Mechanical loading changes expression of genes involved in phosphate homeostasis and bone mineralization

Calcium (Ca2+) and phosphate (PO43−) homeostasis are coordinated by systemic and local factors that regulate intestinal absorption, influx and efflux from bone, and kidney excretion and reabsorption of these ions through a complex hormonal network. Traditionally, the parathyroid hormone (PTH)/vitamin D axis provided the conceptual framework to understand mineral metabolism. PTH secreted by the parathyroid gland in response to hypocalcemia functions to maintain serum Ca2+ levels by increasing Ca2+ reabsorption and 1,25-dihydroxyvitamin D [1,25(OH)2D] production by the kidney, enhancing Ca2+ and PO43− intestinal absorption and increasing Ca2+ and PO43− efflux from bone, while maintaining neutral phosphate balance through phosphaturic effects. FGF23 is a recently discovered hormone, predominately produced by osteoblasts/osteocytes, whose major functions are to inhibit renal tubular phosphate reabsorption and suppress circulating 1,25(OH)2D levels by decreasing Cyp27b1-mediated formation and stimulating Cyp24-mediated catabolism of 1,25(OH)2D. FGF23 participates in a new bone/kidney axis that protects the organism from excess vitamin D and coordinates renal PO43− handling with bone mineralization/turnover. Abnormalities of FGF23 production underlie many inherited and acquired disorders of phosphate homeostasis. This review discusses the known and emerging functions of FGF23, its regulation in response to systemic and local signals, as well as the implications of FGF23 in different pathological and physiological contexts.

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Bone Deformity due to Rickets and Osteomalacia in Children and Adolescents

Journal of Pharmaceutical Research International ◽

10.9734/jpri/2021/v33i47a32989 ◽

2021 ◽

pp. 59-65

Author(s):

Awadh Saeed Alqahtani ◽

Hayazi Mohammed Alshehri ◽

Nazim Faisal Ahmed ◽

Mohammed Hassan Alatawi ◽

Wurud Muteb D. Alshammari ◽

...

Keyword(s):

Vitamin D ◽

Bone Disease ◽

Bone Mineralization ◽

Phosphate Homeostasis ◽

Biochemical Tests ◽

Pathological Fractures ◽

Bone Deformity ◽

Metabolic Bone ◽

Severe Deficiency ◽

Defective Bone

Rickets is a worldwide bone disease that is associated with disorders of calcium and phosphate homeostasis and can lead to short stature and joint deformities. Osteomalacia is a major metabolic bone disease that results from a chronic and severe deficiency of vitamin D or phosphate from any cause after growth has stopped. A deficiency of vitamin D or phosphate leads to defective bone mineralization and generalized or localized vague bone pain in various parts of the skeleton and / or proximal muscle weakness. Rickets and osteomalacia are two different clinical diseases with impaired bone mineralization. Rickets occurs throughout the growing skeleton in infants and children, while osteomalacia occurs in adults after fusion of the growth plates. Rickets and osteomalacia are increasingly common in Saudi Arabia, with vitamin D deficiency being the most common etiological cause. Early skeletal deformities can occur in infants, such as soft, thin skull bones, a condition known as craniotabes. In adults, as a result of demineralization, the bones become less rigid (soft bone) with pathological fractures. The diagnosis of both diseases is based on the medical history and physical examination, radiological characteristics, and biochemical tests. Management depends on the underlying etiology.

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Osteocyte regulation of phosphate homeostasis and bone mineralization underlies the pathophysiology of the heritable disorders of rickets and osteomalacia

Bone ◽

10.1016/j.bone.2013.01.046 ◽

2013 ◽

Vol 54 (2) ◽

pp. 213-221 ◽

Cited By ~ 67

Author(s):

Jian Q. Feng ◽

Erica L. Clinkenbeard ◽

Baozhi Yuan ◽

Kenneth E. White ◽

Marc K. Drezner

Keyword(s):

Bone Mineralization ◽

Phosphate Homeostasis

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Boron Supplementation Influences Bone Mineralization by Modulating Expression of Genes Regulating Calcium Utilization

Animal Nutrition and Feed Technology ◽

10.5958/0974-181x.2017.00021.x ◽

2017 ◽

Vol 17 (2) ◽

pp. 201 ◽

Cited By ~ 1

Author(s):

T. Vijay Bhasker ◽

N.K.S Gowda ◽

S. Mondal ◽

D.T. Pal ◽

H.P. Aithal ◽

...

