I. Introduction :

Osteoarthritis (OA) is the most common chronic disease of human joints specifically in the case of the weakness in immune efficiency . OA is the basis of the catabolic cycles of the pathologic cases changes involves in all the tissues including sharp reductions in anti inflammatory alpha subunits which necessary for restimulating the joints recoveries ; that, at early stage, it has the nature of inflammations with varying degrees of severity, that in the reductions of anti inflammatory main short cycles and tools will lead to change anabolic cycles in all tissues including joints to mostly catabolic processes and cycles, and it's pathogenic changes can grow and increases, exactly as cancer if it's main roots will not recovered through re-strengthen full antiinflammatory cycles .

Muscle weakness, and its relaxations has strong links with the basis of osteoporosis pathogen, and with the weakness and relaxation of arteries compositions and activities , and the dropping in blood pressure , where first definition are declared as a sharp decline in the functions of the tissue cells mitochondria and so sharp decline in the productions of mitochondrial enzymes from its active membrane .

Abstract :

Osteoarthritis is a sharp reduction in Thymine nucleotides that reflect sharp reductions in mitochondrial synthase, phospholipase, and cox2 enzymes lead to reduction in TXA2 alpha subunits productions which will lead to reduction in feedback for VEGF-A alpha subunits productions, lead to decreasing in PPARs reactivities, and increasing in catabolic processes by the effects of VEGF-B on joints, and on muscles.

Osteoprotegerin (OPG), which is a soluble glycoprotein , and is distributed in tissues including bonebuilding cells (osteoblasts) are regulating both bone and vascular anabolism but under control of antiinflammatory engine and its tools productions which are TXA2 alpha subunits and then it's feedback VEGF-A alpha subunits and cells . Where Osteoprotegerin is the alpha subunits that activated by TXA2 alpha subunits productions.

A sharp drop in the productions of TXA2 alpha subunits due to a sharp reductions of the activities of phospholipase, and synthase and Cox2 enzymes on inflammations molecules , will lead to a sharp reductions in VEGF-A alpha subunits productions which occured due to the feedback from the TXA2 alpha subunits which produced from the effect of the active mitochondrial enzymes on toxicities molecules and on inflammations molecules .

Where the so imp feedback from TXA2 alpha subunits to stimulate the production of VEGF-A alpha subunits is considered to be an essential imp steps for the productions of VEGF-A alpha subunits and re-strengthen anti-inflammatory engine and its micro alpha subunits tools ,for re back reproduce endothelin-1 and reactivate G-actin filaments. Where TXA2 & VEGF-A alpha subunits are having so strong basic roots with chromosome composition functions , where, if histone increased in nucleus genes compositions , will cause delaying in many of the productive metabolic cycles in living cells which are controlled originally from the basic of the chromosome compositions .

The mitochondrial synthase enzymes are involved in pyrimidine synthesis specifically from purine nucleotides, which are considered to be the rate of pyrimidine limiting biosynthesis in tissues cells .

Sharp Reductions in anti-inflammatory TXA2 alpha subunits productions which have the so imp feedback steps to produce VEGF-A subunits, is the main reasons for the reduction in VEGF-A alpha subunits productions and inhibition in its reverse cycles for stimulating G-actin filaments and ET-1 reactivities, which are the main reason for osteoporosis with cardiovascular pathogenic disease.

Where sharp drops in TXA2 and VEGF-A alpha subunits productions will lead to accumulations of toxicities and impurities in interstitium fluid and in blood, and will lead to re-feed back from toxicities molecules to reform unknown organic and inorganic toxic molecules that lead precipitations in arteries and forming unknown inorganic molecules in interstitium fluid that will be appear to us are produced from bone cells and Cartilage.

Osteoarthritis is a sharp reductions in Thymine pyrimidine nucleotides synthesis from purines nucleotides which in necessary for Leu synthesis.

Pyrimidine and Purine nucleotide metabolic synthesis and their limit of regulations has strong relations to osteoporosis pathogens.

