July06, 2022,UK

Reachus:+443455280535

Abstract Volume: 4 Issue: 1 ISSN:

Osteoarthritis Linked to Diabetes Characterized  Sharp Decreasing in Ser /Proline /PLCγ2 with Increasing   PLCγ1 , where  Inhibiting S6K/BTK / PLCγ2 Affect TXA2 Synthesis Cause C-lymphocytic Leukemia

Ashraf Marzouk El Tantawi*


Corresponding Authors: Dr. Ashraf Marzouk El Tantawi, Biomedical molecular studies. Cancer and viral infections. Canada, Toronto, Goldwin Av. Egypt, Giza.

Copy Right: © 2022 Dr. Ashraf Marzouk El Tantawi. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


Received Date: December 29, 2021

Published Date: February 03, 2022

Abstract

Proper S6K /BTK and PLCγ2 are the main regulations for thromboxane-A synthesis and are necessary for B-cell maturation and T-cells modulations and functions.

The main factors that cause the Osteoarthritis "OA"  and diabetes and linked between them are the deficiency of Ser amino acids and decreasing or down-regulations of Ser phosphorylation signaling pathway which is necessary for proper S6K productions, where normally the Ser phosphorylation signaling pathway is the basis of Ser /Thr phosphorylation signaling which normally necessary for proper Akt, S6K1 synthesis and necessary for RORs and IFNs synthesis and also necessary for running proper BTK and proper PLCγ2 productions, where S6K is the main regulator for ATPase and for proper PLCγ1 and for PLCγ2 synthesis which necessary for bone growth and for increasing and modulating immune efficiency.

Osteoarthritis "OA" is characterized by a sharp expression in Gamma-Phospholipase C-1 "PLCγ1", with decreasing "or inhibition" in PLCγ2 "PLC beta" productions.

The increase in PLCγ1 with Deficiency in Ser amino acids will lead to deficiency in Ser phosphorylation signaling (which is the main basis for Ser/Thr phosphorylation signaling which has the main function of producing proper S6K), and decreasing in synthase activity will reflect down regulations in BTK pathways and lead to inhibition in PLCγ2 productions which will reflect diabetes (inhibition in Estrogen with the production of  Androgen instead of estrogen )  and can reflect early Osteoarthritis"OA" prognosis dépend on the percentage of Deficiency or inhibition in basic amino acids and in basic necessary signaling pathways.

The proper S6K is so necessary for reactivating both PLCγ1&2, where phospholipase Cγ2 (PLCγ2) is  activated from a variety of cell surface receptors such as SyK "S6K".

As, the B cells are promoted by the function and activities of both PLCγ1&2, as the deficiency in Ser amino acids will reflect decreasing in Ser phosphorylation pathways and then decreasing in Estrogen synthesis, with increasing in Androgen synthesis which leads to decreasing in PLCs isoforms production and lead to pathogenic diabetes problem. So T2DM is strongly connected with OA disease and both are having the same syndrome of causing their pathogenic problems, and any early step from any of those two or more similar diseases can lead to the other.

Pathogenic type 2 diabetes is associated with progressive beta-cell  impairment due to the mutations in the production of normal insulin which is due to missing Ser phosphorylation signaling during mTOR Ser/Thr phosphorylation pathways that reflect Inhibition in the releasing of PS/T-Thymine -Kinase and PS/T-Cytosine -kinase chains (mTORC1) which are regulating hydrophobic amino acids synthesis which can be modified by synthetase enzymes for creating the first active gamma-subunits (upon synthetase effects) that will be modified by synthase effect for  Beta-subunit synthesis than for alpha subunits upon phospholipase effects respectively.

The previous releasing of PS/T-Thymine -Kinase and PS/T-Cytosine -kinase chains (mTORC1) from specifically the phosphorylations of Ser pathway is so necessary steps and mechanism for normal S6K productions, necessary for IFN-Gamma and for PLCγ1 productions, and therefore necessary for normal PLCγ2 synthesis which is necessary for B-cell activities, for T-cells modulations, for modulating anti-inflammatory steps and procedures, for thromboxane-A synthesis, and for bone growth and modulation.

Inhibition in PS/T-Thymine -Kinase and PS/T-Cytosine -kinase chains (mTORC1) productions can be the main reason for inhibition the beta subunits productions that can be the reason of decreasing in the hyperpolarization and then the electrical activity will lead to decreasing in the abolition of Ça+ which will lead to increase in the dropping in blood pressure.

Deficiency in the conversion of glutamate to glutamate and decreasing in proline biosynthesis can affect cartilage synthesis and bone growth due to decreasing in the activities of mitochondrial OPA1 oxidations.

It's imp to note that: Tyrosine phosphatase PTPs are an important regulator of chondrogenic patterning and are critical regulators of tyrosine phosphorylation than it's activity depends on Tyr, Ser synthesis (hydrophobic acids) and on JAK state signaling activities. And so, the proline-rich tyrosine kinases regulate proper PLCs isoforms which compete for the binding site at the very C terminus of fibroblast growth factor for osteoprogenitor embryonic development, and bone formations.

Synthetase is the main regulator for PLCγ1 activities followed by synthase effects for beta-subunits ( "PLCγ2" ) productions which is able to "upregulate phospholipase activity" for alpha subunits (PLC-alpha) productions for reactivating fibroblast growth factor receptor (FGFR2) and for reactivating antigens and TLR4 productions.

Where, PLCγ1 competes for a binding site at the very C terminus of FGFR2 for embryonic development and bones growth, whereas, PLCs isoforms are involved in multiple stages in TLR4, interferon, and in anti-inflammatory steps. And also, PLCγ1 recruit to CSF-1 is following imp stages for producing PLCγ2 which is necessary for activating anti-inflammatory where IFN-γ activates PLC-γ2 via an upstream of tyrosine kinase.