Keyword(s):

Bone Mineralization ◽

Expression Of Genes ◽

Calcium Utilization

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Bone mineralization and regulation of phosphate homeostasis

IBMS BoneKEy ◽

10.1138/20110516 ◽

2011 ◽

Vol 8 (6) ◽

pp. 286-300 ◽

Cited By ~ 42

Author(s):

Rony Sapir-Koren ◽

Gregory Livshits

Keyword(s):

Bone Mineralization ◽

Phosphate Homeostasis

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Cyclic Strain Enhances the Early Stage Mineral Nucleation and the Modulus of Demineralized Bone Matrix

Biomaterials Science ◽

10.1039/d1bm00884f ◽

2021 ◽

Author(s):

Doyoon Kim ◽

Byeongdu Lee ◽

Brittany Paige Marshall ◽

Stavros Thomopoulos ◽

Young-Shin Jun

Keyword(s):

Mechanical Loading ◽

Adaptive Response ◽

Early Stage ◽

Bone Mineralization ◽

Demineralized Bone Matrix ◽

Bone Matrix ◽

Cyclic Strain ◽

Musculoskeletal Development ◽

Demineralized Bone

The adaptive response of bones to mechanical loading is essential for musculoskeletal development. Despite the importance of collagen in bone mineralization, little is known about how cyclic strain influences physicochemical...

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Effect of Jagged1 on the expression of genes in regulation of osteoblast differentiation and bone mineralization ontology in human dental pulp and periodontal ligament cells

Journal of Oral Biology and Craniofacial Research ◽

10.1016/j.jobcr.2019.12.003 ◽

2020 ◽

Vol 10 (2) ◽

pp. 233-237 ◽

Cited By ~ 2

Author(s):

Kanokporn Hansamuit ◽

Thanaphum Osathanon ◽

Jaijam Suwanwela

Keyword(s):

Dental Pulp ◽

Periodontal Ligament ◽

Osteoblast Differentiation ◽

Bone Mineralization ◽

Periodontal Ligament Cells ◽

Expression Of Genes ◽

Human Dental Pulp

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Phosphorylated acidic serine–aspartate-rich MEPE-associated motif peptide from matrix extracellular phosphoglycoprotein inhibits phosphate regulating gene with homologies to endopeptidases on the X-chromosome enzyme activity

Journal of Endocrinology ◽

10.1677/joe.1.07059 ◽

2007 ◽

Vol 192 (1) ◽

pp. 261-267 ◽

Cited By ~ 61

Author(s):

Shiguang Liu ◽

Peter S N Rowe ◽

Luke Vierthaler ◽

Jianping Zhou ◽

L Darryl Quarles

Keyword(s):