II. Materials:

Osteoblasts _(TXA2 alpha subunits) Thromboxane-A2, _(VEGF-A alpha subunits ) vascular endothelial growth factor alpha subunits -VEGF B subunits, _Mitochondrial enzymes: 1,TXA2 synthase, 2,phospholipase enzyme,3, cox2 _Osteoprotegerin (OPG. _AMPK, TOR protein, _endothelin_1, _G_actin filaments isoforms, _TNFα tumor necrosis Factoralpha , _TGF-β subunits, _Osteogenic cells _G protein alpha 13 _(Thymine) pyrimidine and purines _Collagen bone matrix _amidotransferase (PPAT) enzymes

III. Methods And Results

The increasing of histone and glutamine in blood and in tissues interstitium will reflects specifically the reductions of leucine amino acids synthesis and activities, which are so necessary for mostly all metabolic reactivities in tissues cells and joints through the re-synthesis of effective sestrin Leu active carrier tools which are having its own active AMPK and TOR protein and are energized by ribosomal ATPase and G_actin ATPase proper activities.

Oesteogeninc cells due to reductions or deficiency in Leu (CTT) amino acids avaliablities is producing gamma-Glutamine peptides that in normal cases : gamma glutamate (GAA) protein is supposed to give feedback to produce alpha-Leu (CTT) protein through translations processes and that will be done by mitochondrial synthase enzymes , and phospholipase enzymes where have been synthesised from mitochondrial membrane , where synthetase enzymes responsible for reforming and producing Thymine nucleotides from purines, which by mechanism of synthetase enzymes [6].

In case of Osteoporosis, the Collagen bone matrix that have been expressed by calcified plaque is a protein containing gamma-carboxy-glutamate, which are formed due full reductions in carboxyl-phosphatesynthetase enzymes, which has two forms in mitochondria and in cytoplasm [6].

Due to absence of alpha-subunits, the beta (in trace percentage compared to gamma peptides)subunits & gamma subunits peptides will be always produced due to catabolic processes and will always following catabolic processes, and will always miss anabolic processes which should be done through feedback from beta and gamma subunits peptides to produce alpha subunits .

Alpha cells or subunits are the main for Bone synthesis, and the feedback from beta and Gamma peptides subunits to produce alpha peptides subunits are so necessary step to be done by effect of mitochondrial enzymes including phospholipase and synthase enzymes. The synthase mitochondrial enzymes are involved in pyrimidine synthesis specifically from purine nucleotides, which are considered to be the rate of pyrimidine limiting biosynthesis in tissues cells .

Sharp Reductions in anti-inflammatory TXA2 alpha subunits productions which have the so imp feedback steps to produce VEGF-A subunits, is the main reasons for the reduction in VEGF-A alpha subunits productions and inhibition in its reverse cycles for stimulating G-actin filaments and ET-1 reactivities, which are the main reason for osteoporosis with cardiovascular pathogenic disease.

Where sharp drops in TXA2 and VEGF-A alpha subunits productions will lead to accumulations of toxicities and impurities in interstitium fluid and in blood, and will lead to re-feed back from toxicities molecules to reform unknown organic and inorganic toxic molecules that lead precipitations in arteries and forming unknown inorganic molecules in interstitium fluid that will be appear to us are produced from bone cells and cartilages.

The full reductions in leucine amino acids activities will reflect the full reductions in Thymine nucleotides, which need mitochondrial enzymes to be in proper productive conditions to act on toxic & impurities molecules and on inflammations products to produce TXA2 alpha subunits which are the main signals rings for feedbaxk for VEGF-A alpha subunits productions, which are the main control root for resynthesis the VEGF-B , and the stimulations of PPARs proliferation generative genes which will be done by VEGF-A alpha subunits functions .

