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Intercellular communication between macrophages, myoblasts and fibroblasts in the context of rheumatoid arthritis-associated skeletal muscle wasting
Thesis (PhD)--Stellenbosch University, 2022.
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| Format: | Thesis |
| Language: | en_ZA |
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Stellenbosch : Stellenbosch University
2022
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| _version_ | 1867614101417492480 |
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| access_status_str | Open Access |
| author | Ollewagen, Tracey |
| author2 | Smith, Carine |
| author_browse | Ollewagen, Tracey Smith, Carine |
| author_facet | Smith, Carine Ollewagen, Tracey |
| author_sort | Ollewagen, Tracey |
| collection | Thesis |
| dc_rights_str_mv | Stellenbosch University |
| description | Thesis (PhD)--Stellenbosch University, 2022. |
| format | Thesis |
| id | oai:scholar.sun.ac.za:10019.1/124495 |
| institution | Stellenbosch University (South Africa) |
| language | en_ZA |
| last_indexed | 2026-06-10T12:46:41.344Z |
| license_str | Other — see source repository |
| provenance_str_mv | Harvested via OAI-PMH from SUNScholar — Stellenbosch University Repository |
| publishDate | 2022 |
| publishDateRange | 2022 |
| publishDateSort | 2022 |
| publisher | Stellenbosch : Stellenbosch University |
| publisherStr | Stellenbosch : Stellenbosch University |
| record_format | dspace |
| source_str | SUNScholar — Stellenbosch University Repository |
| spelling | oai:scholar.sun.ac.za:10019.1/124495 Intercellular communication between macrophages, myoblasts and fibroblasts in the context of rheumatoid arthritis-associated skeletal muscle wasting Ollewagen, Tracey Smith, Carine Myburgh, Kathryn H Stellenbosch University. Faculty of Science. Dept. of Physiological Sciences. Rheumatoid arthritis -- Diseases -- Treatment Skeletal muscle wasting Bone morphogenetic proteins-7 Cell interaction Inflammation -- Mediators UCTD Thesis (PhD)--Stellenbosch University, 2022. ENGLISH ABSTRACT: Approximately 1% of the global population is afflicted with rheumatoid arthritis (RA), of which over a third experience rheumatoid cachexia, a RA-specific form of skeletal muscle wasting. Current patient research is focused on structural and functional outcomes of rheumatoid cachexia, with limited research focusing on the mechanisms causing this disease and their potential modulation. One of the most vital components to address are the complex cellular interactions occurring within the muscle, and how these interactions are affected by the chronic inflammatory autoimmune disease that is RA. To elucidate these mechanisms further, multiple models were used in this dissertation. Firstly, a rodent collagen-induced arthritis (CIA) model was used to represent RA. The aims of the first two rodent studies were as follows: (1) to determine the extent of ultrastructural change occurring in multiple muscle types as a result of the inflammatory condition; and (2) to assess different cell types, cytokines and growth factors and their relationships to muscle fibre size and number. Secondly, a novel triple cell (myoblast, fibroblast, macrophage) co-culture model was developed from primary human cell isolates, to mimic rheumatoid cachexia with the use of serum derived from RA and healthy participants. This study aimed to elucidate cellular responses to patient serum, as well as determine the efficacy of bone morphogenetic protein-7 (BMP-7) as a treatment strategy. The CIA model was a physiologically relevant and accurate model with which to investigate rheumatoid cachexia; several muscle types exhibited reductions in mass and cross-sectional area, in line with clinical reports. Furthermore, increases in fibrosis was reported in all muscle groups, independent of fibre type category. Furthermore, this model allowed for better understanding into the mechanisms of rheumatoid cachexia, with the persistent inflammation in the skeletal muscle contributing to heightened activation – but dysregulation – of muscle regenerative responses, resulting in inability to maintain the fibre size. Using this cellular profile of arthritis, the triple co-culture model was designed to allow for a human simulation of cellular signalling of co-cultured human primary cells in response to exposure to serum collected from non-RA controls and RA patients. iii Firstly, confirming accurate representation of disease signalling in control and patient serum, RA patient plasma indeed indicated dysregulated IL-6/IL-10 concentrations and a relatively pro-inflammatory state when compared to controls. Assessment of myoblast-, fibroblast- and macrophage-related parameters in the triple co-culture model demonstrated both dysregulated muscle and extracellular matrix formation in response to the treatment non-responding serum. These disease-associated outcomes were corrected/limited in the presence of BMP-7, suggesting a potential beneficial role for BMP-7 in management of rheumatoid cachexia. In conclusion, this dissertation significantly contributes to our understanding of rheumatoid cachexia by consistently illustrating, across in vitro and in vivo, rodent and human models, the dysregulation occurring in skeletal muscle as a result of the persistent inflammation that may contribute to the structural and functional outcomes reported in rheumatoid cachexia, as well as how this dysregulation may potentially be addressed via modulation by BMP-7. AFRIKAANSE OPSOMMING: