Molecular mechanisms of glucocorticoids on skeleton and bone regeneration after fracture

Hachemi, Yasmine; Rapp, Anna E.; Picke, Ann-Kristin; Weidinger, Gilbert; Ignatius, Anita; Tuckermann, Jan

doi:10.1530/jme-18-0024

Cited by 65 publications

(36 citation statements)

References 128 publications

(173 reference statements)

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“…Osteocytes as the major source of RANKL; thyroid hormones; PTH/PTHrP; calcitriol; glucocorticoids; growth factors (FGF, PDGF, EGF); TNF-α; colony-stimulating factors (M-CSF, GM-CSF); IL-1, -6, -7 -8, -11, -15, -17;PGE1, 2, 12;PGH2 (MacDonald, 1986;Dempster et al, 1993;Raisz, 1993;Kawaguchi et al, 1994Kawaguchi et al, , 1995Nash et al, 1994;Holt et al, 1996;Lanske et al, 1999;Roodman, 1999;Lam et al, 2000;Compston, 2001;Ragab et al, 2002;Sher et al, 2004;Eijken et al, 2005;Dai et al, 2006;Zhang et al, 2008;Kini and Nandeesh, 2012;Rauner et al, 2012;Parra-Torres et al, 2013;Paiva and Granjeiro, 2017;Hachemi et al, 2018;Bellido and Gallant, 2019).…”

Section: Systemic and Local Factors That Stimulate Bone Resorptionmentioning

confidence: 99%

Destroy to Rebuild: The Connection Between Bone Tissue Remodeling and Matrix Metalloproteinases

Hardy

Fernández-Patrón

2020

Front. Physiol.

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Bone is a dynamic organ that undergoes constant remodeling, an energetically costly process by which old bone is replaced and localized bone defects are repaired to renew the skeleton over time, thereby maintaining skeletal health. This review provides a general overview of bone's main players (bone lining cells, osteocytes, osteoclasts, reversal cells, and osteoblasts) that participate in bone remodeling. Placing emphasis on the family of extracellular matrix metalloproteinases (MMPs), we describe how: (i) Convergence of multiple protease families (including MMPs and cysteine proteinases) ensures complexity and robustness of the bone remodeling process, (ii) Enzymatic activity of MMPs affects bone physiology at the molecular and cellular levels and (iii) Either overexpression or deficiency/insufficiency of individual MMPs impairs healthy bone remodeling and systemic metabolism. Today, it is generally accepted that proteolytic activity is required for the degradation of bone tissue in osteoarthritis and osteoporosis. However, it is increasingly evident that inactivating mutations in MMP genes can also lead to bone pathology including osteolysis and metabolic abnormalities such as delayed growth. We argue that there remains a need to rethink the role played by proteases in bone physiology and pathology.

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Section: Systemic and Local Factors That Stimulate Bone Resorptionmentioning

confidence: 99%

Destroy to Rebuild: The Connection Between Bone Tissue Remodeling and Matrix Metalloproteinases

Hardy

Fernández-Patrón

2020

Front. Physiol.

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“…Diabetogenic effects, which include increased blood glucose levels, gluconeogenesis, glycogen storage, insulin secretion and/or liver metabolic enzyme transcription are mediated by GR transactivation and requires GR dimerization, were not observed with GR dim (63, 100, 101) or with CpdA (82, 97, 102–104). While, osteoporosis, mediated by both transrepression (osteocalcin transcription) and transactivation (osteoblast differentiation) and thus requiring both GR monomers and dimers (95), was not induced by CpdA, either in vitro or in vivo (105–109), while the GR dim mice still developed osteoporosis concomitant with a potent suppression of osteoblast differentiation both in vitro and in vivo (110–112).…”

Section: Impact Of Gr Dimerization On the Therapeutic Index Of Glucocmentioning

confidence: 99%

GR Dimerization and the Impact of GR Dimerization on GR Protein Stability and Half-Life

Louw

2019

Front. Immunol.

