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Skeletal and extraskeletal disorders of biomineralization

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.

References

  1. Arnold, A. et al. Hormonal regulation of biomineralization. Nat. Rev. Endocrinol. 17, 261–275 (2021).

    CAS  PubMed  Google Scholar 

  2. Hasegawa, T. Ultrastructure and biological function of matrix vesicles in bone mineralization. Histochem. Cell Biol. 149, 289–304 (2018).

    CAS  PubMed  Google Scholar 

  3. Azoidis, I., Cox, S. C. & Davies, O. G. The role of extracellular vesicles in biomineralisation: current perspective and application in regenerative medicine. J. Tissue Eng. 9, 2041731418810130 (2018).

    PubMed  PubMed Central  Google Scholar 

  4. Golub, E. E. Role of matrix vesicles in biomineralization. Biochim. Biophys. Acta 1790, 1592–1598 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Orimo, H. The mechanism of mineralization and the role of alkaline phosphatase in health and disease. J. Nippon Med. Sch. 77, 4–12 (2010).

    CAS  PubMed  Google Scholar 

  6. Ali, S. Y., Sajdera, S. W. & Anderson, H. C. Isolation and characterization of calcifying matrix vesicles from epiphyseal cartilage. Proc. Natl Acad. Sci. USA 67, 1513–1520 (1970).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Morris, D. C., Masuhara, K., Takaoka, K., Ono, K. & Anderson, H. C. Immunolocalization of alkaline phosphatase in osteoblasts and matrix vesicles of human fetal bone. Bone Min. 19, 287–298 (1992).

    CAS  Google Scholar 

  8. Anderson, H. C. The role of matrix vesicles in physiological and pathological calcification. Curr. Opin. Orthop. 18, 428–433 (2007).

    Google Scholar 

  9. Anderson, H. C. Molecular biology of matrix vesicles. Clin. Orthop. Relat. Res. 314, 266–280 (1995).

    Google Scholar 

  10. Asmussen, N., Lin, Z., McClure, M. J., Schwartz, Z. & Boyan, B. D. Regulation of extracellular matrix vesicles via rapid responses to steroid hormones during endochondral bone formation. Steroids 142, 43–47 (2019).

    CAS  PubMed  Google Scholar 

  11. Shapiro, I. M., Landis, W. J. & Risbud, M. V. Matrix vesicles: are they anchored exosomes? Bone 79, 29–36 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Masaoutis, C. & Theocharis, S. The role of exosomes in bone remodeling: implications for bone physiology and disease. Dis. Markers 2019, 9417914 (2019).

    PubMed  PubMed Central  Google Scholar 

  13. Bonucci, E. Bone mineralization. Front. Biosci. 17, 100–128 (2012).

    CAS  Google Scholar 

  14. Balcerzak, M. et al. The roles of annexins and alkaline phosphatase in mineralization process. Acta Biochim. Pol. 50, 1019–1038 (2003).

    CAS  PubMed  Google Scholar 

  15. Kirsch, T., Harrison, G., Golub, E. E. & Nah, H. D. The roles of annexins and types II and X collagen in matrix vesicle-mediated mineralization of growth plate cartilage. J. Biol. Chem. 275, 35577–35583 (2000).

    CAS  PubMed  Google Scholar 

  16. Guicheux, J. et al. A novel in vitro culture system for analysis of functional role of phosphate transport in endochondral ossification. Bone 27, 69–74 (2000).

    CAS  PubMed  Google Scholar 

  17. Yoshiko, Y., Candeliere, G. A., Maeda, N. & Aubin, J. E. Osteoblast autonomous Pi regulation via Pit1 plays a role in bone mineralization. Mol. Cell Biol. 27, 4465–4474 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Millan, J. L. The role of phosphatases in the initiation of skeletal mineralization. Calcif. Tissue Int. 93, 299–306 (2013).

    CAS  PubMed  Google Scholar 

  19. Addison, W. N., Azari, F., Sorensen, E. S., Kaartinen, M. T. & McKee, M. D. Pyrophosphate inhibits mineralization of osteoblast cultures by binding to mineral, up-regulating osteopontin, and inhibiting alkaline phosphatase activity. J. Biol. Chem. 282, 15872–15883 (2007).

