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-ERT2) | 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-ERT2: 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