Bone, Cartilage, Tooth

Ovary

Uterus
Placenta

Prostate

Testis

Bone, Cartilage and Tooth
 Scgfgene is highly up-regulated in proliferating osteoblasts and chondroblasts during bone and cartilage formation(11,  Pat5). It has been reported how several osteogenic molecules affect  scgfgene expression.
(1) Parathyroid hormone (PTH) is osteoplastic and osteolytic when administered intermittently and continuously,
   respectively.Scgfgene is up-regulated in the femur when PTH given continuously (42). The seemingly
   contradictory result that  scgfgene is up-regulated at osteolytic but not at osteoplastic stage indicates that
   osteogenic switch already turns on at osteolytic stage.
(2)Scgfgene is markedly down-regulated when preosteoblast cell line, MC3T3-E1, is differentiated with tricostatin A
   (41).
(3) Osteoblasts secrete collagen during osteogenesis. Lysine and hydroxylysine residue of collagen is catalyzed  
   with lysyl oxidase to aldehyde allysine and hydroxylallysine, respectively, resulting in crosslinking of collagen fibrils  
   to form stable ECM. Mouse preosteoblast cell line, MC3T3-E1, undergoes osteogenic differentiation in response to
   BMP-2, the process of which is blocked by lysyl oxidase inhibitor, Β-aminopropionitrile (BAPN). Scgf gene
   expression is significantly affected in MC3T3-E1 cells by BAPN-induced block in osteogenic differentiation (228).
(4) Wnt5a induces MSCs to differentiate towards osteoblasts.Scgfgene is down-regulated in the calvaria of
   wnt5a^-/-mice as compared with wild typewnt5a^+/+mice (43).
(5) Scgf gene expression is moderately down-regulated in the cranial mesenchymal tissues from E14.5 Fgf8b-  
   overexpressed mice (585).
(6)Scgf  gene is one of the so-called  runx2knockout cluster (44). Runx2 is a transcription factor with an osteogenic
   potential, thusscgfgene is down-regulated in the flat bone (calvaria) and long bones (fore- and hindlegs) of
   runx2^-/-mice as compared with wild typerunx2^+/+mice (40).
(7)Glycogen synthase kinase-3Β-specific inhibitor, 3-[9-Fluoro-2-(piperidine-1-carbonyl)-1,2,3,4-tetrahydro-[1,4]    
   diazepino[6,7,1-hi]indol-7-yl]-4-imidazo[1,2-a]pyridin-3-yl-pyrrole-2,5-dione, induces scgf gene down-regulation
   in the chondrocytes of metatarsals from E17.5 mouse embryo (340).
   SCGF is up-regulated in the enthesis area between human anterior cruciate ligament and femur compared to the ligament (707).
   Microgravity (0.008g) down-regulates scgf gene expression in mouse calvarial osteoblasts as compared with the
unit gravity (1g) (260).
   Osteoclasts express  scgf  gene, and appear to stimulate osteoblast growth (80).  GFPcyan⁺ osteoblasts and GFPtopaz⁺ preosteocytes/osteocytes are FACS-sorted from calvaria cells of Col1a1 promoter-driven GFPcyan and DMP1 promoter-driven GFPtopaz double transgenic mice. Osteoblasts up-regulate scgf  gene expression twice relative to preosteocytes/osteocytes (209). Scgf  gene is up-regulated in osteoclasts differentiated from BM-MNCs  in the presence of M-CSF and RANKL (81).  Human TRAP⁺ multinucleated osteoclasts are differentiated in vitro from CD34⁺ osteoclast progenitor cells in the presence of RANKL and M-CSF, and secrete a significant amount of SCGF on day 3 to 6 of culture (468). Repetitive compression loading up-regulates scgf gene expression in the mouse caudal vertebrate trabecular osteocytes (400). Scgf gene expression is up-regulated in rat UMR-106 osteoblasts co-cultured with human PC3 osteolytic prostate cancer cells through micropore filter (510).
 SCGF has been thought to bind integrins (ITGs) through RGD motif sequence. Of human ITG α4β1, α9β1, α10β1, α11β1, αVβ1, αVβ3, αIIbβ3 and αMβ2 tested, human SCGF selectively binds ITGα10β1 and ITGα11β1 with similar high affinity as human pro-collagen 1α through RGD (594). Mouse SCGF acts on human and mouse MSCs to induce osteogenic differentiation despite lacking RGD through activated Wnt signal transduction, i.e. phosphorylation of GSK3, accumulation of nuclear β-catenin and up-regulation of Wnt target genes of Alp, Axin2, Lef1 and Runx2. ITGα10β1 and ITGα11β1 are not RGD-recognizing integrins and mouse SCGF lacks RGD, indicating that SCGF binds integrins through other mechanisms than RGD.
   SCGF is highly enriched in human umbilical cord (UC)-MSCs-derived exosomes compared to parental MSCs.
Human SCGF-rich UC-MSCs-derived exosomes increase trabecular bone mass, and decrease BM fat accumulation
and osteoclasts when administered intravenously to mice with ovariectomy- or disuse (hindlimb-unloading by tail
suspension)-induced osteoporosis (615). Human  scgf⁺UC-MSCs-derived exosomes enhance and inhibit  in vitro
differentiation of mouse BM-MSCs into osteoblasts and adipocytes/osteoclasts, respectively, but human  scgf^-
(silenced with  scgfshRNA) UC-MSCs-derived exosomes exhibit no such bone effects. Differentiation of mouse
Raw264.7 osteoclast progenitor cells into osteoclasts in the presence of RANKL is blocked by human  scgf⁺but not
scgf^-UC-MSCs-derived exosomes.
   SCGF facilitates dose-dependently  in vitro osteogenesis of porcine BM-MSCs (622). When human adipose MSCs
are cultured in the plate containing no osteogenesis-inducing factors, with or without microarc calcium phosphate(CaP)-coated titanium, they are differentiated to osteoblasts only in the plate with CaP-coated titanium (631). SCGFlevel is not different between both culture systems.
   Scgfgene expression parallels chondroblast differentiation from MSCs (46) and embryonal carcinoma cells (45).
   Treatment with mechanical injury, IL-1β or TNF-α is little detrimental in vitro to SCGF secretion by bovine cartilage (229). SCGF level is declined in the culture supernatants of human iPSCs-derived chondrocytes 24 hrs after 2 Gy but not 3 Gy irradiation (647).
   Liquid chromatography-mass spectrometry analysis of EDTA-soluble tooth proteome identifies SCGF protein, indicating a potential role of SCGF for dentinogenesis and tooth formation (324). Normal human dentin produces and contains SCGF protein (388). Scgf gene expression is significantly up-regulated in human cementoblasts differentiated in the culture of periodontal ligament stem cells with SB431542 and BMP-7 (672). rhSCGF activates ERK, JNK and AKT signaling pathway in human dental pulp cells to differentiate into calcified odontoblasts with up-regulated ALP, DMP-1 and DSPP (695).
   Scgf gene expression is down-regulated in the tenocytes from postnatal day 7 Tgfbr2-deleted mice (618).

