Sp7 transcription factor
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Transcription factor Sp7, also called Osterix (Osx), is a
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...
that in humans is encoded by the ''SP7''
gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
. It is a member of the Sp family of zinc-finger transcription factors It is highly conserved among bone-forming vertebrate species It plays a major role, along with
Runx2 Runt-related transcription factor 2 (RUNX2) also known as core-binding factor subunit alpha-1 (CBF-alpha-1) is a protein that in humans is encoded by the ''RUNX2'' gene. RUNX2 is a key transcription factor associated with osteoblast differentia ...
and ''Dlx5'' in driving the differentiation of mesenchymal precursor cells into
osteoblast Osteoblasts (from the Greek combining forms for " bone", ὀστέο-, ''osteo-'' and βλαστάνω, ''blastanō'' "germinate") are cells with a single nucleus that synthesize bone. However, in the process of bone formation, osteoblasts fu ...
s and eventually
osteocyte An osteocyte, an oblate-shaped type of bone cell with dendritic processes, is the most commonly found cell in mature bone. It can live as long as the organism itself. The adult human body has about 42 billion of them. Osteocytes do not divide an ...
s. Sp7 also plays a regulatory role by inhibiting
chondrocyte Chondrocytes (, ) are the only cells found in healthy cartilage. They produce and maintain the cartilaginous matrix, which consists mainly of collagen and proteoglycans. Although the word '' chondroblast'' is commonly used to describe an immatu ...
differentiation maintaining the balance between differentiation of mesenchymal precursor cells into ossified bone or cartilage. Mutations of this gene have been associated with multiple dysfunctional bone phenotypes in vertebrates. During development, a mouse embryo model with Sp7 expression knocked out had no formation of bone tissue. Through the use of GWAS studies, the Sp7 locus in humans has been strongly associated with bone mass density. In addition there is significant genetic evidence for its role in diseases such as
Osteogenesis imperfecta Osteogenesis imperfecta (; OI), colloquially known as brittle bone disease, is a group of genetic disorders that all result in bones that bone fracture, break easily. The range of symptoms—on the skeleton as well as on the body's other Or ...
(OI).


Genetics

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 finger A zinc finger is a small protein structural motif that is characterized by the coordination of one or more zinc ions (Zn2+) which stabilizes the fold. The term ''zinc finger'' was originally coined to describe the finger-like appearance of a ...
s. 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 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 In genetics and bioinformatics, a single-nucleotide polymorphism (SNP ; plural SNPs ) is a germline substitution of a single nucleotide at a specific position in the genome. Although certain definitions require the substitution to be present in ...
within the 12q13 region were in an area of linkage disequilibrium.


Transcriptional pathway

There are two main pathways which cause in the induction of Sp7/Osx gene expression.
Msx2 MSX is a standardized home computer architecture, announced by ASCII Corporation on June 16, 1983. It was initially conceived by Microsoft as a product for the Eastern sector, and jointly marketed by Kazuhiko Nishi, the director at ASCII Cor ...
induces Sp7 directly, whereas
bone morphogenetic protein 2 Bone morphogenetic protein 2 or BMP-2 belongs to the TGF-β superfamily of proteins. Function BMP-2 like other bone morphogenetic proteins, plays an important role in the development of bone and cartilage. It is involved in the hedgehog path ...
(BMP2) induces it indirectly through either
Dlx5 Homeobox protein DLX-5 is a protein that in humans is encoded by the distal-less homeobox 5 gene, or ''DLX5'' gene. DLX5 is a member of the DLX gene family. Function This gene encodes a member of a homeobox transcription factor gene family si ...
or
Runx2 Runt-related transcription factor 2 (RUNX2) also known as core-binding factor subunit alpha-1 (CBF-alpha-1) is a protein that in humans is encoded by the ''RUNX2'' gene. RUNX2 is a key transcription factor associated with osteoblast differentia ...
. Once Sp7 expression is triggered, it then induces the expression of a slew of mature osteoblast genes such as
Col1a1 Collagen, type I, alpha 1, also known as alpha-1 type I collagen, is a protein that in humans is encoded by the gene. ''COL1A1'' encodes the major component of type I collagen, the fibrillar collagen found in most connective tissues, including ...
,
osteonectin Osteonectin (ON) also known as secreted protein acidic and rich in cysteine (SPARC) or basement-membrane protein 40 (BM-40) is a protein that in humans is encoded by the ''SPARC'' gene. Osteonectin is a glycoprotein in the bone that binds calci ...
,
osteopontin Osteopontin (OPN), also known as bone /sialoprotein I (BSP-1 or BNSP), early T-lymphocyte activation (ETA-1), secreted phosphoprotein 1 (SPP1), 2ar and Rickettsia resistance (Ric), is a protein that in humans is encoded by the ''SPP1'' gene (sec ...
and
bone sialoprotein Bone sialoprotein (BSP) is a component of mineralized tissues such as bone, dentin, cementum and calcified cartilage. BSP is a significant component of the bone extracellular matrix and has been suggested to constitute approximately 8% of all ...
which are all necessary for productive osteoblasts during the creation of ossified bone. Negative regulation of this pathway comes in the form of
p53 p53, also known as tumor protein p53, cellular tumor antigen p53 (UniProt name), or transformation-related protein 53 (TRP53) is a regulatory transcription factor protein that is often mutated in human cancers. The p53 proteins (originally thou ...
,
microRNA Micro ribonucleic acid (microRNA, miRNA, μRNA) are small, single-stranded, non-coding RNA molecules containing 21–23 nucleotides. Found in plants, animals, and even some viruses, miRNAs are involved in RNA silencing and post-transcr ...
s and the TNF inflammatory pathway. 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


