I am going to list and try to draw the effects each gene or protein has on other genes and proteins. The purpose of this post is to allow for me and maybe the readers to get more general broad view of how each of the proteins and hormones involved in the growth process interact with each other. This will help us figure out which hormones are more significant than others.
If you think I forgot something don’t hesitate to inform me since I am going to need all the help I need to fill out this massive biochemical project. I was not trained to be a biochemist.
Note 1: No more posts will be written until this post, the Endocrinology section, and the Orthopaedics section are all described in as much detail as possible.
Note 2: This post is going to take at least 3 weeks to completely fill out. Much of the information was taken from HeightQuest post HERE.
Terminology:
The reason I am using this is to make my life easier, but maybe not the readers. If any of you have ever read a paper on set theory or just another language with unfamiliar symbols in general, like hieroglyphics, then you realize that understanding the notations and syntax rules help you understand what the symbols represent.
+ means two or more elements are needed to form something else
= means it is the same (or goes by another name) as the next product
[…] is a symbol notation taken from elementary mathematics to state that whatever is in the square brackets takes precedent in importance
(=) means it binds to the next compound, like a receptor to a ligand
=> means it turns into
(=)> means it helps or assists in the process with some other element/s
(+)> means it promotes the functions and effects of the next product or phenomena
+> means it increases the presence and existence of the next product by increasing its numbers
(-)> means it inhibits the functions and effects of the next product or phenomena
-> means it decreases the presence and existence of the next product by reducing its numbers
Source 1, Source 2, Source 3, (4), (5), (6), (7) (8), (9), (10), (11), (12), (13), (14),(15)
Osteoclasts are multinuclear cells derived from hematopoietic stem cells (1): Hematopoietic stem cells => Osteoclasts
Receptor activator of NF-κB ligand (RANKL; also called tumor necrosis factor-related activation-induced cytokine (TRANCE), osteoprotegerin ligand (OPGL) or osteoclast differentiation factor (ODF)) (1) : RANKL = TRANCE = OPGL = ODF (I am going to call this RANKL for short)
Thus a promyeloid precursor can differentiate into either an osteoclast, a macrophage or a dendritic cell, depending on whether it is exposed to receptor activator of NF-κB ligand (RANKL; also called tumor necrosis factor-related activation-induced cytokine (TRANCE), osteoprotegerin ligand (OPGL) or osteoclast differentiation factor (ODF)) macrophage colony-stimulating factor (M-CSF) or granulocyte-macrophage colony-stimulating factor (GM- CSF), respectively (1):
- Promyeloid precursor + RANKL => Osteoclast
- Promyeloid precursor + M-CSF => Macrophage
- Promyeloid precursor + GM-CSF => Dendritic cell
Simonet et al. (1997) found that several cells and tissues produce a soluble factor, osteoprotegerin (OPG), that strongly inhibits osteoclast formation in vitro and in vivo. (1) : Osteoprotegerin (OPG) –> Osteoclast formation
The inhibitory effect of OPG on the osteoclast differentiation is due to the fact that it can prevent the binding of RANKL to its receptor, RANK (Hsu et al., 1999) (1);
OPG (-)> [RANKL (=) RANK] (this translates to OPG inhibits the ability of RANKL to bind with RANK)
The molecular mechanism that prevents chondrocyte hypertrophy is distinct from that which drives proliferation. (3)
Chondrocytes arise out of mesenchymal condensations and establish the skeletal element (3)
Vertebrate long bones form through a process called endochondral ossification in which a cartilage template is replaced by a bony matrix. As the element grows, cells in the center become hypertrophic, transitioning from a mitotically active, type II collagen (Col II)-expressing state to a postmitotic, type X collagen (Col X)- expressing state (3)
Continued elongation of the element requires the establishment of a growth plate, where the stage of maturation is correlated with the distance from the articular surface (3)
An important determinant of the growth rate is the total number of proliferating chondrocytes (Hunziker, 1988), which depends on the size of the mitotically active pool of cells and the rate at which these cells proliferate. (3)