 

The PLCγ1 and PLCγ2 (PLCs) are so important in anti-inflammatory processes and can be considered as having the main roles of characterizing the activities of thromboxane and fibrin through re-modulating immune and T cells activities.

Inhibitions or reduction or mutations in S6K, in BTK  and in the original main normal PLCγ2 productions will cause an inherent or inhibition in CXCL12 then followed by inherent or inhibition in CXCR4 then reflect inherently or inhibition in the regulation of B-cell growth, migrations,  adhesions and functions.

Proline amino acids are necessary for reactivating OPA1 anabolic oxidations (started by synthetase, then synthase, then phospholipase for producing gamma "PLCγ1", then beta "PLCγ2", then alpha "PLC-a" subunits respectively ) for cartilage synthesis which promote PLCγ2 synthesis necessary for bone growth including antigen and thromboxane-A synthesis.

Osteoarthritis Linked to Diabetes Characterized Sharp Decreasing in Ser /Proline /PLCγ2 with Increasing PLCγ1 , where Inhibiting S6K/BTK / PLCγ2 Affect TXA2 Synthesis Cause C-lymphocytic Leukemia

Purpose of study:

Understanding the main reasons for causing chronic lymphocytic leukemia "CLL" where proper S6K /BTK and PLCγ2 are main regulations for thromboxane-A synthesis and necessary for  B-cells maturation and T-cells modulations.

Also, it's important to Understand main factors  that cause and link the Osteoarthritis "OA" with diabetes which are the deficiency in Ser amino acids and mutated S6K production lead to deficiency or inhibition in Ser phosphorylation signaling which normally is the basis of Ser /Thr phosphorylation signalling which necessarily for Akt, S6K1 synthesis and necessary for RORs and IFNs synthesis and also necessary for proper PLCγ2 productions , where S6K is main regulator for ATPase and for proper PLCγ2 synthesis , that I have to note that the shortage ratio  of amino acids  (or enzymes or steps) is the ratio that can define the degree and type of specific disease that can differ from others which can linked together with the same Syndromes of disease , and also the shortage ratio between the beta Cytokines producions  and the ratio of sudden high inflammations productions "and the type of its inflammatory molecules" have to be calculated and considered related to the patients ages  (whether child, youth or old ages) and the duration of the chronic disease disease , that some can be confused to differentiate between  auto-immune disease and regular disease problems diagnosis.

That, There was a case of a child with  9-year-old who had a suspicion  of loss of bone maturation and growth, and has a sudden infection in the right lung and a lack of breathing with pain. It was found that there was a pulmonary abscess in the right lung, and there was a development with the appearance of an airbag or "inflammatory fluid bag" surrounding

respiratory cells on the right side. The occurrence of inflammations molecules and their growth was rapid enough faster than IFNs productions and faster than PLCγ2 productions due to to the age of the child, "Note some her regular treating doctors diagnosed her medical conditions as a type of Autoimmune disease and she has weakened immunity due to sudden fast infection related to her young age".

 

Highlights:

Increasing in PLCγ1 with Deficiency in Ser, in proper S6K, and decreasing in synthase activity with inhibition in PLCγ2 will reflect decreasing in anti-inflammatory processes, reflect starting or increasing in Osteoarthritis syndromes, and also reflects the appearance of diabetes syndrome.

_proper healthy PLCγ2 are so necessary for increasing re-modulate immune efficiencies, and for re-modulate antigen and T-cells refunctions, and also proper healthy PLCγ2 production are so imp for recovery from osteoporosis and from both Osteoarthritis and diabetes.

_inhibition in PLCγ2 Bio-Synthesis can reflect decreasing or inhibition in Thromboxane-A 1 percentages and its Molecular structure, Where, CLL is characterized by inhibition in BTK, inhibition in PLCγ2 synthesis, inhibition in main antigen synthesis, and inhibition in the proper normal Thromboxane-A synthesis which is regulated mainly by PLCγ1 then IFNs production then regulated by PLCγ2 proper productions.

_Chronic lymphocytic leukemia (CLL)  observed during treatment with B-cell receptor inhibitors pathway including inhibitor of Bruton’s tyrosine kinase-PLCγ2, where, CLL can be strongly linked to Osteoporosis "OA", and Linked to both Osteoarthritis and diabetes too.

 

Keywords:

_Phospholipase C-1 "PLCγ1",

_Phospholipase C-2 "PLCγ2 "necessary for anti-inflammatory steps,

_Osteoarthritis OA tissue cells

_Osteoporosis tissue cells

_Osteoclast processes _Osteoblast processes

_Ser/Thr phosphorylation signaling,

Deficiency in PS/-Thymine-kinases reflect mutated S6K, deficiency in PLCγ2, deficiency in B cells and T-cells modulation, and deficiency in OPA1 repair,

_S6K, estrogen, androgyne,

_JAK state signaling

_diabetes

pathogenic tissue cells

_Tyrosine phosphatase

PTPs

_Colony-stimulating Factor-1 "CSF-1"

_inositol-1,4,5-triphosphate (IP3) and Diacylglycerol

_thromboxane-A "TXA2"

_CXCR4, CXCL12

_pathogenic chronic lymphocytic leukemia (CLL) tissue cells

_B cells and B cells receptors "BCR"

_osteprogenitor pathway

_Fibroblast growth factor receptor 2 "FGFR2"

_interferon regulatory factors (IRFs)

 

Introduction:

Osteoarthritis is characterized by a sharp expression in Gamma-Phospholipase C-1 "PLCγ1", with decreasing in PLCγ2 "PLC beta" which improved by phospholipase oxidations for producing PLC alpha for proliferation and calcium entry ", where  PLCγ1 was highly  expressed in human OA chondrocytes  [1] )  which is implicated  processes including mitogenesis and calcium entry.   