Mechanism of action

The exact mechanisms of action for Sp7/Osterix are currently in contention and the full protein structure has yet to be solved. 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 Sp1 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 In molecular biology, a GC box, also known as a GSG box, is a distinct pattern of nucleotides found in the promoter region of some eukaryotic genes. The GC box is upstream of the TATA box, and approximately 110 bases upstream from the transcription ...
. creating downstream regulatory effects. There are a number of studies which support this mechanism as also applicable for Sp7, however other researchers were unable to replicate the GC box binding seen in Sp1 when looking at Sp7. Another proposed mechanism of action is indirect gene regulation through the protein known as homeobox transcription factor
Dlx5 Homeobox protein DLX-5 is a protein that in humans is encoded by the distal-less homeobox 5 gene, or ''DLX5'' gene. DLX5 is a member of the DLX gene family. Function This gene encodes a member of a homeobox transcription factor gene family si ...
. 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 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 and is possibly negatively regulated by RIOX1 both of which provide evidence for regulatory mechanisms outside of the GC box paradigm.


Function

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


During development

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 cell Mesenchymal stem cells (MSCs), also known as mesenchymal stromal cells or medicinal signaling cells, are multipotent stromal cells that can Cellular differentiation, differentiate into a variety of cell types, including osteoblasts (bone cells), ...
s 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. Sp7/Osx null mouse embryos displayed a severe phenotype in which there were unaffected chondrocytes and cartilage but absolutely no formation of bone tissue. Ablation of Sp7 genes also led to decreased expression of various other osteocyte-specific markers such as: Sost,
Dkk1 Dickkopf-related protein 1 is a protein that in humans is encoded by the ''DKK1'' gene. Function This gene encodes a protein that is a member of the dickkopf family. It is a secreted protein with two cysteine rich regions and is involved in ...
, Dmp1, and Phe. 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. 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 Transcription factor SOX-9 is a protein that in humans is encoded by the ''SOX9'' gene. Function SOX-9 recognizes the sequence CCTTGAG along with other members of the HMG-box class DNA-binding domain, DNA-binding proteins. It is expressed by ...
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

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. Other studies observed that a conditional knockout of Sp7 in adult mice osteoblasts resulted in
osteopenia Osteopenia, known as "low bone mass" or "low bone density", is a condition in which bone mineral density is low. Because their bones are weaker, people with osteopenia may have a higher risk of fractures, and some people may go on to develop o ...
in the vertebrae of the animals, issues with bone turnover and more porosity in cortical outer surface of the long bones of the body. 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 pseudo- sutures.


Clinical relevance


Osteogenesis imperfecta

The most direct example of the role of Sp7 in human disease has been in recessive
osteogenesis imperfecta Osteogenesis imperfecta (; OI), colloquially known as brittle bone disease, is a group of genetic disorders that all result in bones that bone fracture, break easily. The range of symptoms—on the skeleton as well as on the body's other Or ...
(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 Collagen, type I, alpha 1, also known as alpha-1 type I collagen, is a protein that in humans is encoded by the gene. ''COL1A1'' encodes the major component of type I collagen, the fibrillar collagen found in most connective tissues, including ...
or
Col1a2 Collagen alpha-2(I) chain is a protein that in humans is encoded by the ''COL1A2'' gene. This gene encodes one of the chains for type I collagen, the fibrillar collagen found in most connective tissues. Mutations in this gene are associated with ...
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. 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.


Osteoporosis

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. Abnormal expression of inflammatory cytokines such as
TNF-α Tumor necrosis factor (TNF), formerly known as TNF-α, is a chemical messenger produced by the immune system that induces inflammation. TNF is produced primarily by activated macrophages, and induces inflammation by binding to its receptors o ...
is present in osteoporosis can have detrimental effects on the expression of Sp7.


Rheumatoid Arthritis

Adiponectin Adiponectin (also referred to as GBP-28, apM1, AdipoQ and Acrp30) is a protein hormone and adipokine, which is involved in regulating glucose levels and fatty acid breakdown. In humans, it is encoded by the ''ADIPOQ'' gene and is produced prima ...
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. This data is further backed up by another study in which inflammatory cytokines such as
TNF-α Tumor necrosis factor (TNF), formerly known as TNF-α, is a chemical messenger produced by the immune system that induces inflammation. TNF is produced primarily by activated macrophages, and induces inflammation by binding to its receptors o ...
and
IL-1β Interleukin-1 beta (IL-1β) also known as leukocytic pyrogen, leukocytic endogenous mediator, mononuclear cell factor, lymphocyte activating factor and other names, is a cytokine protein that in humans is encoded by the ''IL1B'' gene."Catabolin" ...
were shown to downregulate gene expression of Sp7 in mouse primary mesenchymal stem cells in culture. These studies seem to indicate that an inflammatory environment is detrimental to the creation of ossified bone.


Bone fracture repair

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. Along similar mechanistic lines as bone repair is the integration of dental implants into
alveolar bone The alveolar process () is the portion of bone containing the tooth sockets on the jaw bones (in humans, the maxilla and the mandible). The alveolar process is covered by gums within the mouth, terminating roughly along the line of the mandibu ...
, since the insertion of these implants causes bone damage that must be healed before the implant is successfully integrated. 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.


Treatment of osteosarcomas

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.


References


Further reading

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External links

* {{Transcription factors, g2 Transcription factors