    CAS  PubMed  Google Scholar 

  20. Terkeltaub, R. A. Inorganic pyrophosphate generation and disposition in pathophysiology. Am. J. Physiol. Cell Physiol. 281, C1–C11 (2001).

    CAS  PubMed  Google Scholar 

  21. Brylka, L. & Jahnen-Dechent, W. The role of fetuin-A in physiological and pathological mineralization. Calcif. Tissue Int. 93, 355–364 (2013).

    CAS  PubMed  Google Scholar 

  22. Zoch, M. L., Clemens, T. L. & Riddle, R. C. New insights into the biology of osteocalcin. Bone 82, 42–49 (2016).

    CAS  PubMed  Google Scholar 

  23. Grynpas, M. D., Chachra, D. & Limeback, H. in The Osteoporosis Primer Vol. 23 318-330 (Cambridge University Press, 2000).

  24. Boivin, G., Chavassieux, P., Chapuy, M. C., Baud, C. A. & Meunier, P. J. Skeletal fluorosis: histomorphometric analysis of bone changes and bone fluoride content in 29 patients. Bone 10, 89–99 (1989).

    CAS  PubMed  Google Scholar 

  25. Grynpas, M. D. Fluoride effects on bone crystals. J. Bone Min. Res. 5 (Suppl. 1), S169–S175 (1990).

    CAS  Google Scholar 

  26. Moreno, E. C., Kresak, M. & Zahradnik, R. T. Physicochemical aspects of fluoride-apatite systems relevant to the study of dental caries. Caries Res. 11 (Suppl. 1), 142–171 (1977).

    PubMed  Google Scholar 

  27. Grynpas, M. D., Patterson-Allen, P. & Simmons, D. J. The changes in quality of mandibular bone mineral in otherwise totally immobilized rhesus monkeys. Calcif. Tissue Int. 39, 57–62 (1986).

    CAS  PubMed  Google Scholar 

  28. Chavassieux, P., Seeman, E. & Delmas, P. D. Insights into material and structural basis of bone fragility from diseases associated with fractures: how determinants of the biomechanical properties of bone are compromised by disease. Endocr. Rev. 28, 151–164 (2007).

    CAS  PubMed  Google Scholar 

  29. Whyte, M. P. Hypophosphatasia-aetiology, nosology, pathogenesis, diagnosis and treatment. Nat. Rev. Endocrinol. 12, 233–246 (2016).

    CAS  PubMed  Google Scholar 

  30. Weiss, M. J. et al. A missense mutation in the human liver/bone/kidney alkaline phosphatase gene causing a lethal form of hypophosphatasia. Proc. Natl Acad. Sci. USA 85, 7666–7669 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Weiss, M. J. et al. Structure of the human liver/bone/kidney alkaline phosphatase gene. J. Biol. Chem. 263, 12002–12010 (1988).

    CAS  PubMed  Google Scholar 

  32. Millan, J. L. & Whyte, M. P. Alkaline phosphatase and hypophosphatasia. Calcif. Tissue Int. 98, 398–416 (2016).

    CAS  PubMed  Google Scholar 

  33. Whyte, M. P. Hypophosphatasia: enzyme replacement therapy brings new opportunities and new challenges. J. Bone Min. Res. 32, 667–675 (2017).

    CAS  Google Scholar 

  34. Whyte, M. P. et al. Asfotase alfa therapy for children with hypophosphatasia. JCI Insight 1, e85971 (2016).

    PubMed  PubMed Central  Google Scholar 

  35. Whyte, M. P., McAlister, W. H., Mumm, S. & Bierhals, A. J. No vascular calcification on cardiac computed tomography spanning asfotase alfa treatment for an elderly woman with hypophosphatasia. Bone 122, 231–236 (2019).

    PubMed  Google Scholar 

  36. Whyte, M. P. et al. Asfotase alfa for infants and young children with hypophosphatasia: 7 year outcomes of a single-arm, open-label, phase 2 extension trial. Lancet Diabetes Endocrinol. 7, 93–105 (2019).