Phospholipase C isoforms (PLCs) are  essential mediators for cellular signaling and metabolism.

PLCs regulate multiple cellular processes including proliferation and biological bones growth by generating bioactive molecules such as inositol-1,4,5-triphosphate (IP3) and diacylglycerol.  

That, PLCγ1 basis of inhibition-driven autophagy of IL-1β-treated chondrocyte confers cartilage protection against osteoarthritis. [2] the only presence of PLCγ1 has the ability and  roles of analyzing biological molecules "Osteoclast" for expressing its specified functions so, slightly inhibition or decreasing in PLCγ1 will decrease osteoclast and also re functioning PLCγ1 for reactivating the expression of PLCγ2 which reduce the analyzing function of PLCγ1 and then  give the priority to PLC-beta "PLCγ2" for beta-oxidation for activating anti-inflammatory processes , and  for PLC-alpha production  for proliferations   functions which for activating osteoblast processes , bone growth , and cells proliferation.  

Where, the availability of proline is necessary for activating and accelerating OPA1 oxidative processes for cartilages synthesis  and also  the availability of necessary hydrophobic amino acids proper synthesis "eg : Tyr, Leu, Pro, Gly, Ser,... etc" will activate and will accelerate proper OPA1 oxidative processes which promote and activate  necessary anabolic cycles for activating BTK which regulate PLCγ2 for bone growth and for modulating  immune effectiveness.   

The Deficiency in the conversion of glutarate to glutamate and decreasing in proline biosynthesis strongly affect cartilage synthesis due to  decreasing in the activation of mitochondrial OPA1 oxidative processes [3]  , also, deficiency in the mitochondrial OPA1 membrane bio-repairs can reflect a deficiency in the proper S6K productions lead to deficiency  in OPA1 mitochondrial repair synthetase activities lead to deficiency in OPA1 synthase, and in phospholipase activities and their molecular   structure lead to decreasing  in antigens synthesis and activities that can reflect decreasing in PLCγ2 then in SIRPα1, and in TLR4 biosynthesis, that can reflect increasing in  catabolic analyzing processes that can analyze the phospholipid  and interstitium fluid molecules.   

Method and Results:

S6K /BTK and PLCγ2 are the main regulations for thromboxane-A synthesis and are necessary for B-cell maturation and T-cells modulations.

Where, it's important to Understand main factors  that cause  Osteoarthritis "OA" and diabetes which are the deficiency in Ser amino acids that lead to mutated S6K production due to  deficiency or inhibition in Ser phosphorylation signaling which normally is the basis of Ser /Thr phosphorylation signaling which normally necessary  for proper Akt, S6K1 synthesis and necessary for RORs and IFNs synthesis and also necessary for proper PLCγ2 productions.  

Proper S6K productions are the main regulator for ATPase, for OPA1 repair, and for BTK and  proper PLCγ1 & PLCγ2 synthesis which is necessary for bone growth.  

Osteoarthritis "OA" is characterized by a sharp expression in Gamma-Phospholipase C-1 "PLCγ1", with decreasing "or  inhibition" in BTK and PLCγ2 "PLC beta" leading to decreasing in beta-cells and T-cells modulations.  

The increasing in PLCγ1 with Deficiency in Ser will reflect mutated  S6K productivity , and in synthase activity with inhibition in PLCγ2 that will reflect Inhibition in estrogen synthesis and androgyne synthesis that reflect diabetes problem and   Osteoarthritis"OA that we'll discuss why both diseases are connected and their causes depend mainly on the availability of Ser amino acids then on the Tyr and their phosphorylation signaling pathway.  

Deficiency or inhibition in the proper S6K, in Ser and Tyr amino a. synthesis ,  in OPA1 synthase activities , and alpha-oxidation with increasing in PLCγ1 will reflect diabetes and  increasing in Osteoarthritis "OA"

PLCγ1 is a protein molecule that its activity depends on Tyr phosphatase , and gamma common receptors synthesis  which re-activated by JAK STAT signaling which is also regulated by synthetase enzyme where synthetase  is the main second enzyme  in OPA1 chains after COX enzyme (followed by synthase and phospholipase respectively ), that proper synthetase enzyme responsible for proper gamma oxidations and pyrimidine synthesis (or extraction) for hydrophobic amino acids (Ser, Tyr, Leu,...) synthesis, that the proper activity of synthetase enzymes is so necessary for creating signals transmission which can reactivate mTOR pathway and for  re-production the active gamma subunits which upon JAK signaling mediate will creation their receptors then upon synthase enzyme effects will produce active beta-subunits  molecules (where, beta subunits chain  contain the modified gamma subunits through beta-oxidation which contain modified hydroponic a.a., then upon phospholipase effect will promote the alpha-oxidations for more  modifications for producing alpha subunits active chain which necessary for proliferation and bones growth.   

The PLCγ1/PLCγ2 double-deficient B cell progenitors have reduced expression of genes related to B cell lineage, IL-7 signaling, and cell cycle. [4]  That the activities of both PLCγ1&2 are linked to each other and are so necessary for re-activation of B-cells maturation , where,  B Cells regulate the productions antigen-specific immunoglobulin necessary for anti-inflammatory processes,  therefore the deficiency or mutations in PLCγ1&2 will lead to decreasing in or lead to Malignant transformation in B cells that can cause mutations and cancers as  chronic lymphocytic leukemia (CLL) and can cause several pathogenic problems as diabetes and OA diseases.  