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Pharmacologically, glucocorticoids, which mediate their effects via the glucocorticoid receptor (GR), are a most effective therapy for inflammatory diseases despite the fact that chronic use causes side-effects and acquired GC resistance. The design of drugs with fewer side-effects and less potential for the development of resistance is therefore considered crucial for improved therapy. Dimerization of the GR is an integral step in glucocorticoid signaling and has been identified as a possible molecular site to target for drug development of anti-inflammatory drugs with an improved therapeutic index. Most of the current understanding regarding the role of GR dimerization in GC signaling derives for dimerization deficient mutants, although the role of ligands biased toward monomerization has also been described. Even though designing for loss of dimerization has mostly been applied for reduction of side-effect profile, designing for loss of dimerization may also be a fruitful strategy for the development of GC drugs with less potential to develop GC resistance. GC-induced resistance affects up to 30% of users and is due to a reduction in the GR functional pool. Several molecular mechanisms of GC-mediated reductions in GR pool have been described, one of which is the autologous down-regulation of GR density by the ubiquitin-proteasome-system (UPS). Loss of GR dimerization prevents autologous down-regulation of the receptor through modulation of interactions with components of the UPS and post-translational modifications (PTMs), such as phosphorylation, which prime the GR for degradation. Rational design of conformationally biased ligands that select for a monomeric GR conformation, which increases GC sensitivity through improving GR protein stability and increasing half-life, may be a productive avenue to explore. However, potential drawbacks to this approach should be considered as well as the advantages and disadvantages in chronic vs. acute treatment regimes.

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“…Despite their unmistakable advantages, therapeutic treatment with glucocorticoids causes metabolic alterations which can lead to insulin resistance, and other problems, e.g., high blood pressure (6, 7). Treatment induced bone fragility partly results from direct effects of excess glucocorticoids on bone forming osteoblasts, which show reduced proliferation (8, 9). In addition, pro-osteoclastogenic effects and changes in other organ systems may contribute to glucocorticoid-induced bone loss (5).…”

Section: Introductionmentioning

confidence: 99%

Glucocorticoid Treatment Leads to Aberrant Ion and Macromolecular Transport in Regenerating Zebrafish Fins

et al. 2019

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Long-term glucocorticoid administration in patients undergoing immunosuppressive and anti-inflammatory treatment is accompanied by impaired bone formation and increased fracture risk. Furthermore, glucocorticoid treatment can lead to impaired wound healing and altered cell metabolism. Recently, we showed that exposure of zebrafish to the glucocorticoid prednisolone during fin regeneration impacts negatively on the length, bone formation, and osteoblast function of the regenerate. The underlying cellular and molecular mechanisms of impairment, however, remain incompletely understood. In order to further elucidate the anti-regenerative effects of continued glucocorticoid exposure on fin tissues, we performed proteome profiling of fin regenerates undergoing prednisolone treatment, in addition to profiling of homeostatic fin tissue and fins undergoing undisturbed regeneration. By using LC-MS (liquid chromatography-mass spectrometry) we identified more than 6,000 proteins across all tissue samples. In agreement with previous reports, fin amputation induces changes in chromatin structure and extracellular matrix (ECM) composition within the tissue. Notably, prednisolone treatment leads to impaired expression of selected ECM components in the fin regenerate. Moreover, the function of ion transporting ATPases and other proteins involved in macromolecule and vesicular transport mechanisms of the cell appears to be altered by prednisolone treatment. In particular, acidification of membrane-enclosed organelles such as lysosomes is inhibited. Taken together, our data indicate that continued synthetic glucocorticoid exposure in zebrafish deteriorates cellular trafficking processes in the regenerating fin, which interferes with appropriate tissue restoration upon injury.

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Molecular mechanisms of glucocorticoids on skeleton and bone regeneration after fracture

Cited by 65 publications

References 128 publications

Destroy to Rebuild: The Connection Between Bone Tissue Remodeling and Matrix Metalloproteinases

Destroy to Rebuild: The Connection Between Bone Tissue Remodeling and Matrix Metalloproteinases

GR Dimerization and the Impact of GR Dimerization on GR Protein Stability and Half-Life

Glucocorticoid Treatment Leads to Aberrant Ion and Macromolecular Transport in Regenerating Zebrafish Fins

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