    CAS  PubMed  Google Scholar 

  37. Mornet, E. Hypophosphatasia: the mutations in the tissue-nonspecific alkaline phosphatase gene. Hum. Mutat. 15, 309–315 (2020).

    Google Scholar 

  38. Whyte, M. P. et al. Hypophosphatasia: validation and expansion of the clinical nosology for children from 25 years experience with 173 pediatric patients. Bone 75, 229–239 (2015).

    CAS  PubMed  Google Scholar 

  39. Whyte, M. P. et al. Enzyme-replacement therapy in life-threatening hypophosphatasia. N. Engl. J. Med. 366, 904–913 (2012).

    CAS  PubMed  Google Scholar 

  40. Guanabens, N. et al. Calcific periarthritis as the only clinical manifestation of hypophosphatasia in middle-aged sisters. J. Bone Min. Res. 29, 929–934 (2014).

    CAS  Google Scholar 

  41. Camacho, P. M. et al. Adult hypophosphatasia treated with teriparatide: report of 2 patients and review of the literature. Endocr. Pract. 22, 941–950 (2016).

    PubMed  Google Scholar 

  42. Sutton, R. A., Mumm, S., Coburn, S. P., Ericson, K. L. & Whyte, M. P. “Atypical femoral fractures” during bisphosphonate exposure in adult hypophosphatasia. J. Bone Min. Res. 27, 987–994 (2012).

    CAS  Google Scholar 

  43. Sobel, E. H., Clark, L. C. Jr, Fox, R. P. & Robinow, M. Rickets, deficiency of alkaline phosphatase activity and premature loss of teeth in childhood. Pediatrics 11, 309–322 (1953).

    CAS  PubMed  Google Scholar 

  44. Ornoy, A., Adomian, G. E. & Rimoin, D. L. Histologic and ultrastructural studies on the mineralization process in hypophosphatasia. Am. J. Med. Genet. 22, 743–758 (1985).

    CAS  PubMed  Google Scholar 

  45. Anderson, H. C., Hsu, H. H., Morris, D. C., Fedde, K. N. & Whyte, M. P. Matrix vesicles in osteomalacic hypophosphatasia bone contain apatite-like mineral crystals. Am. J. Pathol. 151, 1555–1561 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. McKenna, M. J., Martin-Grace, J., Crowley, R., Twomey, P. J. & Kilbane, M. T. Congenital hypophosphataemia in adults: determinants of bone turnover markers and amelioration of renal phosphate wasting following total parathyroidectomy. J. Bone Min. Metab. 37, 685–693 (2019).

    CAS  Google Scholar 

  47. Haffner, D. et al. Clinical practice recommendations for the diagnosis and management of X-linked hypophosphataemia. Nat. Rev. Nephrol. 15, 435–455 (2019).

    PubMed  PubMed Central  Google Scholar 

  48. Marcucci, G. et al. Phosphate wasting disorders in adults. Osteoporos. Int. 29, 2369–2387 (2018).

    CAS  PubMed  Google Scholar 

  49. Manghat, P., Sodi, R. & Swaminathan, R. Phosphate homeostasis and disorders. Ann. Clin. Biochem. 51, 631–656 (2014).

    CAS  PubMed  Google Scholar 

  50. Shimada, T. et al. Targeted ablation of Fgf23 demonstrates an essential physiological role of FGF23 in phosphate and vitamin D metabolism. J. Clin. Invest. 113, 561–568 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Goretti Penido, M. & Alon, U. S. Phosphate homeostasis and its role in bone health. Pediatr. Nephrol. 27, 2039–2048 (2012).

    PubMed  Google Scholar 

  52. Tiosano, D. & Hochberg, Z. Hypophosphatemia: the common denominator of all rickets. J. Bone Min. Metab. 27, 392–401 (2009).

    Google Scholar 

  53. Beck-Nielsen, S. S. et al. FGF23 and its role in X-linked hypophosphatemia-related morbidity. Orphanet J. Rare Dis. 14, 58 (2019).

    PubMed  PubMed Central  Google Scholar 

  54. Bai, X. et al. CYP24 inhibition as a therapeutic target in FGF23-mediated renal phosphate wasting disorders. J. Clin. Invest. 126, 667–680 (2016).