Correct morphogenesis requires integration of proliferation and hypertrophy over the entire element and, for the long bones, this includes defining the long axis of the element along which growth is directed. Understanding growth and morphogenesis of the long bones, therefore, requires elucidation of the mechanisms that (1) maintain a domain of mitotically active chondrocytes, in part through the regulation of chondrocyte maturation, (2) control the rate of proliferation of these cells, (3) drive growth primarily along the long axis of the element, and (4) ossify the element (3)
Null mutations in PTHrP (PTHrP−/−) result in decreased numbers of mitotically active chondrocytes (Karaplis et al., 1996), whereas overexpression of PTHrP increases this pool (Weir et al., 1996), establishing a role for PTHrP in determining the size of the population of proliferating chondrocytes. (3) !!! (Proof that PTHrP increase will increase in overall growth rate for extremely young kids)
Activation of hedgehog signaling can increase the pool of proliferating cells, but this effect requires intact PTHrP signaling (Vortkamp et al., 1996; Lanske et al., 1996). Combined with the ability of Ihh to upregulate PTHrP, this work suggested a model in which Ihh upregulates PTHrP to delay chondrocyte hypertrophy. (3)
These are all the results for source 3 linking the effect of ihh to PTHrP…
- Long bone development in Ihh−/−; PTHrP−/− double mutants is identical to Ihh−/− mice but distinct from PTHrP−/− mice
- Activation of PTHrP signalling has no effect on chondrocyte proliferation or limb size but rescues chondrocyte hypertrophy in Ihh−/− mice
- PTHrP signaling is sufficient to maintain a population of mitotically active chondrocytes in Ihh−/−
- PTHrP signaling does not affect the chondrocyte proliferation rate in Ihh−/− mice
- PTHrP−/− mice display decreased proliferation rates
- Ihh−/− limbs display isotropic growth, in contrast to PTHrP−/− or wild-type limbs
- Ihh is necessary for PTHrP function
- Ihh drives chondrocyte proliferation in a largely PTHrP-independent pathway
- hh is necessary to establish growth primarily along the long axis of the bone
- Ihh coordinates endochondral bone development
From previous post entitled “Increase Height And Grow Taller Using Bone Morphogenetic Proteins, BMPs (Guest Post)“…
- BMP are also known as (aka) CDMPs (Cartilage Derived Morphogenetic Proteins) and GDFs (Growth Differentiation Factors).
- They are associated with BMPRs (BMP receptors). There are two types of BMPRs, Type I and Type II…
- There is at least 20 members in the BMP family/group
- Function: 1. Stimulators of bone formation & 2. Important regulators of growth, differentiation, and morphogenesis.
- BMP-2, -4, and -7 are found in the perchondrium
- BMP-6 is found in the prehypertrophic & hypertrophic chondrocytes. Function: May meditate the ihh & PTHrP growth restraining feedback loop. Also has an autocrine/paracrine role in prehypertrophic chondrocytes.
- Type I of BMPRs is BMPRI. There are two types of BMPRI, type A and type B…
- BMPRI – differentially localized in embryonic limbs
- Type A of BMPRI is BMPRIA – confined to pre-hypertrophic chondrocytes. – Function: controls the pace of chondrocyte differentiation. Critical for chondrocyte hypertrophy.
- Type B of BMPRI is BMPRIB – detected in early mesenchymal condensations. Function: is involved in early cartilage formation and cell death (apoptosis). A targeted disruption of BMPRIB show defects in proliferation of prechondrogenic cells and chondrocyte differentiation in the phalangeal region
- GDF5 is a ligand for BMPRIB.
- Type II of BMPRs is BMPRII – BMPRI heterodimerize with the BMPRII
- GDF-5 and BMP-5 are important mediators of chondrocyte differentiation in mesenchymal condensation at various sites.
- Normal chondrocyte proliferation requires parallel signaling of both Ihh and BMPs and that BMPs are capable of inhibiting chondrocyte differentiation independently of the Ihh/PTHrP pathway.
- Smad1, 5 and 8 are the immediate downstream molecules of BMP receptors and play a central role in BMP signal transduction
- BMPs signal through serine/threonine kinase receptors, composed of type I and II subtypes.
- 1. BMPR-IA is ALK-3
- 2. BMPR-IB is ALK-6
- 3. BMPR type IA is the activin receptor
- The BMP7 type I receptor ALK2 can activate the Smad1 signaling pathways.
- Three type II receptors for BMPs have also been identified and they are type II BMP receptor (BMPR-II) and type II and IIB activin receptors.
