Sp7 transcription factor

Last updated
SP7
Identifiers
Aliases SP7 , OI11, OI12, OSX, osterix, Sp7 transcription factor
External IDs OMIM: 606633 MGI: 2153568 HomoloGene: 15607 GeneCards: SP7
Orthologs
SpeciesHumanMouse
Entrez

121340

170574

Ensembl

ENSG00000170374

ENSMUSG00000060284

UniProt

Q8TDD2

Q8VI67

RefSeq (mRNA)

NM_001173467
NM_001300837
NM_152860

NM_130458
NM_001348205

RefSeq (protein)

NP_001287766.1
NP_001166938
NP_001287766
NP_690599

NP_569725
NP_001335134

Location (UCSC) Chr 12: 53.33 – 53.35 Mb Chr 15: 102.27 – 102.28 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Transcription factor Sp7, also called osterix (Osx), is a protein that in humans is encoded by the SP7 gene. [5] It is a member of the Sp family of zinc-finger transcription factors [5] It is highly conserved among bone-forming vertebrate species [6] [7] It plays a major role, along with Runx2 and Dlx5 in driving the differentiation of mesenchymal precursor cells into osteoblasts and eventually osteocytes. [8] Sp7 also plays a regulatory role by inhibiting chondrocyte differentiation maintaining the balance between differentiation of mesenchymal precursor cells into ossified bone or cartilage. [9] 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. [5] Through the use of GWAS studies, the Sp7 locus in humans has been strongly associated with bone mass density. [10] In addition there is significant genetic evidence for its role in diseases such as Osteogenesis imperfecta (OI). [11]

Contents

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 fingers. [12] 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 [13]

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 disequilibrium. [10]

Transcriptional pathway

There are two main pathways which cause in the induction of Sp7/Osx gene expression. Msx2 induces Sp7 directly, whereas bone morphogenetic protein 2 (BMP2) induces it indirectly through either Dlx5 or Runx2. [8] 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. [6]

Negative regulation of this pathway comes in the form of p53, microRNAs and the TNF inflammatory pathway. [8] 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 [14]

Diagram detailing the positive regulatory transcriptional pathway between genes expressed early in development such as BMP2 and the eventual expression of bone-specific genes. Regulatory pathway for Sp7-Osx.png
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

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. [15] creating downstream regulatory effects. There are a number of studies which support this mechanism as also applicable for Sp7, [16] however other researchers were unable to replicate the GC box binding seen in Sp1 when looking at Sp7. [17] [18] 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 [17] 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

Diagram detailing the role of Sp7 in the differentiation pathway of osteoblasts and the decision pathway between cartilage and ossified bone Sp7diagram2.png
Diagram detailing the role of Sp7 in the differentiation pathway of osteoblasts and the decision pathway between cartilage and ossified bone
Zebrafish skull, 34 days post-fertilication, imaged using a calcein stain showing normal frontal and parietal bones. Overlayed using fuchsia are irregular initiation sites of bone formation seen in an Sp7 mutant fish indicating abnormal pseudo-sutures. Frontal Parietal Cranial Bone Sp7 mutant.png
Zebrafish skull, 34 days post-fertilication, imaged using a calcein stain showing normal frontal and parietal bones. Overlayed using fuchsia are irregular initiation sites of bone formation seen in an Sp7 mutant fish indicating abnormal pseudo-sutures.

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. [20]

Sp7/Osx null mouse embryos displayed a severe phenotype in which there were unaffected chondrocytes and cartilage but absolutely no formation of bone tissue. [5] Ablation of Sp7 genes also led to decreased expression of various other osteocyte-specific markers such as: Sost, Dkk1, Dmp1, and Phe. [21] 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. [8] 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

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. [21] 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. [22] 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. [19]

Clinical relevance

Osteogenesis imperfecta

The most direct example of the role of Sp7 in human disease has been in recessive 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. [11] 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 arms as seen in an adult osteogenesis imperfecta patient. Osteogenesis Imperfecta Type V.jpg
Bowed bones of the arms as seen in an adult osteogenesis imperfecta patient.

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. [10] Abnormal expression of inflammatory cytokines such as TNF-α is present in osteoporosis can have detrimental effects on the expression of Sp7. [14]

Rheumatoid Arthritis

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. [23] 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. [24] These studies seem to indicate that an inflammatory environment is detrimental to the creation of ossified bone. [14]

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. [25] 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. [26] 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. [27]

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. [28]

Related Research Articles

<span class="mw-page-title-main">Osteoblast</span> Cells secreting extracellular matrix

Osteoblasts are cells with a single nucleus that synthesize bone. However, in the process of bone formation, osteoblasts function in groups of connected cells. Individual cells cannot make bone. A group of organized osteoblasts together with the bone made by a unit of cells is usually called the osteon.

