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Transcription factor Sp7, also called Osterix (Osx), is a member of the Sp family of zinc-finger transcription factors[1]. It is highly conserved among bone-forming veterbrate species[2] [3] It plays a major role, along with Runx2 and Dlx5 in driving the differentiation of mesenchymal precursor cells into osteoblasts and eventually osteocytes[4]. Sp7 also plays a regulatory role by inhibiting chondrocyte differentiation maintaining the balance between differentiation of mesenchymal precursor cells into ossified bone or cartilage.[5] Mutations of this gene have been associated with multiple dysfunctional bone phenotypes in vertebrates. During development, severe defects in cranial suture formation have been observed in zebrafish[6] and in an adult mouse model the shutdown of Sp7 expression caused a lack of new bone formation and irregular buildup of cartilage[7]. Through the use of GWAS studies, the Sp7 locus in humans has been strongly associated with bone mass density[8]. In addition there has been genetic evidence discovered for its role in diseases such as Osteogenesis imperfecta (OI)[9] and osteoporosis[10].

Genetics

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In humans Sp7 has been mapped to 12q13.13. It has 78% homology to another Sp family member, Sp1, especially in the regions which code for the three Cys-2 His-2 type DNA-binding zinc fingers. Sp7 consists of three exons the first two of which are alternatively spliced, encoding a 431-residue isoform and an amino-terminus truncated 413-residue short protein isoform[11]

A GWAS study has found that bone mass density(BMD) is associated with the Sp7 locus, adults and children with either low or high BMD were analyzed showing that several common variant SNPs within the 12q13 region were in an area of linkage disequillibrium[8].

Function

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Sp7 acts as a master regulator of bone formation during both embryonic development and during the homeostatic maintenance of bone in adulthood.

During development

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Diagram detailing the role of Sp7 in the differentiation pathway of osteoblasts and the decision pathway between cartilage and ossified bone[1][4]
Zebrafish skull, 34dpf, imaged using a calcein stain showing normal frontal and parietal bones. Overlayed using fuschia are the irregular Runx2+ initiation sites of bone formation seen in an Sp7 mutant fish indicating a highly irregular bone growth pattern[6].

In a developing organism, Sp7 serves as one of the most important regulatory shepherds for bone formation. The creation of ossified bone is preceded by the differentiation of mesenchymal stem cells into chondrocytes and the conversion of some of those chondrocytes into cartilage. Certain populations of that initial cartilage serves as a template for bone cells as skeletogenesis proceeds[12].

Sp7/Osx null mouse embryos displayed a severe phenotype in which there were unaffected chondrocytes and cartilage but absolutely no formation of bone tissue[1]. Ablation of Sp7 genes also led to decreased expression of various other osteocyte-specific markers such as: Sost, Dkk1, Dmp1, and Phe[7]. The close relationship between Sp7/Osx and Runx2 was also demonstrated through this particular experiment because the Sp7 knockout bone phenotype greatly resembled that of the Runx2 knockout, and further experiments proved that Sp7 is downstream of and very closely associated with Runx2[13]. The important conclusion of this particular series of experiments was the clear regulatory role of Sp7 in the decision process made by mesenchymal stem cells to progress from their original highly Sox9 positive osteoprogenitors into either bone or cartilage. Without sustained Sp7 expression the progenitor cells take the pathway into becoming chondrocytes and eventually cartilage rather than creating ossified bone.

In adult organisms

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Outside of the context of development, in adult mice ablation of Sp7 led to a lack of new bone formation, highly irregular cartilage accumulation beneath the growth plate and defects in osteocyte maturation and functionality[14]. Other studies observed that a conditional knockout of Sp7 in adult mice osteoblasts resulted in osteopenia in the vertebrae of the animals, issues with bone turnover and more porosity in cortical outer surface of the long bones of the body[15]. Observation of an opposite effect, overproliferation of Sp7+ osteoblasts, further supports the important regulatory effects of Sp7 in vertebrates. A mutation in the zebrafish homologue of Sp7 caused severe craniofacial irregularities in maturing organisms while leaving the rest of the skeleton largely unaffected. Instead of normal suture patterning along the developing skull, the affected organisms displayed a mosaic of sites where bone formation was being initiated but not completed. This caused the appearance of many small irregular bones instead of the normal smooth frontal and parietal bones. These phenotypic shifts corresponded to an overproliferation of Runx2+ osteoblast progenitors indicating that the phenotype observed was related to an abundance of initiation sites for bone proliferation creating many psuedo-sutures[6].