VEGF can act as a direct proinflammatory mediator during the pathogenesis of RA, and protect rheumatoid synoviocytes from apoptosis, which contributes to synovial hyperplasia [11], also, the same function of VEGF-A alpha subunits which produced from TXA2 alpha subunits by the actions of mitochondrial enzymes on inflammations molecules, are protecting bone-building cells (osteoblasts) joints, and arteries from catabolic processes through reconstructing regulated anabolic cycles including mitochondrial enzymes resynthesis and reactivations to PPARs proliferation genes and resynthesis sestrin Leu carrier activities for re strengthen immune efficiency.

The Symptoms of Pathogenic osteoporosis is : _Poor general health _Low body weight, _Estrogen deficiency, _Poor in general, immune activities, _Poor vision despite correction, _Falling, _Full reduction in physical activity depending on the depree of osteoporosis. The Poor in general, immune activities, and Poor in vision despite correction indicate to me that there are a poor in TXA2 alpha subunits, and thus poor in VEGF-A alpha synthesis productions and then poorly in feedback for endothelin-1 productions and poor in G-actin filaments activities and in signals transmission, then full reduction in PPARs and MAPK pathways. The Decreasing in Muscle contraction and relaxations efficiency, and the appearance of osteoporosis pathogens symptoms are so linked to each others and linked to reductions in anabolic processes and cycles means reductions in PPARs genes activities , and increasing in catabolic processes .

Stimulations to PPARs activities can be reduced by reductions in VEGF-A alpha subunits productivity, due to the reductions in TXA2 alpha subunits productions with deficiency in AMPK proteins activities with its main MAPK pathways activities including reductions in ribosimal ATPase , or in other definitions the mainly reductions in the synthesis of mitochondrial enzymes : Cox2, phospholipase and in synthase enzymes will lead to reductions in TXA2 alpha, thus reduction in VEGF-A alpha subunits productions thus will lead to reductions in PPARs genes activities .

Calcified plaques were also shown to express several bone matrix proteins such as type I collagen, gla (gamma carboxyglutamate)-containing proteins, and matrix-gla protein, bone morphogenetic protein (BMP)-2 and -4, osteopontin, osteonectin, and bone sialoprotein [1,2,3]. Osteogenic cells, called calcifying vascular cells (CVCs), were identified in atherosclerotic plaques (1, 5).

Pyrimidine and Purine nucleotide metabolic synthesis and their limit of regulations has strong relations to osteoporosis pathogens. That Purines begins with the synthesis of a pyrophosphate to carbon 1 of ribose-5phosphate, creating phosphoribosylpyrophosphate (PRPP),

Where the pyrophosphate is replaced by an amine from glutamine in catabolic reactions by the effect of PRPP amidotransferase (PPAT) enzymes which are fully depending on ribosomal ATPase and on G-actin ATPase activities activities , then the product will be 5-phosphoribosylamine (5-PRA), but in case of full reduction in pyrimidine nucleotides , the gamma carboxy glutamate will appear in interstitium fluid and in blood looking for feedback for alpha cells and alpha subunits re-productions, and that collagen, gla (gamma carboxyglutamate has been found in the research works [1,2,3] .

Purine nucleotides

have to be regulated through pyrimidine synthesis and vise versa, and that regulations are fully depending on mitochondrial enzymes that can produce synthetase enz which is so imp for re-producing pyrimidines nucleotides from purines to resynthesis the so imp leucine amino acids which are running the most imp metabolic cycles with the help of other amino acids as tyrosine, Gly, Phe, Ser and therionin amino acids including brain activities and for resynthesis alpha subunits productions TXA2 from the activities of mitochondrial enzymes on toxicity .

Pyrimidine synthesis and their limiting in regulations in tissues cells is so imp for producing avaliablities of Thymine nucleotides for controlling amino acids and for re-synthesis Leu(TTA & TTG) amino acids and other branched amino acids for resynthesis sestrin-Leu carrier activities for anabolic cycles and for muscles, cartilage, and joints recoverable .