1. Transforming Growth Factor Beta (TGF-β)
Function: TGF betas are involved in embryogenesis and cell differentiation and in apoptosis. Causes the transcription of mRNAs involved in apoptosis, extracellular matrix neogenesis and immunosuppression. It is also involved in G1 arrest in the cell cycle. They bind to TGF-beta receptor type-2 (TGFBR2)
TGFβ1 –
TGFβ2 –
TGFβ3 –
2. Bone Morphogenetic Protein (BMP)
Causes:
Function: bind to the bone morphogenetic protein receptor type-2 (BMPR2). They are involved in a multitude of cellular functions including osteogenesis, cell differentiation, anterior/posterior axis specification, growth, and homeostasis. BMP signaling plays critical roles in heart, neural and cartilage development.
Effects: BMPs signal through serine/threonine kinase receptors, composed of type I and II subtypes.
Bone Morphogenetic Protein 2 (BMP-2)
Gene: BMP2 gene
Group: TGF-β superfamily of proteins
Causes:
Function:Is involved in the hedgehog pathway, TGF beta signaling pathway, and in cytokine-cytokine receptor interaction. It is involved also in cardiac cell differentiation and epithelial to mesenchymal transition. Has been shown to interact with BMPR1A
Effects:
- Have been demonstrated to potently induce osteoblast differentiation in a variety of cell types.
- Shown to stimulate the production of bone
- Implantation of BMP-2 in a collagen sponge induces new bone formation and can be used for the treatment of bony defects, delayed union, and non-union
- BMP-2 can be utilized in various therapeutic interventions such as bone defects, non-union fractures, spinal fusion, osteoporosis and root canal surgery.
Bone Morphogenetic Protein 4 (BMP-4)
Gene: BMP4 gene
Group: a member of the bone morphogenetic protein family which is part of the transforming growth factor-beta superfamily
Causes: BMP4 is secreted from the dorsal portion of the notochord, and it acts in concert with sonic hedgehog (released from the ventral portion of the notochord) to establish a dorsal-ventral axis for the differentiation of later structures
Function: Plays an important role in the onset of endochondral bone formation in humans. It has been shown to be involved in muscle development, bone mineralization, and ureteric bud development. In human embryonic development, BMP4 is a critical signaling molecule required for the early differentiation of the embryo and establishing of a dorsal-ventral axis.
Effects: Inhibition of the BMP4 signal (by chorine, noggin, or follistatin) causes the ectoderm to differentiate into the neural plate. If these cells also receive signals from FGF, they will differentiate into the spinal cord; in the absence of FGF the cells become brain tissue
Pathologies: Increase in expression of BMP4 has been associated with a variety of bone diseases, including the heritable disorder Fibrodysplasia Ossificans Progressiva. There is strong evidence from sequencing studies of candidate genes involved in clefting that mutations in the bone morphogenetic protein 4 (BMP4) gene may be associated in the pathogenesis of cleft lip and palate.
Bone Morphogenetic Protein 7 or Osteogenic Protein-1 (BMP7 or OP-1)
Gene: encoded by the BMP-7 gene
Group: a member of the TGF-β superfamily
Causes: Inhibited by noggin and chordin. It is expressed in the brain, kidneys and bladder
Function: plays a key role in the transformation of mesenchymal cells into bone and cartilage.
Effects: Induces the phosphorylation of SMAD1 and SMAD5, which in turn induce transcription of numerous osteogenic genes. treatment is sufficient to induce all of the genetic markers of osteoblast differentiation in many cell types.
Bone Morphogenetic Protein 9 (BMP9) or Growth differentiation factor 2 (GDF2)
Gene: Encoded by the GDF2 gene
Group: Belongs to the transforming growth factor beta superfamily
Causes:
Function:
Effects: GDF2 is one of the most potent BMPs to induce orthotopic bone formation in vivo. BMP3, a blocker of most BMPs seems not to affect GDF2.
3. Insulin-like Growth Factor 1 (IGF-1)
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4. Insulin-like Growth Factor 2 (IGF-2)
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6. Fibroblast Growth Factor (FGF)
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Function: Involved in angiogenesis, wound healing, and embryonic development. Are key players in the processes of proliferation and differentiation of wide variety of cells and tissues. The functions of FGFs in developmental processes include mesoderm induction, antero-posterior patterning,[6] limb development, neural induction and neural development,[14] and in mature tissues/systems angiogenesis, keratinocyte organization, and wound healing processes.