B-cells are promoted by the function of both PLCγ1& 2 , That PLCγ1 synthesis mainly depends on mTOR Ser /Thr  phosphorylations signaling pathways  (mTS/TP ) which produce whether proper active S6K genes or not proper forms which depending on the availability of Ser amino acids in nutrients molecules for running its necessity phosphorylation pathway "that deficiency in Ser amino acids will reflect decreasing in Estrogen and then increasing in Androgen synthesis which lead to pathogenic diabetes problem".[5]  

Proper S6K synthesis is so necessary for reactivating ribosomal ATPase which is necessary for  mitochondrial OPA1 membrane repair (through regulating  GTPase productions ) where normal OPA1  is necessary for activates and regulating proper PLCγ1 production and its roots of activities pathways which supposed to be completed by creating and producing its  second isoforms beta structure form "PLCγ2" upon synthase effect for B-cell maturation, and then for anti-inflammation  followed by creating PLC-alpha upon phospholipase functions for promoting proliferation and bone growth through SIRPa and TLR4 productions.  

In case of deficiency in mTOR Ser/Thr phosphorylations signaling due to deficiency in Ser phosphorylation will produce non proper mutated S6K "missing Ser hydrophobic amino acids" that will lead to diabetes pathogenic problems, and then the PLCγ2 will not be produced or in some cases mutated PLCγ2 can be formed missing necessary hydroponic (Tyr, leu, Pro, etc)  that  will lead to diabetes, OA, and cancer pathogenesis.  

Pathogenic type 2 diabetes is associated with progressive beta-cell  impairment due to the mutations in the production of normal Estrogen which due to missing of Ser phosphorylation signaling during mTOR Ser/Thr phosphorylation pathways will lead to Inhibition or decrease in the releasing of PS/T-Thymine -Kinase and PS/T-Cytosine -kinase chains (mTORC1) that those two kinases are depending on the availability of Ser and its phosphorylation pathway where Ser synthesis in vivo depending on synthetase which are regulate hydrophobic amino acids synthesis which can be modified  by synthetase oxidations for creating  the first active gamma-subunits  that will be modified by synthase effect "beta-oxidation" for active Beta-subunit synthesis which is necessary for "anti-inflammations" then for alpha subunits upon phospholipase effects "alpha-oxidations" which necessary for proliferation respectively.  

The releasing of PS/T-Thymine -Kinase and PS/T-Cytosine -kinase chains or  (mTORC1) from specifically the phosphorylations of Ser signaling pathway is so necessary steps for the mechanism of normal and proper  S6K productions which necessary for IFN-Gamma and PLCγ1 productions, "in proper active forms" and therefore necessary for normal PLCγ2 synthesis which is necessary for B-cell activities , for T-cells modulations, for modulating anti-inflammatory steps and processes , for thromboxane-A synthesis, and for bone growth and maturation. [6A*]

The inhibition in PS/T-Thymine-Kinase and PS/T-Cytosine -kinase chains (mTORC1) productions will be the main reason for the inhibition of the beta subunits productions that can be the reason of decreasing in the hyperpolarization and then the electrical activity  will lead to decreasing in the abolition of Ça+ which will lead to decreasing in blood pressure.  

Also the deficiency in tyrosine amino acids will prevent the production of tyrosine phosphatase which is needed for the synthesis of phospholipase C 1&2 that promote cellular proliferation, and also reduction of and deficiency in Tyr amino acids "hydrophobic acids" will reduce or inhibit Drutons tyrosine kinases "DTK".   

Now it is important to consider that proper S6K is the main regulator for PLCs isoforms synthesis which depend on S6K productions , and it has been reported that the phospholipase Cγ2 (PLCγ2) is  activated from a variety of cell surface receptors such as SyK "S6K",and BTK which  phosphorylate and activate PLCγ2. [6]

S6K1 is the basis for ATPase,and  GTPase where, GTPase is necessary for G-protein synthesis, for OPA1 repair and re-modulations, and ribosomal repairs and reactivations.

As the GTPase is a regulator tool for BH4 and NO 3 productions for synthase repair and activity,As, S6K1 is the main regulator for PLCγ1 synthesis and then for PLCγ2 synthesis upon synthase function which later will migrate for beta-cells servival upon production firstly CXCL12 then CXCR4 productions.  

Also it has been approved that T2DM is connected with OA and both are having the same reason of causing their pathogenic disease , where T2DM has a pathogenic effect on OA through 2 major pathways involving oxidative stress and low-grade chronic inflammation resulting from chronic hyperglycemia and insulin resistance. [7].  Pathogenic type 2 diabetes associated with progressive beta-cell impairment due to the not normal production of insulin which due to deficiency of Ser phosphorylation pathway during mTOR Ser/Thr phosphorylation pathways that will not produce normal S6K "due to deficiency in Ser and some other necessary amino acids  (mainly Ser and Tyr, Leu, Pro a.a.) then will lead to decreasing "or mutation" in the S6K productions, that will lead to Androgen instead of Estrogen where Estrogen characterized by presence of Ser in their molecules, that will lead to high ATPase productions with deficiency estrogen which is the main substrate for  RORs pathway that later will promote the IFN gamma, IFN-beta, and alpha that can lead to increasing in "catabolic effects" with decreasing in the ROR pathways "anabolic process" and decreasing in proper PLCγ2 productions that reflect Ca+ precipitations and  arterial hypertension.  