    PubMed  PubMed Central  Google Scholar 

  55. Beck-Nielsen, S. S., Brock-Jacobsen, B., Gram, J., Brixen, K. & Jensen, T. K. Incidence and prevalence of nutritional and hereditary rickets in southern Denmark. Eur. J. Endocrinol. 160, 491–497 (2009).

    CAS  PubMed  Google Scholar 

  56. Liu, S., Guo, R. & Quarles, L. D. Cloning and characterization of the proximal murine Phex promoter. Endocrinology 142, 3987–3995 (2001).

    CAS  PubMed  Google Scholar 

  57. Weng, C. et al. A de novo mosaic mutation of PHEX in a boy with hypophosphatemic rickets. J. Hum. Genet. 61, 223–227 (2016).

    PubMed  Google Scholar 

  58. Whyte, M. P., Schranck, F. W. & Armamento-Villareal, R. X-linked hypophosphatemia: a search for gender, race, anticipation, or parent of origin effects on disease expression in children. J. Clin. Endocrinol. Metab. 81, 4075–4080 (1996).

    CAS  PubMed  Google Scholar 

  59. Linglart, A. et al. Therapeutic management of hypophosphatemic rickets from infancy to adulthood. Endocr. Connect. 3, R13–R30 (2014).

    PubMed  PubMed Central  Google Scholar 

  60. Alon, U. S. et al. Hypertension in hypophosphatemic rickets — role of secondary hyperparathyroidism. Pediatr. Nephrol. 18, 155–158 (2003).

    PubMed  Google Scholar 

  61. Barros, N. M. et al. Proteolytic processing of osteopontin by PHEX and accumulation of osteopontin fragments in Hyp mouse bone, the murine model of X-linked hypophosphatemia. J. Bone Min. Res. 28, 688–699 (2013).

    CAS  Google Scholar 

  62. Addison, W. N., Masica, D. L., Gray, J. J. & McKee, M. D. Phosphorylation-dependent inhibition of mineralization by osteopontin ASARM peptides is regulated by PHEX cleavage. J. Bone Min. Res. 25, 695–705 (2010).

    CAS  Google Scholar 

  63. Murthy, A. S. X-linked hypophosphatemic rickets and craniosynostosis. J. Craniofac Surg. 20, 439–442 (2009).

    PubMed  Google Scholar 

  64. Zivicnjak, M. et al. Age-related stature and linear body segments in children with X-linked hypophosphatemic rickets. Pediatr. Nephrol. 26, 223–231 (2011).

    PubMed  Google Scholar 

  65. Carpenter, T. O., Imel, E. A., Holm, I. A., Jan de Beur, S. M. & Insogna, K. L. A clinician’s guide to X-linked hypophosphatemia. J. Bone Min. Res. 26, 1381–1388 (2011).

    Google Scholar 

  66. Balsan, S. & Tieder, M. Linear growth in patients with hypophosphatemic vitamin D-resistant rickets: influence of treatment regimen and parental height. J. Pediatr. 116, 365–371 (1990).

    CAS  PubMed  Google Scholar 

  67. Chaussain-Miller, C. et al. Dental abnormalities in patients with familial hypophosphatemic vitamin D-resistant rickets: prevention by early treatment with 1-hydroxyvitamin D. J. Pediatr. 142, 324–331 (2003).

    CAS  PubMed  Google Scholar 

  68. Biosse Duplan, M. et al. Phosphate and vitamin D prevent periodontitis in X-linked hypophosphatemia. J. Dent. Res. 96, 388–395 (2017).

    CAS  PubMed  Google Scholar 

  69. Boukpessi, T. et al. Osteopontin and the dento-osseous pathobiology of X-linked hypophosphatemia. Bone 95, 151–161 (2017).

    CAS  PubMed  Google Scholar 

  70. Che, H. et al. Impaired quality of life in adults with X-linked hypophosphatemia and skeletal symptoms. Eur. J. Endocrinol. 174, 325–333 (2016).

    CAS  PubMed  Google Scholar 

  71. Faraji-Bellee, C. A. et al. Development of enthesopathies and joint structural damage in a murine model of X-linked hypophosphatemia. Front. Cell Dev. Biol. 8, 854 (2020).