Bone marrow
  Bone marrow is the most rich source for stem cells, e.g. HSCs, MAPCs and MSCs, therefore shows the highest expression of scgf gene amongst all organs and tissues (30-39). HSC/progenitor cell marker-sorted BM cells express scgf gene, e.g. Lin^-Rhodamine^loHoechst^lo cells (35), CD34⁺ cells (34, 36, 38, 39), CD34⁺CD38^- cells (37), CD34^-CD33⁺ cells (34), CD34⁺CD45RA^hiCD7⁺ (T/NK progenitor) cells (82), CD34⁺CD45RA^intCD7^- (lymphoid progenitor) cells (82), CD34⁺CD45RA^hiLin^- (myeloid progenitor) cells (82) and CD34⁺CD45RA^hiCD10⁺ (B progenitor) cells (82). Scgf gene expression is lost as HSC/progenitor cells differentiate to mature blood cells (34, 35). Bone marrow CD34⁺ cells express scgf  gene 3 to 6 times higher than umbilical cord blood CD34⁺ cells (36,38).
  Bone marrow stromal cells express scgf gene as demonstrated by RT-PCR (83) and LC-MS/MS (481).　IL-1β-activation unaffects SCGF production by human fibroblasts from bone marrow (479). Bone marrow cells from patients with acute myocardial infarction (AMI) highly express scgf gene (276), which is one of the paracrine mechanisms for improvement of systolic function after AMI by intracoronary infusion of BM cells.