The thermodynamic potential and the regulations limiting of the abiotic synthesis of the common nucleobases adenine, cytosine, guanine, and thymine, and the two monosaccharides ribose and deoxyribose and their concentrations are depending on ribosomal functions and on mitochondrial membrane activities and its production to necessary enzymes for acting on foreign molecules and on toxicities including inflammation.

DNA & RNA activities are depending mainly on Thymine nucleotides synthesis and regulated with purine nucleotides, and dépending on ATPase polarizations activities , that all are necessary for anabolic reactions and catabolic processes. Where the sharp reductions in the anabolic processes reflects sharp reduction in alpha subunits synthesis , and reductions in the stimulations to PPARs genes activities, and will reflect shap increasing in beta subunits activities and in catabolic processes, consequently, will reflect a sharp reductions in anti inflammation cycles, and sharp increasing in toxicities and inorganic molecules in bone marrow and their precipitation in interstitium fluid between cells and in arteries .

Is the reduction in anabolic cycles can leed to Precipitation in capillaries and arteries? Yes, reductions in anabolic processes means reduction in PPARs genes functions means reductions in mitochondrial activities thus reductions in mitochondrial synthase, phospholipase and Cox2 enzymes means reductions in lipid metabolism and in functioning inflammation molecules which lead to their accumulations in interstitium fluid between cells and in blood vessels, consequently will lead to isolations of some tissue cells from other tissues and preventing the G_actin signals transmission genes throughout isolated cells , that can lead to cancer problems too. . Osteoprotegerin (OPG), which is a soluble glycoprotein , and is distributed in tissues including bonebuilding cells (osteoblasts) are regulating both bone and vascular anabolism but under control of antiinflammatory engine and its tools productions which are TXA2 alpha subunits and then it's feedback VEGF-A alpha subunits and cells . Where Osteoprotegerin is the alpha subunits that activated by TXA2 subunits productions. human TXA2 subunits (which is necessary for anti inflammations effects) receptor interact with G alpha 13 ( which plays an important role in controlling cell growth), to activate intracellular signaling [8]. The G-alpha-13 subunit (nucleotide-binding protein) is the alpha subunit that activated by TXA2 alpha subunits productions for osteoblasts activities and vascular anabolic processes, that the activations of G alpha 13 subunits is the main .

The reduction in TXA2 subunits synthesis from the effect of mitochondrial enzymes on inflammations molecules will reflect reductions in G-alpha-13 subunit nucleotide-binding protein, and reductions in the stimulations of PPARs activities , and also, will reflect reductions in Thymine nucleotides, and reductions in Leu activities, and will reflect full reductions in most of pyrimidine nucleotides synthesis and its regulations limits controls (which done be mitochondria proper activities through active synthetase enzyme productions ) , then will lead to increasing in its beta and Gamma subunits and accumulations , where later will be characterized by the appearance of gamma carboxy glutamate which reflect the full reductions in Thymine nucleotides, and deficiency in Leu activities in interstitium fluid between tissues cells, and thus, will lead to reductions in sestrin Leu carrier tools activities, which characterized as the active tool for anabolic processes and for reactivating its proper genes signals transmitting for anabolic processes for all tissues cells including bones cells.

Synthesis of TNF-α require the presence of alpha G-protein "alpha-13 subunit of guanine" for later TGF-β synthesis, but we've to give notice that only TGF-β will cause cartilage damage in the absence & deficiency of TNF-α synthesis .

Where TGF-β subunits is the catabolic arms from alpha subunits (TNFα alpha subunits ) for acting on toxicity in interstitium fluid and in blood for specific alpha subunits re-productions (TXA2 alpha subunits ), which will re-feedback for synthesis higher molecular alpha subunits in functions and responsibilities which is VEGF-A subunits, for later all previous steps will give the final indications for the internal anti-inflammatory tools degree of activities and effecincy . Where, Blood-induced joint damage is fully prevented by blocking IL-1β with a monoclonal antibody or receptor antagonist, not by TNFα blockade [9].

