Table 2 Groups of genes showing a time-dependent expression pattern
From: Kinetics of gene expression and bone remodelling in the clinical phase of collagen-induced arthritis
Gene symbol | Ctrl a | Day 0 to 3 b | Week 1 to 2 c | Week 3 to 4 d | Decline e | |
|---|---|---|---|---|---|---|
Log 2 | Fold change ( P -value) | Protein function in relation to bone | ||||
Osteoclast function: highest differential expression day 0 to 3 | ||||||
Ccl9 | 6.42 | 2.05 (0.01) | 1.78 (0.01) | 1.61 (0.10) | 1.44 (0.10) | Stimulates OC motility and polarisation through CCR1. |
Tyrobp | 10.21 | 4.09 (0.03) | 3.31 (0.02) | 2.47 (0.06) | 1.56 (0.33) | Kinase involved in the generation of the actin cytoskeleton in OC, which is critical for bone resorption. |
Atp6v0d2 | 6.97 | 9.03 (0.01) | 7.18 (0.003) | 5.94 (0.005) | 3.67 (0.02) | ATPase proton pump involved in acidification of the extracellular resorption lacuna created by OC and early OC differentiation. |
Lif | 5.74 | 2.20 (0.01) | 1.12 (0.22) | 0.85 (0.39) | 0.73 (0.10) | Expressed in OC and modulates the recruitment of OB to resorption surfaces in a TGFβ dependent manner. |
Early osteoblast function: highest differentially expression day 0 to 3 | ||||||
Bmp1 | 7.52 | 1.86 (0.07) | 1.67 (0.10) | 1.52 (0.13) | 1.28 (0.30) | Metalloproteinase that may play a role on several levels of bone formation. It processes the c-terminal end of pro-collagen type I, activates other BMPs and processes BGN and DMP1. Expressed in patients with arthritis and acute fractures. |
Crtap | 6.84 | 2.69 (0.02) | 2.43 (0.01) | 1.66 (0.12) | 1.12 (0.77) | Scaffolding protein that associates with others to hydroxylate collagen type I chains. Associated with osteogenesis imperfecta. |
Tnc | 9.19 | 3.01 (0.03) | 2.67 (0.03) | 2.09 (0.05) | 1.72 (0.11) | Pro-inflammatory extracellular matrix protein, expressed in synovium and blood in RA patients. Involved in extracellular matrix remodelling, where it is bound by periostin. |
Lox | 7.13 | 4.51 (0.11) | 3.52 (0.14) | 2.49 (0.23) | 1.57 (0.49) | Catalyses cross-linking of collagen type I. Is activated by BMP1. |
Late osteoblast function: highest differentially expression week 1 to 2 or week 3 to 4 | ||||||
Sp7 | 6.43 | 1.02 (0.90) | 1.67 (0.04) | 1.19 (0.25) | 1.01 (0.95) | Transcription factor with a critical role in osteoblast differentiation. |
Spp1 | 8.37 | 2.90 (0.05) | 4.46 (0.00003) | 3.49 (0.003) | 1.98 (0.14) | OB marker, expressed in OB, OC, and osteocytes. Inhibits formation and growth of hydroxyapatite by binding the crystals. Promotes attachment of OC to bone under control of Acp5 phosphatase. |
Mgp | 10.45 | 2.61 (0.06) | 3.33 (0.04) | 2.45 (0.07) | 1.65 (0.21) | Inhibitor of bone mineralisation. |
Sparc | 11.77 | 2.17 (0.04) | 2.48 (0.03) | 2.13 (0.04) | 1.68 (0.07) | The protein binds hydroxyapatite when bound to collagen type I in vitro. Sparc null mice have normal collagen content in bone, but reduced bone formation and numbers of OC and OB. |
Enpp1 | 9.08 | 2.72 (0.01) | 3.19 (0.0003) | 2.52 (0.01) | 1.60 (0.15) | Expression is induced in OB by MDK. Essential for converting extracellular ATP to inorganic pyrophosphate, thus controlling the levels and functions in bone mineralization and soft tissue calcification. Essential for normal bone development. |
Bglap1 | 9.05 | 0.75 (0.62) | 2.63 (0.0004) | 1.82 (0.04) | 1.37 (0.13) | OB marker and serum marker of bone formation. Expressed in the late mineralisation phase. The exact role of the protein in bone is, however, debated as data is controversial. |