Where, it has been reported that insulin activates the K-ATP channels of pancreatic β-cells and islets, resulting in membrane hyperpolarization , and the abolition of [Ca2+]i oscillations. [8]  

And, the low abolition of [Ca2+]i oscillations in the case of T2DM indicates decreasing or inhibition in PLCγ2 synthesis "that has the role of   modulating inositol 1,4,5-trisphosphate-mediated calcium oscillations for bone growth". Also, decreasing in membrane hyperpolarization  can give a reflection of decreasing in OPA1 synthase oxidations which reflect decreasing in membrane hyperpolarization.  

(PLCγ1)  can be reactivated by platelet-derived growth factor "GF" receptors,  insulin-like GF 1 receptor (which reflect a deficiency in proper cells and bones growth), but  in brief PLCγ1 productions can produce and re-functioned by several active growth factor (GF) receptors through feedback and by firstly reactivating synthetase followed by synthase then phospholipase which promotes growth factor activities as epidermal GF receptor [EGFR], and  platelet-derived GF receptor, where due to activating GFs processes it will be responsible for increasing hyperpolarization and functioning CA throughout the synthesis of PLCs that will responsible for running the pathway of bone growth and cellular biosynthesis processes.   

The main PLCγ1 proper activities is regulated firstly by proper S6K production from mTOR Ser /Thr phosphorylation pathways followed  by JAK STAT signaling for  producing the Tyr-phosphatase, gamma common receptors , and other necessary helical proteins receptors which adopt and activate PLCγ1&2 synthesis and activities for anti-inflammatory, for B-cells maturation, for T-cells modulation, and for bone growth and proper cellular proliferation.   

PLCγ1 is a necessary Protein regulated firstly by S6K which is produced from mTOR Ser /Thr signaling pathway and regulated by OPA1 synthetase and then activated by JAK STAT signaling for both PLCγ1 and then PLCγ2 productions, where PLCγ2 is also regulated by BTK for proper PLCs  productions for cells proliferation and bones growth.   

Hydrophobic acids such as Tyrosine, Ser , proline facilitate the survival and protect proliferation processes of bones development  (also can activate  tumor growth in case of specific  synthase dysfunction when lose or deprived of some necessary amino acids ) through facilitating OPA1 oxidative functions (especially when proline is available in OPA1 enzymes which activate their function ) and activate BTK pathways which necessary for  FGFR2 gene expression for bones developments.   

Where, Tyrosine amino acids increase alertness and bone development through activating tyrosine kinases, that Tyrosine phosphatases are potential therapeutic targets for fighting bone disorders. [9]  

Protein tyrosine phosphatase (PTP) gamma (carry −ve charge regulated firstly by synthetase gamma-oxidations) has been proposed to be an important regulator of chondrogenic patterning, where PTPs are critical regulators of tyrosine phosphorylation at multiple stages of bone development and metabolism. [10]  

And, proline-rich tyrosine kinases regulate osteoprogenitor cells and bone formations, [11]  so Tyrosine and proline (where their synthesis is firstly regulated by synthetase in vivo) are regulated by PIPs and are critical regulators of multiple stages in bone development.   

Tyrosine, Ser , proline are essential hydrophobic acids that produced in vivo upon the effects of synthetase enzymes on nutrients, and on inflammations molecules for running pyrimidine synthesis and production for creating for improving Gamma-subunits then beta, then alpha subunits productions.  

Gamma-subunits is then moderated by JAK STAT signaling for producing their active gamma subunits receptors (as Gamma-common and other helical proteins) which promoted by IFN gamma for  activating

PLCγ1,  PD-1, MHC-class one and two antigens which promote the SIRPα1, and TLR4 productions for  bone growth and cells developments.   

PLCγ1 competes for a binding site at the very C terminus of FGFR2 for embryonic development and bones growth, where, PLC isoforms are involved in multiple stages in TLR4, interferon, and anti-inflammation

 

PLCγ1 competes for a binding site at the  C terminus of fibroblast growth factor receptor (FGFR2) ( which plays an important role in bone growth, particularly during development before birth "embryonic development" ) and is sufficient to upregulate phospholipase activity [12]. That , synthetase is the main regulator for PLCγ1 activities followed by synthase effects for beta-subunits ( "PLCγ2" ) productions which can "upregulate phospholipase activity" for up-regulate phospholipase activity for producing active alpha subunits (PLC-alpha) productions which responsible for reactivating fibroblast growth factor receptor (FGFR2) and for proliferation and bone growth, that it gives strong relationships to the  reactivation and production of the MHC class two antigens which promote SIRPα1 and TLR4 which are having the roles of proliferation,  cells  modulations and T-cells modulations .  

Only Synthetase enzymes in OPA1 mitochondrial membranes are having the ability of hydrolysis biological molecules, inflammations  and phospholipid membranes in vivo , therefore the active gamma subunits - (regulated by synthetase) in absence of beta subunits can analyze cells, inflammations and biological molecules (for producing prostaglandins) , where beta subunits chain contains gamma and beta "upon beta oxidations" chain that during attacking inflammations or microbe in vivo the beta subunits will protect cells while only  gamma subunits (in absence of beta subunits) will analyze biological molecules , but in availability of beta and alpha chains PLCγ2 & PLC-alpha productions will have the roles of modulating and activating anti-inflammatory processes, B-cells maturation, T-cells modulations, and bone growth .

So PLCγ1 is considered as  active gamma chain containing necessary hydroponic amino acids that necessary for promoting and modifing the PLCγ2 productions upon synthase effect that will modulate the increasing in anti-inflammations and modulating T-cells that can  protect cells then will  promote the PLC-alpha synthesis necessary for running proliferation and bone growth which also appears that strongly connected to promoting the activating of both SIRP-a and TLR4 productions which are having the same roles as PLC-alpha of running proliferation and bone growth.  

