Table 2.

Systemic/humoral regulators of phosphate (P_i) homeostasis: Phosphatonins, phosphatonin-like factors, and co-factors

Factor	Expression Pattern Cells/Tissues	Known/Putative Function	Murine KO/Mutation Models	Phenotype:
				General	Teeth
FGF23: Fibroblast growth factor 23	Highest expression in bone and highly expressed during active bone remodeling. Noted in osteocytes, osteoblasts, cementoblasts, odontoblasts, and low levels in chondrocytes, cementocytes, and osteoclasts	Regulates Pi homeostasis by controlling renal reabsorption via modulation of expression of Pi co-transporters (i.e., NPT2a, NPT2c). Inhibits expression of α-hydroxylase required for formation of Vit D. DMP1 may modulate Fgf23 expression. Vit D regulates Fgf23 expression.	Fgf23 KO	General: Premature aging-like features, e.g., shortened lifespan, hypogonadism, emphysema, organ atrophy	Alveolar bone: Accumulation of unmineralized osteoid associated with ankylosis, apoptotic cells
	Lower levels in fetal vs. postnatal and adult tissues	Reports indicate that FGF23 signals through FGF type I receptors and requires Klotho binding for activation. Low FGF23 levels in fetal tissues, with high levels in young adult and adult tissues, suggests a role in mineral homeostasis vs. skeletal development.		Mineralized Tissues: Disorganized growth plate, accumulation of unmineralized osteoid, suppressed bone turnover, ectopic calcification, decreased mass & volume in long bones	Enamel: Defective in continually erupting rodent incisors, cyst-like appearance and lack of polarity to ameloblasts
		Altered circulating levels used to diagnose Pi-wasting diseases.			Pulp: Narrow chamber, ectopic matrix formation
					Cementum: Normal appearance
					PDL: Disorganized, and decreased width
					Dentin: Normal appearance
Klotho	Expressed predominantly in kidney, also in choroid plexus, parathyroid gland, and other tissues.	Single-pass transmembrane domain and short cytoplasmic domain having b-glucuronidase activity	Klotho KO	General: Similar to Fgf23 KO mouse, e.g., rapid aging syndrome including shortened lifespan, skin and muscle atrophy, osteoporosis, and emphysema.	Incisors: Ectopic calcification, altered odontoblast morphology (with defects in predentin and dentin)
	Soluble form in circulation	Extracellular domain: Shed and secreted in blood, considered a cofactor of FGF-23 signaling and suppressor of insulin/IGF-1 signaling.		Mineralized tissues: Accelerated osteoblast aging, ectopic calcification	Molars: Ankylosis with alveolar bone
PHEX: Phosphate regulating gene with homology to endopeptidases on the X chromosome	Highest expression in osteoblasts, osteocytes, and odontoblasts	Interacts with (cleaves) small circulating factors outside of the kidney to control renal Pi homeostasis and mineralization (e.g., MEPE, DMP-1, and other SIBLINGs), releasing acidic serine and aspartic acid-rich MEPE-associated motif (ASARM) peptides (“minhibins”), potent inhibitors of mineralization	Hyp mutant mouse (3’ deletion in Phex gene)	Growth retardation, osteomalacia, reduced mineralization in growth plate, reduced bone volume and osteoclasts in long bone	Alveolar bone: Hypomineralization, increased osteoid
		Regulates expression of Fgf-23 (may be indirect)			Dentin: Hypomineralization, interglobular dentin, widened predentin, irregular dentinal tubules
					Pulp chamber: Enlarged
					Enamel: Appears normal
					Cementum: Disrupted globular appearance at SEM level (appears normal by H&E)
DMP1: Dentin matrix protein 1	High levels in osteocytes, also found in odontoblasts, cementoblasts/cytes	Considered to be required for mineralization; may regulate odontoblast and osteoblast/cyte specific genes; in osteocytes, considered to have a role in protection during mechanical loading; processed to NH2 and COOH fragments that are distributed differently in dentin and may have unique roles; suggested role as a transcription factor (regulates Dspp); may regulate Fgf-23 expression	Dmp1 KO	Increased osteoid, hypomineralized bone, defective osteocyte maturation, osteomalacia rickets, decreased bone mineral, increased crystal size	Dentin: Similar to Hyp mouse, e.g., hypomineralized with widened predentin
					PDL: Disorganized, with detachment from cementum

^*No tooth phenotype reported for Mepe KO mouse; No animal models for loss of FRP4, FGF7.