Transcriptional Pathway

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There are two main pathways which cause in the induction of Sp7/Osx gene expression, indirectly or directly. Msx2 has the ability to directly induce Sp7. Whereas BMP2 indirectly induces Sp7 through either Dlx5 or Runx2. Once Sp7 expression is triggered it then induces the expression of a slew of mature osteoblast genes such as Col1a1, osteonectin, osteopontin and bone sialoprotein which are all necessary for productive osteoblasts during the creation of ossified bone.[16]

Negative regulation of this pathway comes in the form of p53, microRNAs and the TNF inflammatory pathway[4]. Disregulation of the TNF pathway blocking appropriate bone growth by osteoblasts is a partial cause of the abnormal degradation of bone seen in osteoporosis or rheumatoid arthritis[17].

Diagram detailing the positive regulatory transcriptional pathway between genes expressed early in development such as BMP2 and the eventual expression of bone-specific genes.

Mechanism of action

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The exact mechanisms of action for Sp7/Osterix are currently in contention. As a zinc-finger transcription factor, its relatively high homology with Sp1 seems to indicate that it might act in a similar fashion during gene regulatory processes. Previous studies done on Sp1 have shown that it utilizes the zinc-finger DNA binding domains in its structure to bind directly to a GC-rich region of the genome known as the GC box.[18] creating the downstream regulatory effects seen. There are a number of studies which support this mechanism as also applicable for Sp7[19][20], however other researchers were unable to replicate the GC box binding seen in Sp1 when looking at Sp7[21][22]. Another proposed mechanism of action is indirect gene regulation through the protein known as homeobox transcription factor Dlx5. This is plausible because Dlx5 has much higher affinity to AT-rich gene regulatory regions than Sp7 has been shown to have to the GC box[21] thus providing an alternate methodology through which regulation can occur.

Mass spectrometry and proteomics methods have shown that Sp7 also interacts with RNA helicase A[23] and is possibly negatively regulated by RIOX1[24] both of which provide evidence for regulatory mechanisms outside of the GC box paradigm.

Role in human health

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Osteogenesis imperfecta

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The most direct example of the role of Sp7 in human disease has been in recesssive osteogenesis imperfecta(OI), which is a type-I collagen related disease that causes a heterogeneous set of bone-related symptoms which can range from mild to very severe. Generally this disease is caused by mutations in Col1a1 or Col1a2 which are regulators of collagen growth. OI-causing mutations in these collagen genes are generally heritable in an autosomal-dominant fashion. However there has been a recent case of a patient with recessive OI with a documented frameshift mutation in Sp7/Osx as the etiological origin of the disease[9]. This patient displayed abnormal fracturing of the bones after relatively minor injuries and markedly delayed motor milestones, requiring assistance to stand at age 6 and was unable to walk at age 8 due to pronounced bowing of the arms and legs. This provides a direct link between the Sp7 gene and the OI disease phenotype.

Bowed bones of the legs as seen in an adult osteogenesis imperfecta patient.

Osteoporosis

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GWAS studies have shown associations between adult and juvenile bone mass density (BMD) and the Sp7 locus in humans. Though low BMD is a good indicator of susceptibility for osteoporosis in adults, the amount of information currently available from these studies does not allow for a direct correlation to be made between osteoporosis and Sp7[8]. Abnormal expression of inflammatory cytokines such as TNF-α is present in osteoporosis can have detrimental effects on the expression of Sp7[17].

Rheumatoid Arthritis

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Adiponectin is a protein hormone that has been shown to be upregulated in rheumatoid arthritis disease pathology, causing the release of inflammatory cytokines and enhancing the breakdown of the bone matrix. In primary human cell cultures Sp7 was shown to be inhibited by adiponectin thus contributing downregulation of the creation of ossified bone[25]. This data is further backed up by another study in which inflammatory cytokines such as TNF-α and IL-1β were shown to downregulate gene expression of Sp7 in mouse primary mesenchymal stem cells in culture[26]. These studies seem to indicate that an inflammatory environment is detrimental to the creation of ossified bone[17].