Where, Some PLCs isoforms are involved in multiple stages in TLR4 and interferons regulatory factors (IRFs) synthesis [13].   Where it  indicate the involvement of PLCs in the activating interferons regulatory tools (IFN-gamma, IFN-beta and IFN-alpha)  which responsible for promoting MHCs "class one and two", SIRPα1 and TLR4 where Noth SIRPα1 and TLR4 are responsible for the proliferation, bone growth and T_cells modulations. Also indicating that the availability of  S6K1 and PLCγ1 in the proper molecular structure   are so necessary for activating  IFNs and for TLR4.

So, proper PLCγ1 can be considered as important tools produced in vivo for activating IFNs necessary regulatory for anti-inflammation which regulate MHC class one and two and SIRPα1 and TLR4 which are necessary for proliferation and T-cells modulations.  

The PLCγ1 are produced upon OPA1 synthetase oxidative effects and activated by JAK signaling for gamma common, tyrosine Receptors, and other helical protein receptors productions which regulate PLCs isoforms  activities and other genes biosynthesis "eg: antigen, PD-1, SIRP-gamma, and PLCγ1 productions", that PLCγ1 are containing so necessary regulatory  basic amino acids for promoting antigen synthesis, for SIRPα1, for TLR4 biosynthesis, and then for PD-L1 biosynthesis.   

Therefore, PLCγ1 are so important for PLCγ2 production which is regulated  by tyrosine phosphatase  receptors and by  phospho-tyrosine receptors "PTyr-R" for activating PLCγ2 productions and then for PLC-alpha reproduction for bone growth, for B cells maturation, and for promoting anti-inflammatory steps through activating IFNs productions for regulating MHCs synthesis which is necessary for SIRPα1, TLR4, and PD-L1 productions where all are Contributing and activating the bone growth, proper anti-inflammation, T-cells modulations, and necessary cells maturation, Where are depend on JAK signaling for SH2B adaptor protein "that are a Tyr kinase receptor family" which necessary for BCR mediate B cells maturation [14"]  that, "PTyr" phospho-tyrosine"Which necessary for PLCs synthesis ", and for SHP1Src homology region 2 domain?containing phosphatase 1  synthesis are so imp for regulating PLCs synthesis, for reactivating IFNs and their pathways functions in anti-inflammatory processes including proliferation, B-cells maturation.

Notice that PLCγ2 BCR mediates B-cell maturation which is regulated by SH2B adaptor protein so BTK is the so necessary regulatory factor for PLCγ2 production for B-cell maturation and also for modulating T-cells.

PLCγ1 is associated with numerous inflammatory diseases where firstly the productions of PLCγ1 is for acting on infections for modulating the PLCγ2 productions for running the PLCγ2 pathways for firstly anti-inflammation followed by promoting PLC alpha for proliferation, that there are considered limits % between the number of inflammations from its inflammatory Source  and the percentage of the productions of PLCγ1, wherein case of increase in the sudden inflammation related to PLCγ1 productions will overcome in tissue lead to increasing inflammations but in case of providing the salvation through providing PLCγ2 will reflect decreasing in inflammations with increasing in anti-inflammatory processes.

PLCγ1 recruit to Colony-stimulating factor-1 "CSF-1" is followed by imp stages for producing PLCγ2 which is necessary for activating  anti-inflammatory through activating , IFNs which activates PLC-γ2 via an upstream of tyrosine kinase :

The PLCγ1 has the specificity toward colony-stimulating factor receptor (CSF-1) signaling which is expressed on the cell surface that can cause the cells to proliferate and differentiate into specific blood cells, and considered as a class III receptor tyrosine kinase that associated with Neuroinflammation, where PLCγ1 is recruited to the CSF-1 receptor following exposure to the cytokine. [15]  meaning of PLCγ1 recruit to CSF-1 necessary for producing PLCγ2 which is necessary for re-activating anti-inflammatory steps then follow the proliferation steps through activating SIRPα1 and TLR4 and then PD-L1 productions.

So, CSF-1 is a member of the IL-1 receptor family which is involved in completing anti-inflammatory cycles for proliferation is regulated  by PLCγ1 effect and regulations.

Where, CSF1R-expressing cells may play an anti-inflammatory role or a cancer-suppressive role. [16] As PLCγ1 recruiting to CSF-1 for PLCγ2 synthesis (where PLCγ2 play important role in anti-inflammations and modulating BCR and T-cells) so CSF-1 is playing a necessary role in anti-inflammatory processes regulated firstly by OPA1 and then by PLCγ1.  

Also, Tripartite motif (TRIM) 22 plays an important role in interferons (IFNs)-mediated antiviral activity and the Induction of TRIM22 by IFN-γ Involves JAK and PC-PLC/PKC [17].  So PLCs synthesis modulate and regulate Tripartite motif (TRIM) 22 (what has antimicrobial activities) productions through activating IFNs production.

Also, IFN-γ activates PLC-γ2 via an upstream tyrosine kinase to induce activation of PKC-α. [18]  

As PLCs (started by PLCγ1) activate IFNs productions which regulate PLCγ2 productions, as proper  PLCγ1 is the first regulator for PLCγ2 productions for bone growth and  T-cells modulations.  

So, PLCγ1 was recruited  to CSF-1 for re-activating IFNs productions which regulate MHC class one and two for modulating cell-surface protein structure through activating PLCγ2 for modulating T-cells , where PLCγ1 involved in the production of TRIM22  for mediating antiviral activities and  anti-inflammatory processes through reactivating IFNs productions for PLCγ2 which modulate T-cells and activate bone growth with activating necessary proliferation through promoting PLC alpha, SIRPα1, TLR4, and PD-L1 synthesis.  