Ifitm5 | 6.67 | 1.25 (0.11) | 1.47 (0.03) | 1.35 (0.05) | 1.14 (0.27) | Expressed in OB and involved in mineralisation. |
Ibsp | 10.67 | 2.22 (0.02) | 2.59 (0.01) | 2.99 (0.01) | 2.19 (0.02) | Marker of late OB differentiation. Expressed in OB, OC, hypertrophic chondrocytes and osteocytes. Binds to the AvB3 integrin and hydroxyapatite, probably mediating cell attachment to matrix. Nucleates hydroxyapatite. |
Sustained high expression week 0 to 2 | ||||||
Col1a2 | 9.94 | 1.88 (0.08) | 2.25 (0.05) | 2.03 (0.06) | 1.69 (0.10) | This gene encodes the alpha2 chain of collagen type I. Collagen type I is the most abundant protein in bone and a marker of OB activity. |
Col1a1 | 9.84 | 1.80 (0.11) | 2.25 (0.05) | 1.92 (0.09) | 1.69 (0.14) | This gene encodes the alpha1 chain of collagen type I. Collagen type I is the most abundant protein in bone and a marker of OB activity. |
Ogn | 7.83 | 2.28 (0.07) | 3.88 (0.02) | 2.16 (0.09) | 1.43 (0.34) | Proteoglycan belonging to the SLRP family. The protein is processed by BMP1 and regulates collagen type I fibrillogenesis. |
Bgn | 10.63 | 2.18 (0.04) | 2.21 (0.03) | 1.63 (0.09) | 1.08 (0.72) | Proteoglycan belonging to the SLRP family. KO mice have reduced collagen synthesis, reduced bone mass and production of bone precursor cells. The protein is processed by BMP1. |
Col12a1 | 8.24 | 4.59 (0.04) | 4.81 (0.04) | 2.98 (0.08) | 1.75 (0.25) | Expressed by OB in areas of bone formation. COL12A1 KO mice have skeletal abnormalities with less mechanical strength and reduced matrix deposition. |
Ppib | 7.45 | 2.17 (0.04) | 2.27 (0.07) | 1.49 (0.14) | 1.16 (0.64) | Associates with other proteins to hydroxylate collagen type I chains. Associated with osteogenesis imperfecta. |
Lum | 10.18 | 3.37 (0.04) | 3.97 (0.03) | 2.78 (0.05) | 1.69 (0.18) | Proteoglycan belonging to the SLRP family (same as BGN). |
Hapln1 | 6.72 | 1.69 (0.15) | 3.10 (0.01) | 2.88 (0.005) | 2.08 (0.01) | Involved in cartilage biosynthesis by linking aggrecans and hyalyron acid. Polymorphism in this gene is associated with osteophyte formation in osteoarthritis and it is located in a susceptibility locus of AS. |
Postn | 8.52 | 10.33 (0.07) | 9.76 (0.07) | 4.97 (0.12) | 2.53 (0.29) | Promotes cell survival of preosteoblasts and OB. Increases activation of pro-lysyl oxidase, which cross-links collagen type I. |
Cthrc1 | 8.46 | 4.78 (0.06) | 6.79 (0.05) | 3.50 (0.10) | 1.65 (0.43) | Molecule that stimulates bone formation, secreted by OC. |
Others | ||||||
Igf1 | 9.68 | 1.94 (0.04) | 2.61 (0.03) | 1.82 (0.05) | 1.18 (0.59) | Growth factor positively regulating bone formation. Regulates bone mineral density. |
Pappa | 5.99 | 2.24 (0.0002) | 1.20 (0.06) | 1.08 (0.11) | 0.96 (0.68) | IGF-dependent proteinase that regulates the bioavailability of IGF. Expressed in fibroblasts, chondrocytes and OB. Pappa KO mice have reduced bone formation and delayed fracture-healing. |
Dmp1 | 8.30 | 0.74 (0.42) | 1.2 (0.59) | 1.81 (0.17) | 1.47 (0.30) | Extracellular matrix protein that is processed by BMP1 and involved in mineralisation of extracellular matrix. Expressed by hypertrophic chondrocytes, osteocytes, and OB. |
Tissue degradation | ||||||
Mmp13 | 7.57 | 13.15 (0.02) | 17.33 (0.02) | 8.93 (0.02) | 4.53 (0.05) | Bone resorption, OC- and osteoprogenitor differentiation. |
Ctsk | 7.82 | 11.02 (0.04) | 11.75 (0.04) | 7.58 (0.04) | 4.80 (0.08) | Bone resorption. Principle enzyme degrading osteoid. |
