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  • Review Article
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Skeletal and extraskeletal disorders of biomineralization

An Author Correction to this article was published on 17 October 2022

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Abstract

The physiological process of biomineralization is complex and deviation from it leads to a variety of diseases. Progress in the past 10 years has enhanced understanding of the genetic, molecular and cellular pathophysiology underlying these disorders; sometimes, this knowledge has both facilitated restoration of health and clarified the very nature of biomineralization as it occurs in humans. In this Review, we consider the principal regulators of mineralization and crystallization, and how dysregulation of these processes can lead to human disease. The knowledge acquired to date and gaps still to be filled are highlighted. The disorders of mineralization discussed comprise a broad spectrum of conditions that encompass bone disorders associated with alterations of mineral quantity and quality, as well as disorders of extraskeletal mineralization (hyperphosphataemic familial tumoural calcinosis). Included are disorders of alkaline phosphatase (hypophosphatasia) and phosphate homeostasis (X-linked hypophosphataemic rickets, fluorosis, rickets and osteomalacia). Furthermore, crystallopathies are covered as well as arterial and renal calcification. This Review discusses the current knowledge of biomineralization derived from basic and clinical research and points to future studies that will lead to new therapeutic approaches for biomineralization disorders.

Key points

  • The generation of pyrophosphate and matrix vesicles are key steps in regulating the formation of hydroxyapatite, the major building block of all mineralized tissues.

  • Tissue-level pyrophosphate degradation by tissue non-specific alkaline phosphatase, which is expressed by ossifying tissues, allows hydroxyapatite formation to proceed and calcification to take place.

  • Fibroblast growth factor 23 (FGF23) is a major regulator of blood levels of phosphate and 1,25 dihydroxy vitamin D; decreased levels of FGF23 cause rickets or osteomalacia whereas increased levels cause ectopic calcification.

  • Exposure to excessive fluoride leads to substitutions of the hydroxyl group of hydroxyapatite by fluoride and results in altered tooth enamel and skeletal complications, including osteomalacia and fractures (fluorosis).

  • Non-hydroxyapatite crystal formation of minerals or drugs (crystallopathies), often promoted by adhesive proteins or neutrophil extracellular traps (especially in excretory organs), can induce inflammation-related pathogenic responses.

  • Dysregulation of the hormonally controlled critical process of urinary calcium and phosphate reabsorption in the kidney can result in pathological calcification (nephrocalcinosis and nephrolithiasis).

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Fig. 1: Hydroxyapatite formation and regulation.
Fig. 2: Effective treatment of hypophosphatasia.
Fig. 3: Effective treatment of X-linked hypophosphataemia.
Fig. 4: Central nervous system complications of X-linked hypophosphataemia.
Fig. 5: Renal calcification and hypercalciuria.
Fig. 6: Pathophysiology of vascular mineralization.

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Acknowledgements

The Menarini Foundation (Fondazione Internazionale Menarini) supported the conference in Florence, Italy, on Biomineralization in Health and Disease, which served as impetus and inspiration for this article. H.J.A. acknowledges the support of the Deutsche Forschungsgemeinschaft (AN372/16-2, 20-2, 30-1). M.T.C. acknowledges the support of the Division of Intramural Research of the National Institute of Dental and Craniofacial Research, NIH. R.K. acknowledges the support of NIH grants R01 DK 107870 and DK125252, grants from the Fred C. and Katherine B. Andersen Foundation, the Ruth and Vernon Taylor Professorship, and a Distinguished Investigator Award from the Mayo Clinic. A.L. acknowledges the support of the Université de Paris Saclay and Assistance Publique Hôpitaux de Paris, France. D.A.T. acknowledges the support of NIH Grants HL114806 and HL069229, the American Diabetes Association grant #1-18-IBS-224, the J.D. and Maggie E. Wilson Distinguished Chair in Biomedical Research, and the Louis V. Avioli Professorship in Mineral Metabolism Research. R.V.T. acknowledges the support of a Wellcome Trust Investigator Award, National Institute for Health Research (NIHR) Senior Investigator Award, and the NIHR Oxford Biomedical Research Centre Programme.

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All authors researched data for the article. M.T.C., G.M., H.J.A., G.B., J.A.C., P.E., R.K., A.L., L.S., D.A.T., R.W., M.P.W., M.L.B. and R.V.T. contributed substantially to discussion of the content. M.T.C., G.M., H.J.A., G.B., J.A.C., P.E., R.K., A.L., L.S., D.A.T., R.W., M.P.W., M.L.B. and R.V.T. wrote the article. All authors reviewed and/or edited the manuscript before submission.

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Correspondence to Michael T. Collins.

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H.J.A. received consultancy fees from Inositec Inc. in the context of the development of crystallization inhibitors. The other authors declare no competing interests.

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Glossary

Fluorosis

Fluorosis is a condition caused by exposure to high levels of fluoride and is characterized by generalized osteosclerosis or osteopenia, trabecular blurring, osteophytes (including bridging between the vertebral bodies), and rickets in children.

Calcification nodules

Roundish structures that appear between collagen fibrils in mineralizing tissue, formed from coalescing matrix vesicles and growing hydroxyapatite crystals.

Calcification islands

Elongated crystals of forming hydroxyapatite that run parallel to collagen fibrils.

Osteoid

Unmineralized extracellular matrix.

Craniosynostosis

A congenital defect in which the sutures in the skull fuse early, which leads to a misshaped head and, in more severe cases, causes increased intracranial pressure.

Phase 1 mineralization

The rapid mineralization phase immediately following osteoid deposition during which bone reaches approximately 75% of its total mineralized content.

Phase 2 mineralization

A second, longer phase of mineralization during which mineralization is completed.

Enthesophytes

Abnormal bone deposition in the ligaments and/or tendons commonly seen in adults with hypophosphataemic disorders of various aetiologies.

Calculi

In the context of crystal biology, calculi are a dense aggregate of crystals large enough to be seen on radiographs.

Paraproteins

These are normally (or abnormally) appearing proteins, often monoclonal immunoglobulin or immunoglobulin light chain, present in the blood or urine at high enough concentrations to cause pathology.

Neutrophil extracellular traps

Neutrophil extracellular traps are extracellular aggregates of primarily DNA fibres.

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Collins, M.T., Marcucci, G., Anders, HJ. et al. Skeletal and extraskeletal disorders of biomineralization. Nat Rev Endocrinol 18, 473–489 (2022). https://doi.org/10.1038/s41574-022-00682-7

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