Bone Marrow ◽

Enzyme Activity ◽

Stromal Cell ◽

Bone Marrow Stromal Cell ◽

Bone Mineralization ◽

Phosphate Homeostasis ◽

Marrow Stromal Cell ◽

Matrix Extracellular Phosphoglycoprotein ◽

Asarm Peptide

Inactivating PHEX (phosphate regulating gene with homologies to endopeptidases on the X chromosome) mutations cause X-linked hypophosphatemia in humans and mice (Hyp) through overproduction of fibroblast growth factor 23 (FGF23) a phosphaturic factor, by osteocytes. Matrix extracellular phosphoglycoprotein (MEPE) is also elevated in Hyp and other hypophosphatemic disorders. In addition, the administration of an ASARM (acidic serine–aspartate rich MEPE-associated motif) peptide derived from MEPE causes phosphaturia and inhibits bone mineralization in mice, suggesting that MEPE also plays a role in phosphate homeostasis. Since recent studies found that MEPE binds specifically to PHEX in vitro, we tested the effect of recombinant-MEPE and its ASARM peptide on PHEX enzyme activity in vitro and FGF23 expression in bone marrow stromal cell cultures ex vivo. We found that both recombinant MEPE and synthetic phosphorylated ASARM peptide (ASARM-PO4) inhibit PHEX enzyme activities in an in vitro fluorescent-quenched PHEX enzyme activity assay. The ASARM-PO4 peptide inhibits PHEX enzyme activity in a dose-dependent manner with a Ki of 128 nM and Vmax−i of 100%. Recombinant MEPE also inhibits PHEX activity (Ki = 2 nM and Vmax−i = 26%). Long-term bone marrow stromal cell cultures supplemented with 10 μ M ASARM-PO4 peptide resulted in significant elevation of FGF23 transcripts and inhibition of mineralization. These findings suggest that MEPE inhibits mineralization and PHEX activity and leads to increased FGF23 production. The resulting coordination of mineralization and release of a phosphaturic factor by MEPE may serve a physiological role in regulating systemic phosphate homeostasis to meet the needs for bone mineralization.

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Distinct roles for intrinsic osteocyte abnormalities and systemic factors in regulation of FGF23 and bone mineralization in Hyp mice

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00396.2007 ◽

2007 ◽

Vol 293 (6) ◽

pp. E1636-E1644 ◽

Cited By ~ 66

Author(s):

Shiguang Liu ◽

Wen Tang ◽

Jianping Zhou ◽

Luke Vierthaler ◽

L. Darryl Quarles

Keyword(s):

Bone Mineralization ◽

Fibroblast Growth Factor 23 ◽

Local Effect ◽

Wild Type ◽

Mineralization Process ◽

Phosphate Homeostasis ◽

Matrix Mineralization ◽

Age Dependent ◽

Before And After ◽

Systemic Factors

X-linked hypophosphatemia (XLH) is characterized by hypophosphatemia and impaired mineralization caused by mutations of the PHEX endopeptidase (phosphate-regulating gene with homologies to endopeptidases on the X chromosome), which leads to the overproduction of the phosphaturic fibroblast growth factor 23 (FGF23) in osteocytes. The mechanism whereby PHEX mutations increase FGF23 expression and impair mineralization is uncertain. Either an intrinsic osteocyte abnormality or unidentified PHEX substrates could stimulate FGF23 in XLH. Similarly, impaired mineralization in XLH could result solely from hypophosphatemia or from a concomitant PHEX-dependent intrinsic osteocyte abnormality. To distinguish between these possibilities, we assessed FGF23 expression and mineralization after reciprocal bone cross-transplantations between wild-type (WT) mice and the Hyp mouse model of XLH. We found that increased FGF23 expression in Hyp bone results from a local effect of PHEX deficiency, since FGF23 was increased in Hyp osteocytes before and after explantation into WT mice but was not increased in WT osteocytes after explantation into Hyp mice. WT bone explanted into Hyp mice developed rickets and osteomalacia, but Hyp bone explanted into WT mice displayed persistent osteomalacia and abnormalities in the primary spongiosa, indicating that both phosphate and PHEX independently regulate extracellular matrix mineralization. Unexpectedly, we observed a paradoxical suppression of FGF23 in juvenile Hyp bone explanted into adult Hyp mice, indicating the presence of an age-dependent systemic inhibitor of FGF23. Thus PHEX functions in bone to coordinate bone mineralization and systemic phosphate homeostasis by directly regulating the mineralization process and producing FGF23. In addition, systemic counterregulatory factors that attenuate the upregulation of FGF23 expression in Hyp mouse osteocytes are present in older mice.

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