Bone fracture repair

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Accelerated bone fracture healing was found when researchers implanted Sp7 overexpressing bone marrow stroma cells at a site of bone fracture. It was found that the mechanism by which Sp7 expression accelerated bone healing was through triggering new bone formation by inducing neighboring cells to express genes characteristic of bone progenitors.[27] Along similar mechanistic lines as bone repair is the integration of dental implants into alveolar bone, since the insertion of these implants causes bone damage that must be healed before the implant is successfully integrated.[28] Researchers have shown that when bone marrow stromal cells are exposed to artificially elevated levels of Sp7/Osx, mice with dental implants were shown to have better outcomes through the promotion of healthy bone regeneration. [29]

Treatment of osteosarcomas

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Overall Sp7 expression is decreased in mouse and human osteosarcoma cell lines when compared to endogenous osteoblasts and this decrease in expression correlates with metastatic potential. Transfection of the SP7 gene into a mouse osteosarcoma cell line to create higher levels of expression reduced overall malignancy in-vitro and reduced tumor incidence, tumor volume, and lung metastasis when the cells were injected into mice. Sp7 expression was also found to decrease bone destruction by the sarcoma likely through supplementing the normal regulatory pathways controlling osteoblasts and osteocytes.[30]

References

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  1. ^ a b c Nakashima, Kazuhisa; Zhou, Xin; Kunkel, Gary; Zhang, Zhaoping; Deng, Jian Min; Behringer, Richard R.; de Crombrugghe, Benoit (2002-01-11). "The novel zinc finger-containing transcription factor osterix is required for osteoblast differentiation and bone formation". Cell. 108 (1): 17–29. ISSN 0092-8674. PMID 11792318.
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  13. ^ Matsubara, Takuma; Kida, Kumiko; Yamaguchi, Akira; Hata, Kenji; Ichida, Fumitaka; Meguro, Hiroko; Aburatani, Hiroyuki; Nishimura, Riko; Yoneda, Toshiyuki (2008-10-24). "BMP2 Regulates Osterix through Msx2 and Runx2 during Osteoblast Differentiation". Journal of Biological Chemistry. 283 (43): 29119–29125. doi:10.1074/jbc.M801774200. ISSN 0021-9258. PMC 2662012. PMID 18703512.{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link)
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  15. ^ Baek, Wook-Young; Lee, Min-A.; Jung, Ji Won; Kim, Shin-Yoon; Akiyama, Haruhiko; de Crombrugghe, Benoit; Kim, Jung-Eun (2009-6). "Positive regulation of adult bone formation by osteoblast-specific transcription factor osterix". Journal of Bone and Mineral Research: The Official Journal of the American Society for Bone and Mineral Research. 24 (6): 1055–1065. doi:10.1359/jbmr.081248. ISSN 1523-4681. PMC 4020416. PMID 19113927. {{cite journal}}: Check date values in: |date= (help)CS1 maint: PMC format (link)
  16. ^ Renn, Jörg; Winkler, Christoph (2014-02). "Osterix/Sp7 regulates biomineralization of otoliths and bone in medaka (Oryzias latipes)". Matrix Biology. 34: 193–204. doi:10.1016/j.matbio.2013.12.008. ISSN 0945-053X. {{cite journal}}: Check date values in: |date= (help)
  17. ^ a b c Gilbert, L. (2000-11-01). "Inhibition of Osteoblast Differentiation by Tumor Necrosis Factor-". Endocrinology. 141 (11): 3956–3964. doi:10.1210/en.141.11.3956. ISSN 0013-7227.
  18. ^ Kadonaga, James T.; Jones, Katherine A.; Tjian, Robert (1986-01). "Promoter-specific activation of RNA polymerase II transcription by Sp1". Trends in Biochemical Sciences. 11 (1): 20–23. doi:10.1016/0968-0004(86)90226-4. ISSN 0968-0004. {{cite journal}}: Check date values in: |date= (help)