Note that the inhibitions of PLCγ2 productions with continually PLCγ1 productions will lead to osteoclast, but the proper balance of  both PLCγ1 and PLCγ2 productions will lead to osteoblast where PLCγ2 are depending on IFNs productions too.  

Also, the Colony-stimulating factor-1 requires PI3-kinase-mediated metabolism for proliferation [19].  So, as PLCγ1 recruited to Colony-stimulating Factor 1 "CSF-1" which is involved in anti-inflammations and proliferation as PLCγ1 has own strong roles of activities for both anti-inflammation "upon circuit to recruited CSF-1", and for PLCγ2 and PLC-alpha productions for running proliferations including bone growth.

The inhibitions of fatty acid synthase "FAS" activity by C75 is resulted in downregulation of phospho-AKT [20]. PLCγ1 which is regulated by both synthetase and by S6K productions are necessary for activating CSF-1 production which activates PLCγ2 productions (upon synthase effect), but in the inhibition of synthase will reflect down regulations in p13k Akt and inhibition in  PLCγ2 productions.

PLCγ2 synthesis activates osteoblast but PLCγ1 production with inhibition in PLCγ2 will activate osteoclast (OC) by inhibiting re-modulating inositol 1,4,5-trisphosphate-

PLCγ1&2 are modulating a variety of cellular pathways including osteoclast (OC) differentiation.

Where, PLCγ2 production is important for running osteoblast and inhibiting osteoclast, where the increase in PLCγ1 productions with inhibition in PLCγ2 will activate osteoclast (OC) by inhibiting re-modulating inositol 1,4,5-trisphosphate "which mediated calcium oscillations and the up-regulation of the nuclear transcription factor NFATc1". [21]

That, inositol 1,4,5-trisphosphate and diacylglycerol production require phosphoinositide   synthase (PIS) for modulating OC differentiation through regulating transient receptor potential (TRP) channels which need hydrolysis of requires hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP) resulting in the generation of inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG).

So, OPA1 synthase is necessary for creating sphosphoinositide synthase (PIS) "regulated firstly by synthetase gamma-oxidations for activating firstly PLCγ1 production followed by PLCγ2 productions .

Both PLCγ1 and sphosphoinositide   synthase (PIS) is important for promoting PLCγ2 productions and necessary for proliferations and bone growth, Where, increasing in PLCγ1 "with reduction or inhibitions in PLCγ2 productions will activate osteoclast but the reactivating proper percentage of PLCγ2 synthesis will activate osteoblast.

Where, PLCγ2, independent of PLCγ1, was required for receptor activator of NF-κB ligand–induced osteoclastogenesis by differentially regulating nuclear factor of activated T cells c1 (NFATc1),[22]  that JAK signaling is playing imp role in running either osteoclast or osteoblast through mitochondrial OPA1 regulation activities, that high gamma receptors  with decreasing in beta receptors will activate osteoclast but proper percentages of gamma and beta  productions (proper % between PLCγ1 & PLCγ2 productions) will activate proper osteoblast through activating PLCγ2 production Which needed for TXA2 synthesis and beta-cells maturation and activities. 

 PLCγ2 can modulate immune activities and T-cells too , where Bruton tyrosine kinase (Btk) activates PLCγ2 ,11,12 which activate thromboxane A2 re-synthesis Phospholipase Cγ2 is Critical for Dectin-1-mediated Ca2+ Flux and Cytokine Production in Dendritic Cells [23].

PLCγ2 has a critical activity in dendritic cells, where it has a Critical function for the Development of a Murine Model of Inflammatory Arthritis. [24]

And, as PLCγ2 has a critical activity in dendritic cells for activating  NF-κB ligand-induced  osteoclastogenesis by differentially regulating nuclear factor-activated T cells c1 "NFATc1" As PLCγ2 production modulates the capacity of T cells of dendritic cells.

Where,PLCγ2 is critical for B-cell receptor (BCR) for B cells maturation and functions, and PLCγ2 participates in TCR signal transduction and plays a role in T-cell selection [25]

It has been reported that Properdin and factor H production by human dendritic cells modulates their T?cell stimulatory. [26]

but I report that modulations of T-cells run  by the functions of PLCγ2  for re-activating  NF-κB by regulating NFATc1, while Properdin subunits composition can  modulate NFATc1 or not .

The increase in PLCγ1 productions with deficiency or mutation in PLCγ2 will reflect decreasing in B cells maturation and function and can lead to  Autoinflammation and immune dysregulation (APLAID) which can cause rare monogenic autoinflammatory disease.

That, the diverse pathologies associated with PLCγ2 are exemplified by distinct genetic variants, where inherited mutations at this locus cause PLCγ2-associated antibody deficiency and immune dysregulation. [27]

Thrombine activation is highly reactivated intermediate the true fibrin monomer and it rapidly, and irreversibly. [28]

PLCγ2 is involved with fibrin formation, where Bruton tyrosine kinase (Btk) activates PLCγ2 ,11,12 leading to thromboxane A2 (TXA2) synthesis.  [29]

So, PLCγ2 synthesis can define the availability of the synthesis and activities of thromboxane-A  and fibrin and re-modulating immune and T cells activities.

Also, the antiplatelet and antithrombotic effects of Fc are carried out through the oppression of PLCγ2 and subsequent DAG-PKC-TXA2 and IP3-[Ca2+]. [30]

The activation of PLCβ through Gq, which results in the formation of IP3 and diacylglycerol, plays an important role in mediating αIIbβ3 activation. [31]

So, in brief BTK is necessary for PLCγ2 productions which is necessary for B-cell maturation and functions, and also PLCγ2 is so important for thromboxane-A synthesis.