<span class="mw-page-title-main">Adenosine receptor</span> Class of four receptor proteins to the molecule adenosine

The adenosine receptors (or P1 receptors) are a class of purinergic G protein-coupled receptors with adenosine as the endogenous ligand. There are four known types of adenosine receptors in humans: A1, A2A, A2B and A3; each is encoded by a different gene.

<span class="mw-page-title-main">Chondrocyte</span> Cell that makes up cartilage

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 immature chondrocyte, the term is imprecise, since the progenitor of chondrocytes can differentiate into various cell types, including osteoblasts.

<span class="mw-page-title-main">Neural crest</span> Pluripotent embyronic cell group giving rise to diverse cell lineages

Neural crest cells are a temporary group of cells that arise from the embryonic ectoderm germ layer, and in turn give rise to a diverse cell lineage—including melanocytes, craniofacial cartilage and bone, smooth muscle, peripheral and enteric neurons and glia.

<span class="mw-page-title-main">Osteochondroma</span> Medical condition

Osteochondromas are the most common benign tumors of the bones. The tumors take the form of cartilage-capped bony projections or outgrowth on the surface of bones exostoses. It is characterized as a type of overgrowth that can occur in any bone where cartilage forms bone. Tumors most commonly affect long bones about the knee and in the forearm. Additionally, flat bones such as the pelvis and scapula may be affected. Hereditary multiple exostoses usually present during childhood. Yet, the vast majority of affected individuals become clinically manifest by the time they reach adolescence. Osteochondromas occur in 3% of the general population and represent 35% of all benign tumors and 8% of all bone tumors. The majority of these tumors are solitary non-hereditary lesions and approximately 15% of osteochondromas occur as hereditary multiple exostoses preferably known as hereditary multiple osteochondromas (HMOs). Osteochondromas do not result from injury and the exact cause remains unknown. Recent research has indicated that multiple osteochondromas is an autosomal dominant inherited disease. Germ line mutations in EXT1 and EXT2 genes located on chromosomes 8 and 11 have been associated with the cause of the disease. The treatment choice for osteochondroma is surgical removal of solitary lesion or partial excision of the outgrowth, when symptoms cause motion limitations or nerve and blood vessel impingements. In hereditary multiple exostoses the indications of surgery are based upon multiple factors that are taken collectively, namely: patient's age, tumor location and number, accompanying symptomatology, esthetic concerns, family history and underlying gene mutation. A variety of surgical procedures have been employed to remedy hereditary multiple exostoses such as osteochondroma excision, bone lengthening, corrective osteotomy and hemiepiphysiodesis. Sometimes a combination of the previous procedures is used. The indicators of surgical success in regard to disease and patient characteristics are greatly disputable. Because most studies of hereditary multiple exostoses are retrospective and of limited sample size with missing data, the best evidence for each of the currently practiced surgical procedures is lacking.

<span class="mw-page-title-main">Chondroblast</span> Mesenchymal progenitor cell that forms a chondrocyte

Chondroblasts, or perichondrial cells, is the name given to mesenchymal progenitor cells in situ which, from endochondral ossification, will form chondrocytes in the growing cartilage matrix. Another name for them is subchondral cortico-spongious progenitors. They have euchromatic nuclei and stain by basic dyes.

<span class="mw-page-title-main">Chondrogenesis</span> Process by which cartilage is developed

Chondrogenesis is the process by which cartilage is developed.

<span class="mw-page-title-main">RUNX2</span> Protein-coding gene in humans

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 differentiation.

<span class="mw-page-title-main">Bone sialoprotein</span> Protein-coding gene in the species Homo sapiens

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 non-collagenous proteins found in bone and cementum. BSP, a SIBLING protein, was originally isolated from bovine cortical bone as a 23-kDa glycopeptide with high sialic acid content.

mir-133 microRNA precursor family

mir-133 is a type of non-coding RNA called a microRNA that was first experimentally characterised in mice. Homologues have since been discovered in several other species including invertebrates such as the fruitfly Drosophila melanogaster. Each species often encodes multiple microRNAs with identical or similar mature sequence. For example, in the human genome there are three known miR-133 genes: miR-133a-1, miR-133a-2 and miR-133b found on chromosomes 18, 20 and 6 respectively. The mature sequence is excised from the 3' arm of the hairpin. miR-133 is expressed in muscle tissue and appears to repress the expression of non-muscle genes.

<span class="mw-page-title-main">CYR61</span> Protein-coding gene in the species Homo sapiens

Cysteine-rich angiogenic inducer 61 (CYR61) or CCN family member 1 (CCN1), is a matricellular protein that in humans is encoded by the CYR61 gene.

