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2.Bone physiology and mineralization
Bone is a highly specialized connective tissue which has important physiological and mechanical functions 10. In addition to its role in providing rigidity to the skeleton for locomotion and protection of visceral organs; it plays other crucial vital functions 11. Bone formation occurs by either process: endochondral ossification or intramembraneous ossification 12.
Bone as a structure consists of matrix, minerals and osteogenic cells. The matrix is composed mainly of type I collagen, proteoglycans, and non-collagenous proteins including osteopontin (OPN), osteocalcin (OCN) and osteonectin secreted by osteoblasts. Two thirds of total bone matrix is made up of HA crystals or calcium phosphate ions. Other minerals include magnesium, potassium, and sodium 10.
Cells within the bone include osteoblast, osteoclast, and osteocytes. Osteoblasts major function is the synthesis of collagen and organic matrix. Osteoclasts functions in bone remodeling i.e. degradation of the bone matrix by the release of acid and lytic enzymes 13. Osteocytes act as mechanosensors converting the mechanical force stimulus into biochemical signals and actively involved in bone turnover 14.
2.1Biomineralization Process
Biomineralization is the process of mineral deposition in particular tissues leading to hardening and stiffening of the mineralized tissue. It occurs in various living organisms, of which are the vertebrates where the deposited mineral is HA. It is a well-orchestrated process of crystal formation within matrix vesicles (MVs) budding from the surface of hypertrophic chondrocytes, osteoblasts and odontoblast and their deposition in between collagen fibrils lying in the extracellular matrix.15 Recent in vitro studies have shown that MVs are not the exclusive vesicles which function in HA nucleation. Rather, in various osteoblastic cultures, nucleation occurs within various cell derived structures including in addition to MVs, calcospherulites and biomineralization foci.16 In this manuscript focus will be on MVs because these are the most studied and well defined. MVs are membrane invested vesicles that contain all necessary biochemical machinery required for availability of raw mineralization materials and balancing the inorganic pyrophposphate/ inorganic phosphate (PPi/Pi) ratio. A recent proposed mechanism for mineralization steps include: 1) HA crystals nucleation within MVs, 2) MVs bud from bone (cartilage or dentin) forming cells and interact with collagen fibrils through specific proteins and lipids, 3) MVs rupture and release HA into extracellular matrix (ECM).17 Tissue nonspecific alkaline phosphatase (TNAP) is an ectoenzyme linked to MVs membrane by glycosylphosphatidylinositol and function in hydrolysis of PPi providing Pi. 18PPi inhibit hydroxyapatite formation by binding to these crystals and preventing further growth. PPi is provided by ectonucleotidepyrophoshatase (NPP1) by the hydrolysis of adenosine triphosphate (ATP) preferentially and other nucleoside triphosphates such as guanosine triphosphates (GTP). PPi can also be provided from the membrane transporter: progressive Ankylosis protein homolog (ANKH). Within MVs Pi are provided by type III sodium/inorganic phosphate (Na/Pi) cotransporter and PHOSPHO1. PHOSPHO1 is a cytosolic phosphatase which cleaves Phosphatidylethanolamine (PE) and Phosphatidylcholine (PC) releasing Pi.19 The internal layer of MVs is rich in phosphatidylserine, a lipid with high affinity for both calcium and phosphate. MVs have the ability of interaction with collagen type II and X mediated by membrane bound annexin A5 (AnxA5) which are Ca2+ and phospholipid binding proteins stimulating Ca2+ influx into the vesicles.20 The process is mediated by the action of several molecules and steps making it highly regulated and complex(Figure 1).
Ectopic expression of TNAP is a very imortant factor behind pathological calciification knowing that TNAP and collagen type I proteins are sufficient for triggering extracellular matrix mineralization.20

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