Chronic lymphocytic leukemia [CLL]  reflect Inhibition in BTK and then in PLCγ2 synthesis which can reflect Inhibition or impaire in Thromboxane-A :

Proline amino acids are required for Collagen synthesis [32] where, Collagen binds to its receptors and then activates both the PLCγ2-DAG-PKC and PI3 kinase/Akt-p38 MAPK cascades, where p38 MAPK can activate cPLA2, which catalyzes arachidonic acid (AA) release to produce thromboxane A2 (TxA 2 ) formation [33]

Bruton's tyrosine kinase "BTK" activates PLCγ 2 variants mediating ibrutinib resistance in human CLL. [34]

BTK inhibitors [ibrutinib , CNX?774 ] significantly attenuated TPA?induced cell invasion and migration in MCF?7 cells and inhibited the activation of the phospholipase Cγ2/PKCβ signaling pathways [35]

BTK was initially shown to be defective in the primary immunodeficiency X-linked agammaglobulinemia (XLA) and is essential both for B cell development and function of maturity. [36]

So, both Collagen synthesis and BTK are the main functions for re-activating PLCγ2 which catalyzes arachidonic acid (AA) release to produce thromboxane-A2 (TXA 2 ) formation ( note the inhibition in BTK and PLCγ2 will affect TXA2 synthesis and will cause Chronic lymphocytic leukemia ), and both BTK and PLCγ2 are so necessary for B cells maturation and functions and are critical for B-cell receptor (BCR), where, inhibition or reduction in BTK and PLCγ2 will reflect the Chronic lymphocytic leukemia "CLL".

Results and Conclusion:

Chronic lymphocytic leukemia [CLL] reflects Inhibition in PLCγ2 synthesis "may due to inhibition in OPA1 synthase" lead to inhibition in CXCR12 where CXCR12 is the main activator and regulator for CXCR4 synthesis Upton phospholipase effects on CXCR12. Also inhibition in PLCγ2 Bio-Synthesis will reflect reduction or inhibition in thromboxane-A production.

Osteoarthritis "OA" is characterized by a sharp expression in Gamma-Phospholipase C-1 "PLCγ1" (which catabolizes inflammations) , with decreasing "or inhibition" in PLCγ2 "PLC beta" productions (which is necessary for immune modulation, for B-cell maturation and T-cells modulation and regulate TXA2 synthesis).

The increase in PLCγ1 with Deficiency in Ser amino acids, and deficiency in proper S6K, with decreasing or inhibition in OPA1-synthase activity will lead to inhibition in PLCγ2 which leads to diabetes and early Osteoarthritis"OA" prognosis.

PLCγ2 are so necessary for  re-modulating T-cells and immune efficiencies, and necessary for regulating antigen and thromboxane-A synthesis .

The inhibitions or reduction or mutations in BTK  and its main proper PLCγ2 productions will cause an inherent inhibition or reduction in CXCL12 then will be followed by inhibition or reduction in CXCR4 then will lead to  inhibition in the regulation of B-cell maturation, migration,  adhesion, and also lead to severe decreasing in anti-inflammatory processes of immune productive efficiency.

Also inhibition in BTK and PLCγ2 mainly will reflect Inhibition in the two antigens IgM in and IgD  synthesis.

Chronic lymphocytic leukemia "CLL" reflect decreasing or inhibition of growth-promoting signaling via the B-cell receptor. The Bruton tyrosine kinase (BTK) is the important for PLCγ2 systems which are necessary for  B-cell activities and T-cells modulation.  

Bruton tyrosine kinase (Btk) is necessary to activate PLCγ2 ,11,12 which necessary to activate thromboxane A2 and necessary for modulating  immune activities and T-cells too.

Both Collagen and BTK pathways are necessary tools for re-activating PLCγ2 which catalyzes arachidonic acid (AA) release to produce thromboxane-A2 (TXA 2 ) synthesis , and necessary for B cells maturation  and critical for B-cell receptor (BCR), where, inhibition in BTK and PLCγ2 will reflect diabetes, Osteoarthritis, and the Chronic lymphocytic leukemia "CLL" disease depending on the percentage of Ser & hydroponic amino acids shortage and depending on the percentage of inhibition of necessary pathways needed for PLCγ2 synthesis and reactivities.

Also, inhibition in the availability of Ser, Tyr, Leu, Pro with inhibition in necessary hydrophobic amino acids synthesis and in BTK and then in PLCγ2 can lead to Osteosarcoma which is a cancer case that produces immature bone  (due to mutins in PLCγ2 and TLR4 productions ) found at the end of long bones, often around the knee.

Deficiency in proline with inhibition in Ser, Tyr,  leu (or mutations in synthase) and  in specific beta-subunits-calcium carrier can reflect  mutations in the  PLCγ2 (beta subunits) productions due to deficiency in proper beta-oxidation that can lead to deficiency or inhibition  in the PLCγ2 and PLC alpha, and  in MHC class two, that will lead to deficiency or inhibition "or mutations" in  "SIRPα1 and in TLR4, PD-L1 then in PD-L1" lead to isolations to that area (due to precipitation of the un functioned calcium by PLCs) that can lead to mutated immature bone and tissue synthesis.

Figure 1, Figure 2

Conflict Of Interest Statement: The author declares that the research work has been conducted in the absence of any commercial or financial relationships, that could be construed as a potential conflict of interest.

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Figure 1

Figure 2