<span class="mw-page-title-main">KLF4</span> Protein-coding gene in the species Homo sapiens

Kruppel-like factor 4 is a member of the KLF family of zinc finger transcription factors, which belongs to the relatively large family of SP1-like transcription factors. KLF4 is involved in the regulation of proliferation, differentiation, apoptosis and somatic cell reprogramming. Evidence also suggests that KLF4 is a tumor suppressor in certain cancers, including colorectal cancer. It has three C2H2-zinc fingers at its carboxyl terminus that are closely related to another KLF, KLF2. It has two nuclear localization sequences that signals it to localize to the nucleus. In embryonic stem cells (ESCs), KLF4 has been demonstrated to be a good indicator of stem-like capacity. It is suggested that the same is true in mesenchymal stem cells (MSCs).

<span class="mw-page-title-main">Msh homeobox 2</span> Protein-coding gene in the species Homo sapiens

Homeobox protein MSX-2 is a protein that in humans is encoded by the MSX2 gene.

<span class="mw-page-title-main">DLX5</span> Mammalian protein found in Homo sapiens

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 DLX gene family.

<span class="mw-page-title-main">Matrilin-3</span> Protein-coding gene in the species Homo sapiens

Matrilin-3 is a protein that in humans is encoded by the MATN3 gene. It is linked to the development of many types of cartilage, and part of the Matrilin family, which includes Matrilin-1, Matrilin-2, Matrilin-3, and Matrilin-4, a family of filamentous-forming adapter oligomeric extracellular proteins that are linked to the formation of cartilage and bone, as well as maintaining homeostasis after development. It is considered an extracellular matrix protein that functions as an adapter protein where the Matrilin-3 subunit can form both homo-tetramers and hetero-oligomers with subunits from Matrilin-1 which is the cartilage matrix protein. This restricted tissue has been strongly expressed in growing skeletal tissue as well as cartilage and bone.

<span class="mw-page-title-main">PRRX1</span> Protein-coding gene in the species Homo sapiens

Paired related homeobox 1 is a protein that in humans is encoded by the PRRX1 gene.

<span class="mw-page-title-main">HAND2</span> Protein-coding gene in the species Homo sapiens

Heart- and neural crest derivatives-expressed protein 2 is a protein that in humans is encoded by the HAND2 gene.

<span class="mw-page-title-main">Adipogenesis</span>

Adipogenesis is the formation of adipocytes from stem cells. It involves 2 phases, determination, and terminal differentiation. Determination is mesenchymal stem cells committing to the adipocyte precursor cells, also known as preadipocytes which lose the potential to differentiate to other types of cells such as chondrocytes, myocytes, and osteoblasts. Terminal differentiation is that preadipocytes differentiate into mature adipocytes. Adipocytes can arise either from preadipocytes resident in adipose tissue, or from bone-marrow derived progenitor cells that migrate to adipose tissue.

<span class="mw-page-title-main">Osteochondroprogenitor cell</span>

Osteochondroprogenitor cells are progenitor cells that arise from mesenchymal stem cells (MSC) in the bone marrow. They have the ability to differentiate into osteoblasts or chondrocytes depending on the signalling molecules they are exposed to, giving rise to either bone or cartilage respectively. Osteochondroprogenitor cells are important for bone formation and maintenance.

miR-214

miR-214 is a vertebrate-specific family of microRNA precursors. The ~22 nucleotide mature miRNA sequence is excised from the precursor hairpin by the enzyme Dicer. This sequence then associates with RISC which effects RNA interference.

References

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  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000060284 - Ensembl, May 2017
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  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
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  13. ↑ Milona MA, Gough JE, Edgar AJ (November 2003). "Expression of alternatively spliced isoforms of human Sp7 in osteoblast-like cells". BMC Genomics. 4 (1): 43. doi: 10.1186/1471-2164-4-43 . PMC   280673 . PMID   14604442.
  14. 1 2 3 Gilbert L, He X, Farmer P, Boden S, Kozlowski M, Rubin J, Nanes MS (November 2000). "Inhibition of osteoblast differentiation by tumor necrosis factor-alpha". Endocrinology. 141 (11): 3956–64. doi: 10.1210/endo.141.11.7739 . PMID   11089525.
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  19. 1 2 Kague E, Roy P, Asselin G, Hu G, Simonet J, Stanley A, Albertson C, Fisher S (May 2016). "Osterix/Sp7 limits cranial bone initiation sites and is required for formation of sutures". Developmental Biology. 413 (2): 160–72. doi:10.1016/j.ydbio.2016.03.011. PMC   5469377 . PMID   26992365.
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  27. ↑ Xu B, Zhang J, Brewer E, Tu Q, Yu L, Tang J, et al. (November 2009). "Osterix enhances BMSC-associated osseointegration of implants". Journal of Dental Research. 88 (11): 1003–7. doi:10.1177/0022034509346928. PMC   2831612 . PMID   19828887.
  28. ↑ Cao Y, Zhou Z, de Crombrugghe B, Nakashima K, Guan H, Duan X, et al. (February 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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