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FGF7
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FGF18
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FGF23
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Fibroblast Growth Factor Receptors (FGFR)
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FGFR1 (Fibroblast growth factor receptor 1)
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FGFR4 (Fibroblast growth factor receptor 4)
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FGFR6
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7. Vascular endothelial growth factor (VEGF)
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8. SOX9 – Transcription factor
Gene: SOX9 gene
Group: SOX9 sits in a gene desert on 17q24 in humans
Causes:
Function: Recognizes the sequence CCTTGAG along with other members of the HMG-box class DNA-binding proteins. It acts during chondrocyte differentiation and, with steroidogenic factor 1, regulates transcription of the anti-Müllerian hormone (AMH) gene.
Effects: SOX9 has been shown to interact with Steroidogenic factor 1, MED12 and MAF
9. Parathyroid hormone-related protein (or PTHrP)
Gene:
Group: A protein member of the parathyroid hormone family
Causes:
Function: Acts as an endocrine, autocrine, paracrine, and intracrine hormone. It regulates endochondral bone development by maintaining the endochondral growth plate at a constant width. It also regulates epithelial-mesenchymal interactions during the formation of the mammary glands
Effects:
PTHrP shares the same N-terminal end as parathyroid hormone and therefore it can bind to the same receptor, the Type I PTH receptor (PTHR1). PTHrP can simulate most of the actions of PTH including increases in bone resorption and distal tubular calcium reabsorption, and inhibition of proximal tubular phosphate transport.
However, PTHrP is less likely than PTH to stimulate 1,25-dihydroxyvitamin D production. Therefore, PTHrP does not increase intestinal calcium absorption.
Parathyroid hormone-related protein has been shown to interact with KPNB1 and Arrestin beta 1
10. Parathyroid Hormone (PTH)
Gene:
Group:
Causes: Secreted by the chief cells of the parathyroid glands as a polypeptide containing 84 amino acids.
- Decreased serum [Ca2+].
- Mild decreases in serum [Mg2+].
- An increase in serum phosphate (increased phosphate causes it to complex with serum calcium, forming calcium phosphate, which reduces stimulation of Ca-sensitive receptors (CaSr) that do not sense calcium phosphate, triggering an increase in PTH)
Function: It acts to increase the concentration of calcium (Ca2+) in the blood by acting upon the parathyroid hormone 1 receptor (high levels in bone and kidney) and the parathyroid hormone 2 receptor (high levels in the central nervous system, pancreas, testis, and placenta)
Effects:
It enhances the release of calcium from the large reservoir contained in the bones. Bone resorption is the normal destruction of bone by osteoclasts, which are indirectly stimulated by PTH. Stimulation is indirect since osteoclasts do not have a receptor for PTH; rather, PTH binds to osteoblasts, the cells responsible for creating bone. Binding stimulates osteoblasts to increase their expression of RANKL and inhibits their expression of Osteoprotegerin (OPG). OPG binds to RANKL and blocks it from interacting with RANK, a receptor for RANKL. The binding of RANKL to RANK (facilitated by the decreased amount of OPG) stimulates these osteoclast precursors to fuse, forming new osteoclasts, which ultimately enhances bone resorption.
It enhances active reabsorption of calcium and magnesium from distal tubules and the thick ascending limb. As bone is degraded, both calcium and phosphate are released. It also decreases the reabsorption of phosphate, with a net loss in plasma phosphate concentration. When the calcium:phosphate ratio increases, more calcium is free in the circulation.
- Hyperparathyroidism, the presence in the blood of excessive amounts of parathyroid hormone, occurs in two very distinct sets of circumstances. Primary hyperparthyroidism is due to autonomous, abnormal hypersecretion of PTH in the parathyroid gland while secondary hyperparathyroidism is an appropriately high PTH level seen as a physiological response to hypocalcaemia
- A low level of PTH in the blood is known as hypoparathyroidism and is most commonly due to damage to or removal of parathyroid glands during thyroid surgery.
11. Estrogen receptor alpha (ER-α)
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12. Estrogen receptor beta (ER-β), also known as NR3A2
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13. Indian hedgehog homolog (Drosophila), also known as IHH
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Activation of Ihh signaling upregulates PTHrP at the articular surface and prevents chondrocyte hypertrophy in wild-type but not PTHrP null explants, suggesting that Ihh acts through PTHrP.
