The Enthesopathy of XLH Is a Mechanical Adaptation to Osteomalacia: Biomechanical Evidence from Hyp Mice

A major comorbidity of X-linked hypophosphatemia (XLH) is fibrocartilaginous tendinous insertion site mineralization resulting in painful enthesophytes that contribute to the adult clinical picture and significantly impact physical function. Enthesophytes in Hyp mice, a murine model of XLH are the r...

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Bibliographic Details
Published in:Calcified tissue international 2022-09, Vol.111 (3), p.313-322
Main Authors: Macica, Carolyn M., Luo, Jack, Tommasini, Steven M.
Format: Article
Language:English
Subjects:
Alkaline phosphatase
Animal models
Biochemistry
Biomechanics
Biomedical and Life Sciences
Bone matrix
Cell Biology
Comorbidity
Endocrinology
Hyperplasia
Hypophosphatemia
Life Sciences
Mechanical loading
Mechanical properties
Mechanical unloading
Mineralization
Original Research
Orthopedics
Osteomalacia
Phosphatase
Sox9 protein
Unloading
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Summary:A major comorbidity of X-linked hypophosphatemia (XLH) is fibrocartilaginous tendinous insertion site mineralization resulting in painful enthesophytes that contribute to the adult clinical picture and significantly impact physical function. Enthesophytes in Hyp mice, a murine model of XLH are the result of a hyperplastic expansion of resident alkaline phosphatase, Sox9-positive mineralizing fibrochondrocytes. Here, we hypothesized hyperplasia as a compensatory physical adaptation to aberrant mechanical stresses at the level of the entheses interface inserting into pathologically soft bone. To test this hypothesis, we examined the Achilles insertion of the triceps surae developed under normal and impaired loading conditions in Hyp and WT mice. Tensile stiffness, ultimate strength, and maximum strain were measured and compared. Biomechanical testing revealed that under normal loading conditions, despite inserting into a soft bone matrix, both the enthesophyte development (9 weeks) and progression (6–8 months) of Hyp mice were equivalent to the mechanical properties of WT mice. Unloading the insertion during development significantly reduced alkaline phosphatase, Sox9-positive fibrochondrocytes. In WT mice, this correlated with a decrease in stiffness and ultimate strength relative to the control limb, confirming the critical role of mechanical loading in the development of the enthesis. Most significantly, in response to unloading, maximum strain was increased in tensile tests only in the setting of subchondral osteomalacia of Hyp mice. These data suggest that mineralizing fibrochondrocyte expansion in XLH occurs as a compensatory adaptation to the soft bone matrix.
ISSN:1432-0827
0171-967X
1432-0827
DOI:10.1007/s00223-022-00989-7