Cellular and Molecular Alterations Underlying Abnormal Bone Growth in X-Linked Hypophosphatemia
Abstract
:1. Introduction
2. X-Linked Hypophosphatemia (XLH)
2.1. Pathogenesis of XLH
2.2. Hyp Mice
3. XLH and Growth
4. Growth Plate Alterations in XLH
4.1. Changes in the Organization of GP
4.2. Impaired Hypertrophic Chondrocyte Differentiation
4.3. Alteration of Growth Factors and Local Regulators Associated with Growth Plate
5. Treatment Effects in XLH
5.1. Therapeutic Effects of 1,25D and Pi
5.2. Therapeutic Effects of GH
5.3. Therapeutic Effects of FGF23-Neutralizing Antibody (FGF23Ab) or FGF23 Signaling Blockade
6. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Skeletal manifestations |
Short stature |
Rickets in children |
Osteomalacia in adults (less severe in females) |
Osteoarthritis (common in the ankles, wrists, knees, feet, and sacroiliac joints) |
Joint and bone pain (in adults) |
Impaired mobility |
Bowed legs (valgus or varus deformities) |
Enthesophaty or calcification of tendons, ligaments, and joint capsules (in adults) |
Premature cranial synostosis and increased antero-posterior head length |
Dental abnormalities (abscesses, enamel and dentin defects) such as oral pain, delayed eruption, enlarged pulp chambers, and taurodontism of permanent molars. |
Spinal cord stenosis |
Hearing loss (in adults) |
Renal disorders |
Impaired renal tubular reabsorption of phosphate |
Renal phosphate wasting |
Biochemical abnormalities |
Hypophosphatemia |
Elevated circulating FGF23 concentrations |
Low or normal levels of 1.25(OH)2D or calcitriol |
Normal or slightly increased levels of serum PTH |
Increased levels of circulating α-Klotho |
Elevated levels of serum alkaline phosphatase |
Normal calcemia |
FGF23: Fibroblast growth factor 23; 1.25(OH)2D: 1.25-dihydroxyvitamin D; PTH: Parathyroid hormone. |
Syndromes | Cause |
---|---|
XLH | PHEX mutations |
ADHR | FGF23 mutations |
ARHR1 | DMP1 mutations |
ARHR2 | ENPP1 mutations |
ARHR3 or Raine syndrome | FAM20C mutations |
Osteoglophonic dysplasia * | FGFR1 mutations |
Jansen-type metaphyseal chondrodysplasia | PTHRP1 mutations |
Epidermal nevus syndrome | FGFR3 mutations |
DAKGM | KL mutations |
McCune–Albright syndrome | GNAS |
Epidermal nevus syndrome |
Regulators | Expression/Effect at the GP | X-Linked Hypophosphatemia | |
---|---|---|---|
Systemic regulators | |||
GH | Resting and Proliferative zones | Normal/Low levels | |
Serum Calcium | Hypertrophic | Normal levels | |
Urine calcium | − | Low levels | |
Circulating phosphate | − | Increased | |
Urine phosphate | − | Increased | |
1.25(OH)2D3 | Proliferative and hypertrophic | Normal/Low levels | |
PTH | Hypertrophic | Normal/high levels | |
Local regulators | |||
FGF23 | Prehypertrophic | Increased | |
FGFR1 | Prehypertrophic and hypertrophic | Increased | |
FGFR3 | Prehypertrophic and hypertrophic | Increased | |
PTHrP | Prehypertrophic | Increased levels | |
MEPE | Hypertrophic | Increased levels | |
AQP1 | Hypertrophic | Decreased levels | |
NKCC1 | Hypertrophic | Decreased levels | |
Col10a1 | Hypertrophic | Increased expression in bone | |
MMP13 | Hypertrophic | Increased levels | |
MMP9 | Hypertrophic | Decreased levels | |
VEGF | Hypertrophic | Decreased levels | |
IGF1 | Hypertrophic | Decreased levels | |
pERK1/2 | Proliferative and prehypertrophic | Increased levels | |
ALP | Hypertrophic | Increased levels | |
OCN | Hypertrophic | Decreased levels | |
BSP | Hypertrophic | Decreased levels | |
ON | Hypertrophic | Increased levels | |
TRAP | Late hypertrophic | Increased levels | |
CLCN7 | Hypertrophic | Increased levels | |
ATPase H+ | − | Increased levels | |
NHEDC2 | − | Increased levels |
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Fuente, R.; García-Bengoa, M.; Fernández-Iglesias, Á.; Gil-Peña, H.; Santos, F.; López, J.M. Cellular and Molecular Alterations Underlying Abnormal Bone Growth in X-Linked Hypophosphatemia. Int. J. Mol. Sci. 2022, 23, 934. https://doi.org/10.3390/ijms23020934
Fuente R, García-Bengoa M, Fernández-Iglesias Á, Gil-Peña H, Santos F, López JM. Cellular and Molecular Alterations Underlying Abnormal Bone Growth in X-Linked Hypophosphatemia. International Journal of Molecular Sciences. 2022; 23(2):934. https://doi.org/10.3390/ijms23020934
Chicago/Turabian StyleFuente, Rocío, María García-Bengoa, Ángela Fernández-Iglesias, Helena Gil-Peña, Fernando Santos, and José Manuel López. 2022. "Cellular and Molecular Alterations Underlying Abnormal Bone Growth in X-Linked Hypophosphatemia" International Journal of Molecular Sciences 23, no. 2: 934. https://doi.org/10.3390/ijms23020934