Blood cells
  Mature PB-MNCs, eosinophils, macrophages and lymphocytes usually do not express scgf  gene (84, 85), but are activated to express it by thymosin-α1 (86,246), SARS virus (87), nontypeable Haemophilus influenzae (88) and TNF-α overexpression (89). Erythropoietin down-regulates scgf gene expression in the TNF-α-primed PB-MNCs (462).
Scgf gene is up-regulated when K562 cells are differentiated with PMA to megakaryocyte (90). Scgf gene is down-regulated in PB-MNCs after vaccination with HPV-virus-like particle (91) and in mouse bronchoalveolar lavage fluid cells after LPS inhalation (92). Herpes simplex virus 1 infection stimulates human macrophages to down-regulate scgf gene expression (243). Proteome analysis on the cortisol-elicited stress response in THP-1 cells reveals up-regulated production of SCGF (67). An exceptional report is scgf gene up-regulation in human CD15⁺ cells differentiated in vitro from CD34⁺ cells in the presence of KL+FL+IL-3+G-SCF+GM-CSF relative to the original CD34⁺ cells (341).
  Transfection of CD21-lacking human Nalm6 and Laz221 pre-B cells with a full-length CD21 but not with a mutant CD21 lacking cytoplasmic tail up-regulates scgf gene expression (454).
  Analysis on leukocyte gene expression in southern Morocco residents demonstrates that there is no significant scgf gene expression variation between geography, lifestyle, gender and race, but differential scgf gene expression in Ighrem men relative to Ighrem women and Boutroch people (226).
  Scgf gene is down-regulated along differentiation of CD4^-CD8^- immature thymocytes, i.e. CD44^hic-kit⁺CD25⁺→CD44^loCD25⁺→CD44^loCD25^-  (250). Human naive CD4⁺ T cells are activated i n vitro  with anti-CD3 antibody, anti-CD28 antibody and IL-2 for 6 days to induce a small increase in elaboration of SCGF as compared with non-activated controls, and the effect is little altered when further treated with tranilast (335). Human CCR6⁺CD4⁺memory T cells are activated with anti-CD3 and anti-CD28 antibodies to down-regulate scgf gene expression (441). Human CD62L⁺CD45RA⁺ naive T cells, but not CD62L⁺CD45RA^- central memory T cells, express scgf gene (405). Scgf gene is down-regulated in human CD161⁺⁺ T cells irrespective of coexpressing CD4, CD8 or TCRγδ (476).
  SCGF is not detected in the conditioned medium of any coculture of human CD4⁺ T cells and monocytes unstimulated or stimulated with ani-CD3/CD28 antibodies, LPS or PMA/ionomycin (533).
  Scgf is identified to be one of the human-specific innate immune response genes in LPS-stimulated monocytes compared with those of chimpanzee and rhesus macaque (299). Scgf gene expression is down-regulated in vitro in human monocytes during inflammatory response to LPS, TNF-α and IFN-γ, then up-regulated during anti-inflammatory resolution with IL-10 and TGF-β (443). LPS or IFN-γ down-regulates scgf gene expression in fluticasone propionate-primed human macrophages (444). SCGF is relocated from lysosome to endoplasmic reticulum in THP-1 cells and almost secreted within 24 hrs after LPS-stimulation (660). Human classical CD14⁺⁺CD16^- monocytes up-regulate scgf  gene expression relative to intermediate CD14⁺⁺CD16⁺ and non-classical CD14⁺CD16⁺⁺ monocytes (336). Scgf  gene is 8.4- and 15.3-fold up-regulated in the non-adherent and adherent macrophages, respectively, developed in a 3-week culture of human PB-CD34⁺ cells with M-CSF+GM-CSF+IL-6+KL+flt3L (201). Scgf gene expression is up-regulated in the human monocytes treated with Bacillus anthracis' lethal toxin (385).
  Scgf gene expression is down-regulated in the peripheral blood leukocytes from healthy elderly subjects administered orally with Lactobacillus rhamnosus GG for 28 days (518).
  Rapamycin induces apoptosis and suppresses SCGF production in human anti-inflammatory M2 macrophages polarized by IL-4, but not in pro-inflammatory M1 macrophages polarized by LPS and IFN-Γ (247). SCGF is adsorbed on cyclohexyl methacrylate/isodecyl methacrylate (2:1) co-polymer that polarizes human macrophages to M2 phenotype (625).
  Monocytes are induced in vitro with GM-CSF and IL-4 to generate immature dendritic cells (DCs), which are further stimulated with LPS, 1-palmitoyl-2-arachidoyl-sn-glycerol-3-phosphorylcholin and human rhinovirus to differentiate into mature Th-1-oriented DCs, Th-2-oriented DCs and tolerogenic DCs, respectively. Secretome analysis demonstrates that SCGF is produced by TH-1-oriented DCs, but not by tow other types of DCs (204). Scgf gene is expressed in human peripheral blood CD14^-CD16⁺ and CD14⁺CD16^- monocyte subsets, CD11c^-CD123⁺/BDCA2⁺ plasmacytoid DC and CD1⁺CD11c⁺CD123^-/BDCA2^- monocytoid DC subsets, CD14^-CD1a⁺ and CD14⁺CD1a^- dermal DC subsets, and CD1a⁺HLA-DR⁺ epidermal Langerhans cells (401). Scgf gene expression is up-regulated in human CD1c⁺CD5^lo DCs relativeto CD1c⁺CD5^hi DCs (547). Scgf is a signature gene in the DCs differentiated in vitro from human cord blood CD34⁺ cells in the presence of GM-CSF+IL-4+TNF-α+c-kitL (403). Ag-1^hiB220⁺CD11c^int plasmacytoid DCs express scgf gene more abundantly than CD11c^hiCD103^hi conventional DCs in colon-draining mesenteric lymph nodes from Citrobacter rodentium-infected mice (525). Scgf gene expression is up-regulated in plasmacytoid DC leukemia cells compared to normal plasmacytoid DCs (642)
  Scgf gene expression is significantly up-regulated in immortalized stromal fibroblastic reticular cells from mesenteric lymph nodes compared to those from peripheral skin lymph nodes (569).
  Human erythroblasts express scgf gene (321). SCGF protein is found in rat reticulocyte-derived exosomes (486, Exosome Database ExoCarta).
  A high level of SCGF is also present in the lysate and cytosol of human erythrocytes (576). SCGF level is down-regulated in human erythrocytes primed in vitro with A549 lung adenocarcinoma cells (619).
  SCGF protein exists in platelets from healthy donors (419). Human platelet lysate contains high level of SCGF and is used for osteogenic differentiation of MSCs (628).