Mmp3 | 7.24 | 23.11 (0.02 ) | 11.87 (0.01) | 5.24 (0.04) | 2.94 (0.11) | Metalloproteinase associated with arthritis. |
Timp1 | 7.53 | 19.45 (0.002) | 9.33 (0.001) | 5.30 (0.03) | 3.44 (0.02) | Inhibitor of metalloproteinases. |
Mmp9 | 7.15 | 4.24 (0.02) | 3.79 (0.02) | 2.95 (0.04) | 2.20 (0.08) | Resorption, OC- and osteoprogenitor differentiation. |
Ctss | 8.32 | 3.62 (0.04) | 2.99 (0.05) | 2.29 (0.08) | 1.68 (0.20) | Expressed in hypertrophic chondrocytes and OC. |
Mmp19 | 5.99 | 2.18 (0.02) | 2.05 (0.01) | 1.45 (0.16) | 1.26 (0.09) | Degradation of extracellular tissue. |
Mmp14 | 7.92 | 2.63 (0.02) | 2.82 (0.02 ) | 2.11 (0.02) | 1.77 (0.05) | Involved in tissue destruction in RA. |
Acp5 | 7.30 | 3.68 (0.02) | 3.46 (0.03) | 3.59 (0.03) | 2.50 (0.03) | The encoded protein is a phosphatase, also called Trap. It is a marker of OC function and is extensively expressed in OC. It is activated by Cathepsin K and dephosphorylates SPP1 and IBSP. Plays an inhibitory role in collagen type I synthesis, degradation, and mineralisation. |
Genes of the BMP pathway | ||||||
Bmp2 | 7.16 | 1.67 (0.30) | 1.68 (0.29) | 1.24 (0.63) | 1.26 (0.59) | Ligand of the BMP pathway. |
Bmpr1a | 6.88 | 1.84 (0.13) | 2.01 (0.10) | 1.91 (0.11) | 1.15 (0.72) | Type I receptor of the BMP pathway. |
Bmpr2 | 8.36 | 2.05 (0.04) | 1.65 (0.08) | 1.40 (0.15) | 1.30 (0.28) | Receptor type II in the BMP pathway. |
Smad2 | 7.23 | 2.05 (0.14) | 2.14 (0.12) | 1.70 (0.22) | 1.44 (0.37) | Regulatory Smad involved in BMP signalling. |
Smad6 | 7.27 | 0.55 (0.08) | 0.58 (0.0045) | 0.72 (0.04) | 0.76 (0.12) | Inhibitory Smad antagonising BMP signalling. |
Smad4 | 8.16 | 1.28 (0.18) | 1.27 (0.19) | 1.18 (0.32) | 1.04 (0.84) | Co-Smad associating with regulatory Smads. |
Smad5 | 7.07 | 1.40 (0.04) | 1.28 (0.06) | 1.20 (0.17) | 0.99 (0.92) | Regulatory Smad involved in BMP signalling. |
Bmp4 | 7.68 | 0.59 (0.04) | 0.68 (0.04) | 0.99 (0.95) | 0.95 (0.61) | Ligand of the BMP pathway. |
Bmp6 | 8.44 | 0.62 (0.07) | 0.75 (0.15) | 0.88 (0.67) | 0.93 (0.63) | Ligand of the BMP pathway. |
Bmp7 | 5.82 | 0.78 (0.19) | 0.86 (0.31) | 0.94 (0.67) | 1.26 (0.17) | Ligand of the BMP pathway. |
Inhba | 7.20 | 5.65 (0.01) | 3.94 (0.01) | 2.09 (0.07) | 1.17 (0.77) | Non-steroidal hormone reported to increase bone formation in transgenic mice overexpressing human inhibin A. Associated with human arthritis. |
Acvr2a | 7.23 | 1.27 (0.33) | 1.29 (0.03) | 1.18 (0.04) | 0.91 (0.34) | Type II receptor of the TGFβ pathway. |
Acvr2b | 6.21 | 0.80 (0.01) | 0.73 (0.0034) | 0.76 (0.03) | 0.85 (0.29) | Type II receptor of the TGFβ pathway. |
Genes of the WNT pathway | ||||||
Fzd1 | 6.91 | 1.70 (0.05) | 1.57 (0.05) | 1.39 (0.08) | 1.18 (0.37) | Receptor of the WNT pathway. |
Hif1a | 8.35 | 4.23 (0.02) | 3.56 (0.02) | 2.49 (0.03) | 1.43 (0.34) | Regulates the cellular response to hypoxia during endochondral bone formation and inhibits WNT signalling in OB in cooperation with Sp7. |
Sost | 7.28 | 0.48 (0.03) | 0.61 (0.02) | 0.62 (0.03) | 0.73 (0.15) | WNT antagonist and marker of mature osteocytes. |
Ndrg2 | 10.56 | 0.18 (0.01) | 0.31 (0.0014) | 0.37 (0.01) | 0.52 (0.01) | Down-regulates WNT-signalling mediated TCF-promotor activity and GSK3β phosphorylation synergistically with PRA1. |
Dkk1 | 7.19 | 0.67 (0.18) | 0.85 (0.25) | 1.15 (0.32) | 1.09 (0.43) | Antagonist of the WNT pathway. |
Tcf4 | 7.96 | 1.46 (0.09) | 1.73 (0.03) | 1.30 (0.28) | 0.99 (0.94) | Transcription factor of the WNT pathway. |