TNFα is secreted by the same cells in joints that synthesize IL-1β, and its increased concentration is also observed in the same elements, such as synovial fluid, synovial membrane, cartilage, and subchondral bone layer [10].

In the cells of the joints, in regular normal cases of synovial fluid the compositions of IL-1β have to follow active imp steps of autocrine process under the effects of mitochondrial synthase, phospholipase, and Cox2 enzymes, then Cox2 respectively for acting on and functioning the toxicity of the bonded inflammation molecules through IL-1B, then by feedback process will re-produce TNFα subunites, which will stimulate the re-synthesis of their main cytokines alpha subunits TNFα, IL-6 in a limit regulations.

have to be regulated by pyrimidine synthesis and vise versa, and that regulations are fully depending on mitochondrial active enzymes that can produce synthetase enz which is so imp for re-producing and synthesis the Thymine pyrimidines nucleotides from purines for re-synthesis the so imp leucine amino acids which are running the most imp metabolic cycles.

The main autocrine imp steps between beta and alpha subunits productions are the so imp steps for anti inflammations processes, and are mainly controlled by mitochondrial membrane functions, by ribosomal ATPase activities and by G-actin filaments isoforms polarization activities.

Where the TNFα subunits has been observed to be secreted by cells in the joints for IL1B synthesis for functioning the inflammation molecules in the joint .

I would like to give my imp notes that all beta subunits and beta cells are for catabolic processes for functioning inflammation molecules and foreign bodies, and in normal situations are having the limit regulations effects that have to follow the autocrine imp process by the effects of mitochondrial phospholipase, cox2 and synthases enzymes for re-producing VEGF-A alpha subunits for reactivations G-actin filaments again and reactivate endothelin-1 biological molecules for ensuring and re continuing their recoveries functions through re-stimulations to MAPK pathways and PPARs activities in the proper avaliablities of ribosomal ATPase activities, but alpha subunits and alpha cells are for running anabolic cycles and processes including tissue cells synthesis, and for controlling and regulating beta cells productions and activities .

Imp notes Appearance of VEGF-B in rumors and in interstitium fluid or in blood indicate a reductions in Thymine nucleotides synthesis may due to a sever reductions in mitochondrial membrane functions and a full reductions in TXA2 alpha subunits synthesis and therefore a reductions in VEGF-A alpha subunits productions and lead to sever reductions in back stimulations to G-actin filaments functions and feedback for endothelin-1 resynthesis and then full reductions in anti-inflammations engine and in its tools that can CAS many more dangerous health problems include Osteoarthritis, cancer, and cardiovascular disease and heart fail.

Many diseases are followed by deficiency in proper synthesis of blood cells , or deficiency in muscles functions , or poor anti inflammatory tools VEGF-A productiins through deficiency in its feedback from TXA2 alpha subunits , which produced from mitochondrial three enzymes (synthases, phospholipase, cox2) , so it is so imp to realize that skeletal and vascular activities are recoveries from several diseases are fully depending on the increasing the anti inflammatory alpha subunits keys productions (TXA2 subunits), and increasing its feedback steps for VEGF-A alpha reproductions. TXA2 alpha subunits productions, that are activated by the effects of mitochondrial enzymes : phospholipase, cox2, and TXA2 synthase enzymes on inflammations molecules are so imp for re-feedback for resynthesis the VEGF-A alpha subunits, which are carrying more active sites and functions for re-stimulate the endothelin_1 productions and re-stimulate G-actin filaments functions for re complete their imp metabolic anti-

IV. Results:

the reductions in TXA2 alpha subunits productions through reductions in the effect of mitochondrial enzymes on inflammations molecules will reflect reductions in the feedback for VEGF-A synthesis, that will reflect deficiency in the feedback for endothelin-1 re-synthesis and deficiency in restimulating G-actin filaments which are considered to be the necessary tools for genes signals transmission, then will reflect deficiency and reduction in PPARs genes activities, then reduction in inflammatory system and in its necessary tools which are TXA2 and VEGF-A subunits .