    PubMed  PubMed Central  Google Scholar 

  72. Sun, G. E., Suer, O., Carpenter, T. O., Tan, C. D. & Li-Ng, M. Heart failure in hypophosphatemic rickets: complications from high-dose phosphate therapy. Endocr. Pract. 19, e8–e11 (2013).

    PubMed  Google Scholar 

  73. Currarino, G. Sagittal synostosis in X-linked hypophosphatemic rickets and related diseases. Pediatr. Radiol. 37, 805–812 (2007).

    PubMed  Google Scholar 

  74. Glass, L. R., Dagi, T. F. & Dagi, L. R. Papilledema in the setting of x-linked hypophosphatemic rickets with craniosynostosis. Case Rep. Ophthalmol. 2, 376–381 (2011).

    PubMed  PubMed Central  Google Scholar 

  75. Rothenbuhler, A. et al. High incidence of cranial synostosis and Chiari I malformation in children with X-linked hypophosphatemic rickets (XLHR). J. Bone Min. Res. 34, 490–496 (2019).

    CAS  Google Scholar 

  76. Christie, P. T., Harding, B., Nesbit, M. A., Whyte, M. P. & Thakker, R. V. X-linked hypophosphatemia attributable to pseudoexons of the PHEX gene. J. Clin. Endocrinol. Metab. 86, 3840–3844 (2001).

    CAS  PubMed  Google Scholar 

  77. Harrell, R. M., Lyles, K. W., Harrelson, J. M., Friedman, N. E. & Drezner, M. K. Healing of bone disease in X-linked hypophosphatemic rickets/osteomalacia. Induction and maintenance with phosphorus and calcitriol. J. Clin. Invest. 75, 1858–1868 (1985).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Imel, E. A. et al. Burosumab versus conventional therapy in children with X-linked hypophosphataemia: a randomised, active-controlled, open-label, phase 3 trial. Lancet 393, 2416–2427 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Kinoshita, Y. & Fukumoto, S. X-Linked Hypophosphatemia and FGF23-Related hypophosphatemic diseases: prospect for new treatment. Endocr. Rev. 39, 274–291 (2018).

    PubMed  Google Scholar 

  80. Huiming, Y. & Chaomin, W. Recombinant growth hormone therapy for X-linked hypophosphatemia in children. Cochrane Database Syst. Rev. https://doi.org/10.1002/14651858.CD004447.pub2 (2005).

    Article  PubMed  Google Scholar 

  81. Lecoq, A. L. et al. Hyperparathyroidism in Patients With X-Linked Hypophosphatemia. J. Bone Miner. Res. 35, 1263–1273 (2020).

    CAS  PubMed  Google Scholar 

  82. Carpenter, T. O. The expanding family of hypophosphatemic syndromes. J. Bone Min. Metab. 30, 1–9 (2012).

    CAS  Google Scholar 

  83. Econs, M. J. & McEnery, P. T. Autosomal dominant hypophosphatemic rickets/osteomalacia: clinical characterization of a novel renal phosphate-wasting disorder. J. Clin. Endocrinol. Metab. 82, 674–681 (1997).

    CAS  PubMed  Google Scholar 

  84. Imel, E. A., Biggin, A., Schindeler, A. & Munns, C. F. FGF23, hypophosphatemia, and emerging treatments. JBMR Plus 3, e10190 (2019).

    PubMed  PubMed Central  Google Scholar 

  85. Imel, E. A. et al. Iron modifies plasma FGF23 differently in autosomal dominant hypophosphatemic rickets and healthy humans. J. Clin. Endocrinol. Metab. 96, 3541–3549 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Rutsch, F. et al. Mutations in ENPP1 are associated with ‘idiopathic’ infantile arterial calcification. Nat. Genet. 34, 379–381 (2003).

    CAS  PubMed  Google Scholar 

  87. Levy-Litan, V. et al. Autosomal-recessive hypophosphatemic rickets is associated with an inactivation mutation in the ENPP1 gene. Am. J. Hum. Genet. 86, 273–278 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Alon, U. S. Clinical practice. Fibroblast growth factor (FGF)23: a new hormone. Eur. J. Pediatr. 170, 545–554 (2011).

