Exploring the role of local glucocorticoid metabolism in osteoblasts during chronic inflammation

Fareed, Syeda (2023). Exploring the role of local glucocorticoid metabolism in osteoblasts during chronic inflammation. University of Birmingham. M.Res.

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Abstract

Glucocorticoids (GCs) are extensively utilised in the management of chronic inflammatory polyarthritides, such as rheumatoid arthritis (RA) due to profound anti-inflammatory properties. However, their prolonged use results in the development of adverse effects, which limit their therapeutic application. Such adverse effects include systemic bone loss, which may be mediated by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) – an enzyme which works bidirectionally to convert inactive GCs to their active counterparts. 11β-HSD1 is highly expressed in osteoblasts (OBs) and potently induced by combinations of GCs and inflammatory factors. Hence, inhibiting 11β-HSD1 may be an effective mechanism by which the side effect profile of GCs can be managed. This thesis studied the role local steroid metabolism has on the inflammatory suppression of osteoblast differentiation, with the aim to provide valuable insights into how endogenous glucocorticoids mediate bone protection in response to inflammation and inform future therapeutic approaches. Primary cultures of human osteoblasts were established and the inflammatory suppression of their differentiation and function was characterised using alizarin red staining, RT-PCR and ELISA. The role of steroid metabolism in this process in response to endogenously derived steroids in combination with selective inhibitors of steroid metabolism was assessed by TLC using radio-labelled steroids. These findings were examined in vivo using mouse models of chronic inflammation with osteoblast targeted disruption of steroid metabolism, where the bone phenotype was assessed by micro-CT. Our results validated strong synergistic upregulation of 11β-HSD1 in GC activation in OBs in response to pro-inflammatory mediators and in combination with GCs. This increase in 11β-HSD1 was shown to be functional, where GCs exerted a negative effect on OB formation as they suppressed collagen formation and suppressed osteoblast differentiation. Some suppression of pro-inflammatory mediators was also observed. However, the murine models show limited changes in the architecture of cortical bone following GC treatment, implying that 11β-HSD1 is not influencing cortical bone metabolism over the timeframes studied in this thesis. Whilst limited changes were seen in cortical bone, further analysis of trabecular bone and other bone parameters are required to fully understand the role of therapeutic GCs.

Type of Work:

Thesis (Masters by Research > M.Res.)

Award Type:

Masters by Research > M.Res.

Supervisor(s):