alan Šućur Alan Šućur Antonio Markotić Antonio Markotić Nina Lukač Nina Lukač Dino Šisl Dino Šisl Marina Ikić Matijašević Zrinka Jajić Tomislav Kelava Tomislav Kelava Vedran Katavić Vedran Katavić Nataša Kovačić Nataša Kovačić Danka Grčević Danka Grčević |
| author_sort |
Darja Flegar |
| title |
Preventive CCL2/CCR2 Axis Blockade Suppresses Osteoclast Activity in a Mouse Model of Rheumatoid Arthritis by Reducing Homing of CCR2hi Osteoclast Progenitors to the Affected Bone |
| title_short |
Preventive CCL2/CCR2 Axis Blockade Suppresses Osteoclast Activity in a Mouse Model of Rheumatoid Arthritis by Reducing Homing of CCR2hi Osteoclast Progenitors to the Affected Bone |
| title_full |
Preventive CCL2/CCR2 Axis Blockade Suppresses Osteoclast Activity in a Mouse Model of Rheumatoid Arthritis by Reducing Homing of CCR2hi Osteoclast Progenitors to the Affected Bone |
| title_fullStr |
Preventive CCL2/CCR2 Axis Blockade Suppresses Osteoclast Activity in a Mouse Model of Rheumatoid Arthritis by Reducing Homing of CCR2hi Osteoclast Progenitors to the Affected Bone |
| title_full_unstemmed |
Preventive CCL2/CCR2 Axis Blockade Suppresses Osteoclast Activity in a Mouse Model of Rheumatoid Arthritis by Reducing Homing of CCR2hi Osteoclast Progenitors to the Affected Bone |
| title_sort |
preventive ccl2/ccr2 axis blockade suppresses osteoclast activity in a mouse model of rheumatoid arthritis by reducing homing of ccr2hi osteoclast progenitors to the affected bone |
| publisher |
Frontiers Media S.A. |
| publishDate |
2021 |
| url |
https://doaj.org/article/19b1ea8888ac4196b38ea6e603c61165 |
| work_keys_str_mv |
AT darjaflegar preventiveccl2ccr2axisblockadesuppressesosteoclastactivityinamousemodelofrheumatoidarthritisbyreducinghomingofccr2hiosteoclastprogenitorstotheaffectedbone AT darjaflegar preventiveccl2ccr2axisblockadesuppressesosteoclastactivityinamousemodelofrheumatoidarthritisbyreducinghomingofccr2hiosteoclastprogenitorstotheaffectedbone AT masafilipovic preventiveccl2ccr2axisblockadesuppressesosteoclastactivityinamousemodelofrheumatoidarthritisbyreducinghomingofccr2hiosteoclastprogenitorstotheaffectedbone AT masafilipovic preventiveccl2ccr2axisblockadesuppressesosteoclastactivityinamousemodelofrheumatoidarthritisbyreducinghomingofccr2hiosteoclastprogenitorstotheaffectedbone AT alansucur preventiveccl2ccr2axisblockadesuppressesosteoclastactivityinamousemodelofrheumatoidarthritisbyreducinghomingofccr2hiosteoclastprogenitorstotheaffectedbone AT alansucur preventiveccl2ccr2axisblockadesuppressesosteoclastactivityinamousemodelofrheumatoidarthritisbyreducinghomingofccr2hiosteoclastprogenitorstotheaffectedbone AT antoniomarkotic preventiveccl2ccr2axisblockadesuppressesosteoclastactivityinamousemodelofrheumatoidarthritisbyreducinghomingofccr2hiosteoclastprogenitorstotheaffectedbone AT antoniomarkotic preventiveccl2ccr2axisblockadesuppressesosteoclastactivityinamousemodelofrheumatoidarthritisbyreducinghomingofccr2hiosteoclastprogenitorstotheaffectedbone AT ninalukac preventiveccl2ccr2axisblockadesuppressesosteoclastactivityinamousemodelofrheumatoidarthritisbyreducinghomingofccr2hiosteoclastprogenitorstotheaffectedbone AT ninalukac preventiveccl2ccr2axisblockadesuppressesosteoclastactivityinamousemodelofrheumatoidarthritisbyreducinghomingofccr2hiosteoclastprogenitorstotheaffectedbone AT dinosisl preventiveccl2ccr2axisblockadesuppressesosteoclastactivityinamousemodelofrheumatoidarthritisbyreducinghomingofccr2hiosteoclastprogenitorstotheaffectedbone AT dinosisl preventiveccl2ccr2axisblockadesuppressesosteoclastactivityinamousemodelofrheumatoidarthritisbyreducinghomingofccr2hiosteoclastprogenitorstotheaffectedbone AT marinaikicmatijasevic preventiveccl2ccr2axisblockadesuppressesosteoclastactivityinamousemodelofrheumatoidarthritisbyreducinghomingofccr2hiosteoclastprogenitorstotheaffectedbone AT zrinkajajic preventiveccl2ccr2axisblockadesuppressesosteoclastactivityinamousemodelofrheumatoidarthritisbyreducinghomingofccr2hiosteoclastprogenitorstotheaffectedbone AT tomislavkelava preventiveccl2ccr2axisblockadesuppressesosteoclastactivityinamousemodelofrheumatoidarthritisbyreducinghomingofccr2hiosteoclastprogenitorstotheaffectedbone AT tomislavkelava preventiveccl2ccr2axisblockadesuppressesosteoclastactivityinamousemodelofrheumatoidarthritisbyreducinghomingofccr2hiosteoclastprogenitorstotheaffectedbone AT vedrankatavic preventiveccl2ccr2axisblockadesuppressesosteoclastactivityinamousemodelofrheumatoidarthritisbyreducinghomingofccr2hiosteoclastprogenitorstotheaffectedbone AT vedrankatavic preventiveccl2ccr2axisblockadesuppressesosteoclastactivityinamousemodelofrheumatoidarthritisbyreducinghomingofccr2hiosteoclastprogenitorstotheaffectedbone AT natasakovacic preventiveccl2ccr2axisblockadesuppressesosteoclastactivityinamousemodelofrheumatoidarthritisbyreducinghomingofccr2hiosteoclastprogenitorstotheaffectedbone AT natasakovacic preventiveccl2ccr2axisblockadesuppressesosteoclastactivityinamousemodelofrheumatoidarthritisbyreducinghomingofccr2hiosteoclastprogenitorstotheaffectedbone AT dankagrcevic preventiveccl2ccr2axisblockadesuppressesosteoclastactivityinamousemodelofrheumatoidarthritisbyreducinghomingofccr2hiosteoclastprogenitorstotheaffectedbone AT dankagrcevic preventiveccl2ccr2axisblockadesuppressesosteoclastactivityinamousemodelofrheumatoidarthritisbyreducinghomingofccr2hiosteoclastprogenitorstotheaffectedbone |
| _version_ |
1718373916393603072 |