    CAS  PubMed  Google Scholar 

  89. Liu, T. et al. DMP1 ablation in the rabbit results in mineralization defects and abnormalities in Haversian canal/osteon microarchitecture. J. Bone Min. Res. 34, 1115–1128 (2019).

    CAS  Google Scholar 

  90. Ferreira, C. R. et al. Prospective phenotyping of long-term survivors of generalized arterial calcification of infancy (GACI). Genet. Med. 23, 396–407 (2021).

    CAS  PubMed  Google Scholar 

  91. Jaureguiberry, G., Carpenter, T. O., Forman, S., Juppner, H. & Bergwitz, C. A novel missense mutation in SLC34A3 that causes hereditary hypophosphatemic rickets with hypercalciuria in humans identifies threonine 137 as an important determinant of sodium-phosphate cotransport in NaPi-IIc. Am. J. Physiol. Ren. Physiol. 295, F371–F379 (2008).

    CAS  Google Scholar 

  92. Lorenz-Depiereux, B. et al. Hereditary hypophosphatemic rickets with hypercalciuria is caused by mutations in the sodium-phosphate cotransporter gene SLC34A3. Am. J. Hum. Genet. 78, 193–201 (2006).

    CAS  PubMed  Google Scholar 

  93. Bergwitz, C. & Miyamoto, K. I. Hereditary hypophosphatemic rickets with hypercalciuria: pathophysiology, clinical presentation, diagnosis and therapy. Pflug. Arch. 471, 149–163 (2019).

    CAS  Google Scholar 

  94. Haito-Sugino, S. et al. Processing and stability of type IIc sodium-dependent phosphate cotransporter mutations in patients with hereditary hypophosphatemic rickets with hypercalciuria. Am. J. Physiol. Cell Physiol. 302, C1316–C1330 (2012).

    CAS  PubMed  Google Scholar 

  95. Wrong, O. M., Norden, A. G. & Feest, T. G. Dent’s disease; a familial proximal renal tubular syndrome with low-molecular-weight proteinuria, hypercalciuria, nephrocalcinosis, metabolic bone disease, progressive renal failure and a marked male predominance. QJM 87, 473–493 (1994).

    CAS  PubMed  Google Scholar 

  96. Devuyst, O. & Thakker, R. V. Dent’s disease. Orphanet J. Rare Dis. 5, 28 (2010).

    PubMed  PubMed Central  Google Scholar 

  97. Hoopes, R. R. Jr. et al. Dent disease with mutations in OCRL1. Am. J. Hum. Genet. 76, 260–267 (2005).

    CAS  PubMed  Google Scholar 

  98. Florenzano, P. et al. Tumor-induced osteomalacia. Calcif. Tissue Int. 108, 128–142 (2021).

    CAS  PubMed  Google Scholar 

  99. Lee, J. C. et al. Characterization of FN1-FGFR1 and novel FN1-FGF1 fusion genes in a large series of phosphaturic mesenchymal tumors. Mod. Pathol. 29, 1335–1346 (2016).

    CAS  PubMed  Google Scholar 

  100. Endo, I. et al. Nationwide survey of fibroblast growth factor 23 (FGF23)-related hypophosphatemic diseases in Japan: prevalence, biochemical data and treatment. Endocr. J. 62, 811–816 (2015).

    CAS  PubMed  Google Scholar 

  101. Jiang, Y. et al. Tumor-induced osteomalacia: an important cause of adult-onset hypophosphatemic osteomalacia in China: Report of 39 cases and review of the literature. J. Bone Min. Res. 27, 1967–1975 (2012).

    Google Scholar 

  102. Minisola, S. et al. Tumour-induced osteomalacia. Nat. Rev. Dis. Prim. 3, 17044 (2017).

    PubMed  Google Scholar 

  103. Wang, H. et al. Overexpression of fibroblast growth factor 23 suppresses osteoblast differentiation and matrix mineralization in vitro. J. Bone Min. Res. 23, 939–948 (2008).