Ihh positively regulates PTHrP, which is sufficient to prevent chondrocyte hypertrophy and maintain a normal domain of cells competent to undergo proliferation. In contrast, Ihh is necessary for normal chondrocyte proliferation in a pathway that can not be rescued by PTHrP signaling. This identifies Ihh as a coordinator of skeletal growth and morphogenesis, and refines the role of PTHrP in mediating a subset of Ihh’s actions.
14. Collagen Type -I
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15. Collagen Type-2
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16. Androgen Receptor (AR), also known as NR3C4 (nuclear receptor subfamily 3, group C, member 4)
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17. Somatropin (GH)
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18. Glucocorticoid Receptor (GR, or GCR) also known as NR3C1 (nuclear receptor subfamily 3, group C, member 1)
19. Growth Differentiation Factor Number 5 (GDF-5)
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Effects: Genomic mutations in the human GDF5 gene have been shown to cause chondrodysplasia Grebe type, acromesomelic chondrodysplasia Hunter Thompson type, and brachydactyly type C, all of which are mainly characterized by defects of the limbs, with increasing severity toward the distal regions
20. Cyclic guanosine monophosphate (cGMP)
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21. Beta-catenin (or β-catenin)
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22. Epidermal Growth Factor Receptor (EGFR; ErbB-1; HER1)
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23. Runt-related Transcription Factor 2 (RUNX2) or Core-Binding Factor Subunit Alpha-1 (CBF-alpha-1)
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24. Follistatin also known as activin-binding protein
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25. Follicle-stimulating hormone (FSH)
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26. Activin
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Function: involved in embryogenesis and osteogenesis. They also regulate many hormones including pituitary, gonadal and hypothalamic hormones as well as insulin. They are also nerve cell survival factors. causes the transcription of mRNAs involved in gonadal growth, embryo differentiation and placenta formation.
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Activin A,
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Activin B
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Activin AB
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27. Noggin (NOG)
Gene:
Group: similar in function to chordin.
Causes:
Function: Noggin is an antagonist of BMPs. They bind BMPs preventing the binding of the ligand to the receptor.
Effects: Several mutations in the BMP antagonist noggin result in proximal symphalangism and multiple synostoses syndrome.
28. Growth differentiation factors (GDFs) – (all from Wikipedia article on GDF)
- GDF1 is expressed chiefly in the nervous system and functions in left-right patterning and mesoderm induction during embryonic development.[2]
- GDF2 (also known as BMP9) induces and maintains the response embryonic basal forebrain cholinergic neurons (BFCN) have to a neurotransmitter called acetylcholine, and regulates iron metabolism by increasing levels of a protein called hepcidin.[3][4]
- GDF3 is also known as “Vg-related gene 2” (Vgr-2). Expression of GDF3 occurs in ossifying bone during embryonic development and in the thymus, spleen, bone marrow brain, and adipose tissue of adults. It has a dual nature of function; it both inhibits and induces early stages of development in embryos.[5][6][7]
- GDF5 is expressed in the developing central nervous system, with roles in the development of joints and the skeleton, and increasing the survival of neurones that respond to a neurotransmitter calleddopamine.[8][9][10]
- GDF6 interacts with bone morphogenetic proteins to regulate ectoderm patterning, and controls eye development.[11][12][13]
- GDF8 is now officially known as myostatin and controls the growth of muscle tissue.[14]
- GDF9, like GDF3, lacks one cysteine relative to other members of the TGF-β superfamily. Its gene expression is limited to the ovaries, and it has a role in ovulation.[15][16]
- GDF10 is closely related to BMP3 and has a roles in head formation and, it is presumed, in skeletal morphogenesis.[17][18] It is also known as BMP-3b.
- GDF11 controls anterior-posterior patterning by regulating the expression of Hox genes,[19] and regulates the number of olfactory receptor neurons occurring in the olfactory epithelium,[20] and numbers of retinal ganglionic cells developing in the retina.[21]
- GDF15 (also known as TGF-PL, MIC-1, PDF, PLAB, and PTGFB) has a role in regulating inflammatory and apoptotic pathways during tissue injury and certain disease processes.
29. MMP
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30. Smad
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Effects: Smad1, 5 and 8 are the immediate downstream molecules of BMP receptors and play a central role in BMP signal transduction
SMAD1
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Causes: BMP receptors
Function: play a central role in BMP signal transduction
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SMAD2
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SMAD3
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SMAD5
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Causes: BMP receptors
Function: play a central role in BMP signal transduction
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SMAD9
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