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Serum

TNF-α // Tumor Necrosis Factor alpha

Tumor Necrosis Factor α (TNFα) is a pleiotropic cytokine mainly produced by monocytes and macrophages. It was initially found to have a cytotoxic effect on tumor cells and took its name from this. This cytokine exists as a soluble and mature form and as an unprocessed membrane bound form. The soluble form can form an active homo-dimer and an homo-trimer (Barbara et al., 1996; Semenzato, 1990). TNF is shed from the membrane by the metalloprotease ADAM17 (or TACE) and released on the circulation were it can have its central role in the inflammatory response (Gooz, 2010; Old, 1985)

TIMP-1 // Tissue Inhibitor of Metalloproteinase 1

The MMPs family comprises at least 24 different MMPs with high sequence similarity in their catalytic domains. MMPs are synthetized as pro-enzymes which are inactive until removal of their pro-domain (Löffek et al., 2011; Nagase and Woessner, 1999). Tissue Inhibitor of Metalloproteinase family comprises 4 members. They are two-domain proteins with a N-Terminal domain of approximately 125 residues and a C terminal domain of about 65 residues (Brew et al., 2000).

TGF-β1 // Transforming Growth Factor beta 1

Transforming Growth Factor β1 (TGF-β1), an homodimer of two 12.5 kDa subunits, belongs to the TGF β superfamily which comprises Bone Morphogenetic Proteins, activins, inhibins, growth differentiation factors and myostatin. There are three isoforms of TGF β (TGF-β1, TGF-β2 and TGF-β3) encoded by three different genes. Even if these three isoforms interact with the same receptor (heterodimer of TGFR-1 and TGFR-2), they are implicated in slightly different biological functions (Lafyatis, 2014).

Survivin

Survivin is the smallest member of the Inhibitor of Apoptosis Protein (IAP) family. The eight members of the IAPs family contain Baculoviral IAP Repeat (BIR) motifs. Initially identified in bacculovirus, BIR motif is a sequence of approximately 70 amino acids that coordinates a zinc ion (through histidine and cystine residues)(Srinivasula and Ashwell, 2008). Survivin expression was detected in different solid cancers and lymphomas (Ambrosini et al., 1997).

SOST // Sclerostin

Scleroteosis is a genetic disorder caused by the loss of the SOST gen product. Studies of this disease characterized, among other clinical features, by progressive bone overgrowth, facial distortion, entrapment of cranial nerves and high intracranial pressure have allowed the identification of the Sclerostin (SOST) protein, which is implicated in the regulation of bone mass (Balemans et al., 2001). SOST is a glycoprotein with a cysteine-knot motif which belongs to the DAN/Cerberus family and is secreted mainly by bone dwelling osteocytes (Veverka et al., 2009).

sRANKL // Free Soluble Receptor Activator of Nuclear Factor Kappa B Ligand

Formerly known as TNF-related activation-induced cytokine (TRANCE), the receptor activator of Nf-κB ligand (RANKL) was initially identified as an osteoprotegerin ligand (Lacey et al., 2012). RANKL is a member of the TNF superfamily and exists as a transmembrane protein and in a soluble form (after proteolytic cleavage or alternative mRNA splicing). There are three known spliced variants in human and the smallest of these three variants lacks the transmembrane and the intracellular domain and is directly secreted.

PTH, Intact // Intact Parathyroid Hormone

PTH is produced in the parathyroid gland and is a key regulator in skeletal and mineral homeostasis. PTH is a 84 amino-acid peptide, with an helical conformation in the 1-34 portion of its binding domain to its receptor of type 1 (PTH1R) (Jin et al., 2000). PTH and PTH-related peptide (PTHrP) have highly conserved sequences and activates PTH1R. The C terminal fragments of the intact PTH, PTH(39-84) or PTH(53-84) bind another receptor CPTHR, expressed on bone cells (Divieti et al., 2001).

PSA // Prostate Specific Antigen

Prostate Specific Antigen (PSA) is a member of the Kallikrein related peptidase and is also known as Kallikrein-Related peptidase 3 (KLK3). Its major physiological function is the liquefaction of seminal fluid through its proteolysis activity against gel proteins. PSA is normally found in seminal fluid and only a small proportion is found in blood. The release of PSA in blood circulation is believed to be the result of architecture modification and alterations in the basement membrane when prostate tumors develop (Lilja et al., 2008).

PINP // Procollagen Type I N-Propeptide

In bone, type I collagen constitute 90% of the organic matrix. Type I collagen is first synthetized as a type I procollagen and then cleaved at its two extremities. The two cleavage fragments, named N-terminal propeptide of type I collagen (PINP) and carboxy-terminal pro-peptide (PICP) are released and are measurable in blood. Their presence in the peripheral circulation is indicative of bone formation (but not specific)(Garnero et al., 2008; Naylor and Eastell, 2012).

PIIINP // Intact N-Terminal Propeptide Of Type III Collagen

Type III collagen is present in many tissues, such as skin, vascular vessels, ligaments, skeletal muscles, synovial membrane and connective tissues. Type III collagen is an homotrimer of α1 chains encoded by a single gene (Wu et al., 2010). Collagen type III is synthetized as a large procollagen which is subjected to cleavage of its N-terminal peptide and this N-terminal propeptide of collagen type III (PIINP) is released in the blood circulation in direct proportion to newly formed type III collagen.

PIIANP // Procollagen Type IIA N-Propeptide

Type II collagen constitute 60% of cartilage weight and is found exclusively in cartilaginous tissues. Type II pro-collagen is subjected to differential splicing and produces two forms of amino-pro-peptide: PIIANP and PIIBNP, containing respectively the type IIA and type IIB exons (Rousseau, 2004). The IIB form is lacking the domain codded by exon 2: a 69-amino-acid cysteine-rich globular domain (Garnero et al., 2002). PIIANP can be specifically measured and is a biomarker for a collagen type II synthesis (Elsaid and Chichester, 2006; Rousseau, 2004).

Phosphorus

Phosphorus is present in the organism under different forms and, as a key element, is indispensable in cell processes and metabolism. In soft tissues, phosphorus exists as inorganic and organic forms (incorporated in macromolecules). Bones and teeth contain more than 80% of total phosphorus. Inorganic phosphorus is also present in serum and higher levels may reflect increased bone resorption (Takeda et al., 2012). Higher serum levels are also associated with higher risk of cardiovascular diseases (Menon and Ix, 2013).

OPG // Osteoprotegerin

Osteoprotegerin (OPG) is a secretory glycoprotein composed of 401 amino acids (mature form with 380 amino acids) and seven structural domains. OPG exists as a disulfide-linked homodimer or as a monomer (Simonet et al., 1997). OPG belongs to the TNF receptor superfamily and was initially described as a cytokine, binding essentially the Receptor Activator of Nuclear Factor κβ Ligand (RANKL).Since, OPG have been found to be implicated in other pathways (Baud’huin et al., 2013).

OC // Osteocalcin

Osteocalcin (OC), also called bone γ-carboxyglutamic acid protein (BGP), is a 49 residues containing non-collagenous protein found in bone and dental tissues. OC is produced by osteoblasts and is a vitamin K dependent protein implicated in bone formation. Initially identified as a protein limiting bone formation, new functions such as implication in glucose metabolism, reproduction and cognition have been identified since (Ducy et al., 1996; Zoch et al., 2016). OC binds to hydroxyapatite and a fraction of the newly synthetized protein is then released in blood circulation.

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