    CAS  Google Scholar 

  104. Brandi, M. L. et al. Challenges in the management of tumor-induced osteomalacia (TIO). Bone 152, 116064 (2021).

    CAS  PubMed  Google Scholar 

  105. Hartley, I. R. et al. Targeted FGFR blockade for the treatment of tumor-induced osteomalacia. N. Engl. J. Med. 383, 1387–1389 (2020).

    PubMed  PubMed Central  Google Scholar 

  106. Ketteler, M., Gross, M. L. & Ritz, E. Calcification and cardiovascular problems in renal failure. Kidney Int. Suppl. https://doi.org/10.1111/j.1523-1755.2005.09428.x (2005).

    Article  PubMed  Google Scholar 

  107. Ramnitz, M. S., Gafni, R. I. & Collins, M. T. in GeneReviews Vol. NBK476672 (eds M. P. Adam et al.) (University of Washington, 2018).

  108. Topaz, O. et al. Mutations in GALNT3, encoding a protein involved in O-linked glycosylation, cause familial tumoral calcinosis. Nat. Genet 36, 579–581 (2004).

    CAS  PubMed  Google Scholar 

  109. Benet-Pages, A., Orlik, P., Strom, T. M. & Lorenz-Depiereux, B. An FGF23 missense mutation causes familial tumoral calcinosis with hyperphosphatemia. Hum. Mol. Genet. 14, 385–390 (2005).

    CAS  PubMed  Google Scholar 

  110. Ichikawa, S. et al. A homozygous missense mutation in human KLOTHO causes severe tumoral calcinosis. J. Clin. Invest. 117, 2684–2691 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Roberts, M. S. et al. Autoimmune hyperphosphatemic tumoral calcinosis in a patient with FGF23 autoantibodies. J. Clin. Invest. 128, 5368–5373 (2018).

    PubMed  PubMed Central  Google Scholar 

  112. Ramnitz, M. S., Gafni, R. I. & Collins, M. T. in GeneReviews Vol. NBK476672 (eds M. P. Adam et al.) (University of Washington, 2018).

  113. Ramnitz, M. S. et al. Phenotypic and genotypic characterization and treatment of a cohort with familial tumoral calcinosis/hyperostosis-hyperphosphatemia syndrome. J. Bone Min. Res. 31, 1845–1854 (2016).

    CAS  Google Scholar 

  114. Clerin, V. et al. Selective pharmacological inhibition of the sodium-dependent phosphate cotransporter NPT2a promotes phosphate excretion. J. Clin. Invest. 130, 6510–6522 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Mannstadt, M. et al. Hypoparathyroidism. Nat. Rev. Dis. Prim. 3, 17055 (2017).

    PubMed  Google Scholar 

  116. Bilezikian, J. P. et al. Management of hypoparathyroidism: present and future. J. Clin. Endocrinol. Metab. 101, 2313–2324 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Underbjerg, L., Sikjaer, T. & Rejnmark, L. Long-term complications in patients with hypoparathyroidism evaluated by biochemical findings: a case-control study. J. Bone Min. Res. 33, 822–831 (2018).

    CAS  Google Scholar 

  118. Topaz, O. et al. A deleterious mutation in SAMD9 causes normophosphatemic familial tumoral calcinosis. Am. J. Hum. Genet. 79, 759–764 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Levine, M. A. Diagnosis and management of vitamin D dependent rickets. Front. Pediatr. 8, 315 (2020).

    PubMed  PubMed Central  Google Scholar 

  120. Gara, N. et al. Renal tubular dysfunction during long-term adefovir or tenofovir therapy in chronic hepatitis B. Aliment. Pharmacol. Ther. 35, 1317–1325 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Grey, A. et al. Low-dose fluoride in postmenopausal women: a randomized controlled trial. J. Clin. Endocrinol. Metab. 98, 2301–2307 (2013).

    CAS  PubMed  Google Scholar 

  122. Jha, S. K., Mishra, V. K., Sharma, D. K. & Damodaran, T. Fluoride in the environment and its metabolism in humans. Rev. Env. Contam. Toxicol. 211, 121–142 (2011).

    CAS  Google Scholar 

  123. Chen, J. et al. Coal utilization in China: environmental impacts and human health. Env. Geochem. Health 36, 735–753 (2014).