Ongeveer 1% van die wêreldbevolking word geaffekteer deur rumatoïede artritis (RA). Meer as ‘n derde van hierdie groep lei ook aan rumatoïede kakeksie, ‘n RA- spesifieke vorm van skeletspierverlies. Huidige navorsing is gefokus op strukturele en funksionele uitkomste van rumatoïede kakeksie, met beperkte navorsing wat fokus op die meganismes wat hierdie toestand veroorsaak, of moontlike teenvoeters daarvan. Een van die belangrikste aspekte wat aangespreek behoort te word, is die komplekse sellulêre kommunikasie binne-in die spier en hoe hierdie interaksies beïnvloed word deur die kroniese inflammatoriese outo-immuunsiekte wat RA is. Om hierdie meganismes verder toe te lig, is verskeie modelle in hierdie tesis gebruik. Eerstens is ‘n knaagdier model van kollageen-geïndusserde artritis (CIA) gebruik om RA te verteenwoordig. Die mikpunte van die eerste twee knaagdierstudies was as volg: (1) om die omvang van artritis-geassosieerde ultrastrukturele skade in verskillende spiere te bepaal; en (2) om die verskillende seltipes, sitokiene en groeifaktore, asook hul verhoudings tot spierveselgrootte en –getal te kwantifiseer. Tweedens is ‘n nuwe drievoudige (mioblast, fibroblast en makrofaag) selkultuur uit primêre sel-isolate van menslike bloed ontwikkel, waarmee rumatoïede kakeksie nageboots kon word deur gebruik te maak van serum afkomstig van gesonde en RA skenkers. Hierdie studie het gemik om die sellulêre reaksie op RA serum toe te lig, as ook om die effek van been morfogenetiese proteïen-7 (BMP-7) as moontlike behandeling te evalueer. Die CIA model was ‘n fisiologies relevante en akkurate model vir ondersoeke na rumatoïede kakeksie; verskeie spiergroepe het dalings in massa en deursnit-area getoon, in lyn met kliniese verslae. Verder is verhoogde omvang van fibrose in alle spiere gemeet, wat onafhanklik van spierveseltipe kategorie was. Hierdie model het tot ‘n verbeterde begrip van die meganismes van rumatoïede kakeksie bygedra, en het getoon dat die voortdurende inflammasie in die skeletspier bygedra het tot ‘n verhoogde aktivering – maar ongekoördineerdheid – van spiervernuwings prosesse, wat tot ‘n onvermoë om spierveselgrootte te onderhou, gelei het. Deur gebruik te maak van hierdie selvlakprofiel van RA, is die drievoudige kultuur ontwerp om ‘n simulasie van menslike sellulêre seine in gekweekte normale menslike selle in reaksie op blootstelling aan serum van normale of RA skenkers, toe te laat. Eerstens is die akkurate verteenwoordiging van siekte seinoordrag in RA bevestig, met RA serum wat inderdaad ‘n wanregulering van IL-6/IL-10 konsentrasies en ‘n relatief pro-inflammatoriese toestand in vergelyking met gesonde serum getoon het. Assessering van mioblast-, fibroblast- en makrofaag-verwante parameters in die drievoudige kultuur het wanregulering van beide spier- en ekstrasellulêre matriksvorming getoon na blootstelling aan serum van RA pasiënte wat nie op behandeling reageer nie. Hierdie siekte-geassosieerde uitkomste is verder ook gekorrigeer/beperk in die teenwoordigheid van BMP-7, wat op ‘n potensieel voordelige rol van BMP-7 in die bestuur van rumatoïede kakeksie dui. Ten slotte, hierdie tesis maak ‘n beduidende bydrae tot ons begrip van rumatoïede kakeksie deur herhaaldelik, in in vitro en in vivo modelle, in mense en in knaagdiere, die wanregulering in skeletspier aan te dui, wat volg op die onopgeloste inflammasie in RA en wat bydra tot die strukturele en funksionele uitkomste van skeletspier in RA. Verder dui tesisdata daarop dat hierdie wanregulering potensieel aangespreek kan word deur behandeling met BMP-7. Doctoral 2022-01-24T13:03:02Z 2022-04-29T09:16:16Z 2022-01-24T13:03:02Z 2022-04-29T09:16:16Z 2022-04 Thesis http://hdl.handle.net/10019.1/124495 en_ZA Stellenbosch University vii, 175 pages : illustrations (some color) application/pdf Stellenbosch : Stellenbosch University |
| spellingShingle | Rheumatoid arthritis -- Diseases -- Treatment Skeletal muscle wasting Bone morphogenetic proteins-7 Cell interaction Inflammation -- Mediators UCTD Ollewagen, Tracey Intercellular communication between macrophages, myoblasts and fibroblasts in the context of rheumatoid arthritis-associated skeletal muscle wasting |
| title | Intercellular communication between macrophages, myoblasts and fibroblasts in the context of rheumatoid arthritis-associated skeletal muscle wasting |
| title_full | Intercellular communication between macrophages, myoblasts and fibroblasts in the context of rheumatoid arthritis-associated skeletal muscle wasting |
| title_fullStr | Intercellular communication between macrophages, myoblasts and fibroblasts in the context of rheumatoid arthritis-associated skeletal muscle wasting |
| title_full_unstemmed | Intercellular communication between macrophages, myoblasts and fibroblasts in the context of rheumatoid arthritis-associated skeletal muscle wasting |
| title_short | Intercellular communication between macrophages, myoblasts and fibroblasts in the context of rheumatoid arthritis-associated skeletal muscle wasting |
| title_sort | intercellular communication between macrophages myoblasts and fibroblasts in the context of rheumatoid arthritis associated skeletal muscle wasting |
| topic | Rheumatoid arthritis -- Diseases -- Treatment Skeletal muscle wasting Bone morphogenetic proteins-7 Cell interaction Inflammation -- Mediators UCTD |
| url | http://hdl.handle.net/10019.1/124495 |
| work_keys_str_mv | AT ollewagentracey intercellularcommunicationbetweenmacrophagesmyoblastsandfibroblastsinthecontextofrheumatoidarthritisassociatedskeletalmusclewasting |