Table Info

Table 1.

Phenotypes of 11β-HSD1/2 and glucocorticoid receptor genetically modified mouse models in ageing related skeletal diseases

Genetic model	Cre promoter	Cells targeted	Age/Sex studied	Phenotype	Reference
Osteoporosis
11β-HSD2 transgenic (C57BL/6)	Osteocalcin gene 2 (OG2)	Mature osteoblasts and osteocytes	21 months males and females	Vertebrae: higher BMD, cancellous BV, BFR and greater compression strength. Femur: higher BMD and bending strength. Osteoblast and osteocyte apoptosis reduced. Protected from age-related deteriorations in bone vasculature.	[73]
11β-HSD2 transgenic (CD-1)	2.3kb Pro-a1(I) collagen (Col1a1)	Osteoblasts and osteocytes	12 and 18 months males and females	Vertebrae: females displayed higher trabecular thickness, but no change in BV/TV in either gender. 18-month-old mice protected from fat accumulation, and insulin and leptin resistance.	[91]
GR KO (C57BL/6)	Osterix (Osx)	Osteoblast progenitor cells (plus hypertrophic chondrocytes)	21 months females	Femur: reduced femoral cortical bone area and trabecular bone mass. Serum markers of bone formation (PINP) and resorption (TRAcP5b) reduced.	[98]
Sarcopenia
11β-HSD1 KO (C57BL/6)	Myogenic differentiation 1 (MyoD)	Myogenic progenitor cells	22 months males	Increased muscle mass and strength.	[108]
11β-HSD1 over-expressing (C57BL/6)	Global	All cells	2 months males	Glucocorticoid overexpression induced muscle atrophy.	[108]
GR KO (C57BL/6)	Skeletal muscle actin (ACTA1)	Striated myofibers	20 weeks old males and females	Increased muscle mass. Diurnal variation and fasting-dependent temporal elevation of plasma alanine levels reduced. Lipolysis increased in adipose tissue.	[109]
GR KO (FVB/Balb/c)	Muscle creatine kinase (MCK)	Striated and cardiac myofibers	3–4 months females	Increased muscle mass. Protected from glucocorticoid-induced muscle atrophy. Attenuated expression of atrophy related genes (MuRF1 and MAFbx, 4E-BP1, and MT2) induced by nutritional deprivation. No effect on muscle atrophy induced by denervation.	[110]
GR KO (C57BL/6)	Myosin light chain 1F (Mlc1f)	Striated myofibers	12 weeks old males	Attenuated muscle atrophy. Reduced expression of proteolysis-associated genes induced by reduced food intake.	[112]
Osteoarthritis
11β-HSD2 transgenic (CD-1)	2.3kb Pro-a1(I) collagen (Col1a1)	Osteoblasts and osteocytes	26 and 38 weeks old males	In young mice, no change in cartilage loss, subchondral bone sclerosis and osteophyte formation. In aged mice, cartilage loss, subchondral bone sclerosis, and osteophyte size were reduced. No changes in synovial inflammation.	[3]
GR KO (C57BL/6)	Pro-a1(II) collagen (Col2a1)-tamoxifen inducible Cre (Cre-ER^T2)	Chondrocytes	24, 26, 30, and 38 weeks old males	Less severe cartilage loss (all timepoints) and reduced synovial inflammation (at 24 weeks). Decreased chondrocyte and synoviocyte hypoxia inducible factor (HIF)-2α expression. Reduced chondrocyte senescence and catabolic signaling. No change in subchondral bone sclerosis and osteophytes.	[128]

GR: glucocorticoid receptor; 11β-HSD1/2: 11β-hydroxysteroid dehydrogenase types 1 and 2; KO: knockout; Cre: cre recombinase; BMD: bone mineral density; BV: bone volume; BFR: bone formation rate; BV/TV: bone volume/tissue volume; Cre-ER^T2: cre fused with a mutated ligand-binding domain of estrogen receptor that is tamoxifen inducible; PINP: procollagen type I N-propeptide; TRAcP5b: tartrat-resistant acid phosphatase 5b; MuRF1: muscle RING-finger protein-1; MAFbx: muscle atrophy F-box; 4E-BP1: eukaryotic translation initiation factor 4E-binding protein 1; MT2: metallothionein 2; HIF-2α: hypoxia inducible factor 2α; kb: kiloba

Declarations

Author contributions

EM: Conceptualization, Writing—original draft, Writing—review & editing. HZ: Writing—review & editing. MJS: Writing—review & editing. All authors read and approved the submitted version.

Conflicts of interest

The authors declare that they have no conflicts of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

The authors would like to acknowledge the ongoing research support by the National Health and Medical Research Council (NHMRC) of Australia through NHMRC Ideas [APP2028787] and NHMRC Investigator [APP1196062] grants. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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