Prostate
  Scgf gene expression is androgen-responsive in the rat ventral (93), dorsal and lateral (94) prostate, i.e. scgf gene is down-regulated after castration, then up-regulated by administration of testosterone and/or 2,4,4'-trihydroxybenzophenone (95). Proliferation-related genes including scgf gene are up-regulated in the ventral prostate from homeobox transcription factor Nkx3.1^-/- mice fed with antioxidant N-acetylcysteine relative to vehicle-treated control Nkx3.1^-/- mice (393).

Testis
  Testicular germ (50) and somatic (51) cells express scgf gene, the level of which depends little upon age or meiosis.

Placenta/Uterus
  Scgf gene is expressed in human myometrium (460).Scgf  gene is expressed at the distal tip of allantois including allantois, amnion and yolk sac (96), indicating a potential action of SCGF on allantoic outgrowth and chorioallantoic fusion. Scgf gene is up-regulated in proliferative endometrium as compared with secretory one (97). Chorionic gonadotropin suppresses SCGF-production by human endometrial epithelial cells (438).
  SCGF level is 11-fold down-regulated in the amniotic fluid at term of pregnancy (37-42 weeks) compared to midtrimester (16-24 weeks) (664).
  SAGE in mouse uterus on day 5 of pregnancy indicates that scgf gene is significantly down-regulated in the implantation site as compared with interimplantation site (200).
  Conditional ablation of ihh (indian hedgehog) gene induces a failure in embryo implantation, when scgf gene is down-regulated in the murine uterus (235).
  Murine term (18.5dpc) myometrium up-regulates miR-200 family relative to pregnant (15.5dpc) one, of which scgf-targeted mmu-miR-221 and 222 are not up-regulated, whereas scgf gene expression is 2.8-fold down-regulated in the term uterus (292).
  Estrogen-responsive up-regulation of scgf gene expression in the bovine endometrium is further amplified by progesterone priming (294). Bovine endometrial intercaruncular stromal cells release SCGF-containing exosomes (534).
Scgf gene expression is significantly up-regulated in human endocervical tissues at follicular phase relative to luteal phase (526), indicating the possibility that scgf is regulated by estrogen.
  SCGF level is significantly higher in the cervicovaginal mucus from healthy young women using hormone contraceptives such as norethisterone enanthate or depot medroxyprogesterone acetate (MPA) than non-user controls, and further higher in the mucus with lactobacillus less than 50% of microbiome (601). Higher plasma concentration of MPA correlates inversely with SCGF level in the cervicovaginal lavage fluid from women administered with MPA (627).

Ovary
   Scgf  gene is expressed in mouse ovarian female germline stem cells (FGSCs) (680). Daidzein up-regulates scgf to phosphorylate Akt, and promotes viability and proliferation of FGSCs.
  Scgf  gene is down-regulated in theca cells during ovarian antral follicle development (98).
  No significant change is observed in the follicular fluid SCGF level from women undergoing ovum donation with gonadotropin-releasing hormone agonist or antagonist administration (432).
  Scgf gene expression is significantly down-regulated in the cumulus cells from older women (>40yr old) relative to younger women (<35yr old). Suz12 is a transcription factor for scgf  (532).

Muscle
  Scgf gene expression is significantly up-regulated in human skeletal muscle (m. vastus lateralis) after 12 week physical training (508,550). SCGF is significantly up-regulated in rat skeletal muscle tissue 7 days after impact trauma (624). SCGF is conventionally secreted (551, 552) and released as microvesicles (551) in the conditioned medium of human skeletal muscle cells.

Bone  marrow

Blood  cells

Muscle