  19. ^ Zhang, Chi; Tang, Wanjin; Li, Yang (2012-11-21). "Matrix Metalloproteinase 13 (MMP13) Is a Direct Target of Osteoblast-Specific Transcription Factor Osterix (Osx) in Osteoblasts". PLoS ONE. 7 (11): e50525. doi:10.1371/journal.pone.0050525. ISSN 1932-6203.{{cite journal}}: CS1 maint: unflagged free DOI (link)
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  21. ^ a b Hojo, Hironori; Ohba, Shinsuke; He, Xinjun; Lai, Lick Pui; McMahon, Andrew P. (2016-05). "Sp7/Osterix Is Restricted to Bone-Forming Vertebrates where It Acts as a Dlx Co-factor in Osteoblast Specification". Developmental Cell. 37 (3): 238–253. doi:10.1016/j.devcel.2016.04.002. ISSN 1534-5807. PMC 4964983. PMID 27134141. {{cite journal}}: Check date values in: |date= (help); no-break space character in |first4= at position 5 (help); no-break space character in |first5= at position 7 (help)CS1 maint: PMC format (link)
  22. ^ Hekmatnejad, Bahareh; Gauthier, Claude; St-Arnaud, René (2013-06-12). "Control ofFiat(factor inhibiting ATF4-mediated transcription) expression by Sp family transcription factors in osteoblasts". Journal of Cellular Biochemistry. 114 (8): 1863–1870. doi:10.1002/jcb.24528. ISSN 0730-2312.
  23. ^ "The transcriptional factor Osterix directly interacts with RNA helicase A". Biochemical and Biophysical Research Communications. 355 (2): 347–351. 2007-04-06. doi:10.1016/j.bbrc.2007.01.150. ISSN 0006-291X.
  24. ^ Sinha, Krishna M.; Yasuda, Hideyo; Coombes, Madelene M.; Dent, Sharon Y. R.; de Crombrugghe, Benoit (2010-01-06). "Regulation of the osteoblast-specific transcription factor Osterix by NO66, a Jumonji family histone demethylase". The EMBO journal. 29 (1): 68–79. doi:10.1038/emboj.2009.332. ISSN 1460-2075. PMC 2780536. PMID 19927124.{{cite journal}}: CS1 maint: PMC format (link)
  25. ^ Krumbholz, Grit; Junker, Susann; Meier, Florian M. P.; Rickert, Markus; Steinmeyer, Jürgen; Rehart, Stefan; Lange, Uwe; Frommer, Klaus W.; Schett, Georg (2017-5). "Response of human rheumatoid arthritis osteoblasts and osteoclasts to adiponectin". Clinical and Experimental Rheumatology. 35 (3): 406–414. ISSN 0392-856X. PMID 28079506. {{cite journal}}: Check date values in: |date= (help)
  26. ^ Lacey, D.C.; Simmons, P.J.; Graves, S.E.; Hamilton, J.A. (2009-06). "Proinflammatory cytokines inhibit osteogenic differentiation from stem cells: implications for bone repair during inflammation". Osteoarthritis and Cartilage. 17 (6): 735–742. doi:10.1016/j.joca.2008.11.011. ISSN 1063-4584. {{cite journal}}: Check date values in: |date= (help)
  27. ^ Tu Q, Valverde P, Li S, Zhang J, Yang P, Chen J (2007). "Osterix overexpression in mesenchymal stem cells stimulates healing of critical-sized defects in murine calvarial bone". Tissue Engineering. 13 (10): 2431–40. doi:10.1089/ten.2006.0406. PMC 2835465. PMID 17630878.
  28. ^ Tu Q, Valverde P, Chen J (2006). "Osterix enhances proliferation and osteogenic potential of bone marrow stromal cells". Biochemical and Biophysical Research Communications. 341 (4): 1257–65. doi:10.1016/j.bbrc.2006.01.092. PMC 2831616. PMID 16466699.
  29. ^ Xu B, Zhang J, Brewer E, Tu Q, Yu L, Tang J, Krebsbach P, Wieland M, Chen J (2009). "Osterix enhances BMSC-associated osseointegration of implants". Journal of Dental Research. 88 (11): 1003–7. doi:10.1177/0022034509346928. PMC 2831612. PMID 19828887.
  30. ^ Cao Y, Zhou Z, de Crombrugghe B, Nakashima K, Guan H, Duan X, Jia SF, Kleinerman ES (2005). "Osterix, a transcription factor for osteoblast differentiation, mediates antitumor activity in murine osteosarcoma". Cancer Research. 65 (4): 1124–8. doi:10.1158/0008-5472.CAN-04-2128. PMID 15734992.
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