IBMS BoneKEy. 2011 June;8(6):286-300 http://www.bonekey-ibms.org/cgi/content/full/ibmske;8/6/286 doi: 10.1138/20110516 286 Copyright 2011 International Bone & Mineral Society PERSPECTIVES Bone Mineralization and Regulation of Phosphate Homeostasis Rony Sapir-Koren and Gregory Livshits Human Population Biology Research Unit, Department of Anatomy and Anthropology, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel Abstract The physiological process of biomineralization (calcification) that occurs in bone tissue takes place throughout an individual's life. Complex biological systems carefully orchestrating crosstalk between skeletal tissue and mineralization modulators include environmental and physiological factors acting as promoters or inhibitors. They consist of local mineralization promoters synthesized by osteoblasts, the phosphatases, namely, tissue-nonspecific alkaline phosphatase (TNAP) and phosphatase orphan 1 (PHOSPHO1). The local inhibitors are produced by osteoblasts and osteocytes and include inorganic pyrophosphate (PPi) and organic non-collagenous proteins or peptides of the extracellular matrix, such as osteopontin. While these modulators act in a paracrine/autocrine manner, locally synthesized fibroblast growth factor 23 (FGF23) regulates systemic phosphate levels by creating bone–kidney–parathyroid feedback loops. Locally, the active role in regulation of mineralization and phosphate homeostasis is played by inorganic forms of phosphate itself, and in particular the Pi/PPi ratio. The upper control of this ratio is mediated by circulating effects of FGF23 on phosphate homeostasis. Bone cell products allow bone to play an active role in coordinating its mineralization with total systemic phosphate regulation. IBMS BoneKEy. 2011 June;8(6):286-300. 2011 International Bone & Mineral Society Keywords: Pi/PPi ratio; Osteopontin; FGF23; PHEX; SIBLING proteins; DMP1 Bone Tissue The physiological process of biomineralization (calcification) that occurs in bone tissue takes place throughout the entire human life cycle, both during growth and development and in adult life, and is characterized by age- and gender- dependent differences. Complex biological systems carefully orchestrating crosstalk between skeletal tissue and mineralization modulators include environmental and physiological factors acting as promoters or inhibitors. This Perspective reviews major local and systemic bone mineralization regulators, emphasizing feedback loop relations with phosphate homeostasis. Bone is a specialized connective tissue. Physiologically, the mineralization process is restricted to bone tissue and teeth. Bone tissue consists of several types of functioning cells and a complex extracellular matrix (ECM). Osteoblasts, present at the bone surface, are specialized for formation and secretion of both inorganic and organic constituents of the ECM. Secreted hydroxyapatite (HA), calcium hydroxy phosphate crystals, is deposited in the spaced “hole regions” of triple helical fibrils of collagen 1 under the influence of non- collagenous proteins (1;2). Osteocytes, representing 90-95% of all bone cells, are old osteoblasts embedded within the matrix that they have produced. Osteocytogenesis, the process of osteoblast differentiation into osteocytes, is accompanied by down- regulation of many previously expressed bone markers, including alkaline phosphatase and collagen type I (3), and increased expression of genes coding for non-collagenous bone matrix polyanionic proteins, such as matrix extracellular phosphoglycoprotein (MEPE) and dentin matrix protein 1 (DMP1) (4). Osteoclasts are the third type of bone cell. They are bone- resorbing cells that appear at the bone