    CAS  Google Scholar 

  124. Majumdar, K. K. Health impact of supplying safe drinking water containing fluoride below permissible level on flourosis patients in a fluoride-endemic rural area of West Bengal. Indian. J. Public Health 55, 303–308 (2011).

    PubMed  Google Scholar 

  125. Mousny, M. et al. Fluoride effects on bone formation and mineralization are influenced by genetics. Bone 43, 1067–1074 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Pramanik, S. & Saha, D. The genetic influence in fluorosis. Env. Toxicol. Pharmacol. 56, 157–162 (2017).

    CAS  Google Scholar 

  127. Tamer, M. N. et al. Osteosclerosis due to endemic fluorosis. Sci. Total. Env. 373, 43–48 (2007).

    CAS  Google Scholar 

  128. Pei, J. et al. Fluoride decreased osteoclastic bone resorption through the inhibition of NFATc1 gene expression. Env. Toxicol. 29, 588–595 (2014).

    CAS  Google Scholar 

  129. Liu, Q. et al. Analysis of the role of insulin signaling in bone turnover induced by fluoride. Biol. Trace Elem. Res. 171, 380–390 (2016).

    CAS  PubMed  Google Scholar 

  130. Teotia, S. P. S., Teotia, M., Singh, K. P. & India. in 4th International Workshop on Fluorosis Prevention and Defluoridation of Water (ed. Dahi, E.) (The International Society for Fluoride Research, 2004).

  131. Khairnar, M. R., Dodamani, A. S., Jadhav, H. C., Naik, R. G. & Deshmukh, M. A. Mitigation of fluorosis — a review. J. Clin. Diagn. Res. 9, ZE05–ZE09 (2015).

    PubMed  PubMed Central  Google Scholar 

  132. Mulay, S. R. & Anders, H. J. Crystallopathies. N. Engl. J. Med. 374, 2465–2476 (2016).

    CAS  PubMed  Google Scholar 

  133. Munoz, L. E. et al. Neutrophil extracellular traps initiate gallstone formation. Immunity 51, 443–450.e444 (2019).

    CAS  PubMed  Google Scholar 

  134. Chiti, F. & Dobson, C. M. Protein misfolding, amyloid formation, and human disease: a summary of progress over the last decade. Annu. Rev. Biochem. 86, 27–68 (2017).

    CAS  PubMed  Google Scholar 

  135. Mulay, S. R., Steiger, S., Shi, C. & Anders, H. J. A guide to crystal-related and nano- or microparticle-related tissue responses. FEBS J. 287, 818–832 (2020).

    CAS  PubMed  Google Scholar 

  136. Kzhyshkowska, J. et al. Macrophage responses to implants: prospects for personalized medicine. J. Leukoc. Biol. 98, 953–962 (2015).

    CAS  PubMed  Google Scholar 

  137. Sheikh, Z., Brooks, P. J., Barzilay, O., Fine, N. & Glogauer, M. Macrophages, foreign body giant cells and their response to implantable biomaterials. Materials 8, 5671–5701 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Wang, F., Gomez-Sintes, R. & Boya, P. Lysosomal membrane permeabilization and cell death. Traffic 19, 918–931 (2018).

    CAS  PubMed  Google Scholar 

  139. Franklin, B. S., Mangan, M. S. & Latz, E. Crystal formation in inflammation. Annu. Rev. Immunol. 34, 173–202 (2016).

    CAS  PubMed  Google Scholar 

  140. Martinon, F., Petrilli, V., Mayor, A., Tardivel, A. & Tschopp, J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 440, 237–241 (2006).

    CAS  PubMed  Google Scholar 

  141. Mulay, S. R. et al. Mitochondria permeability transition versus necroptosis in oxalate-induced AKI. J. Am. Soc. Nephrol. 30, 1857–1869 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Schauer, C. et al. Aggregated neutrophil extracellular traps limit inflammation by degrading cytokines and chemokines. Nat. Med. 20, 511–517 (2014).

    CAS  PubMed  Google Scholar 

  143. Desai, J. et al. Particles of different sizes and shapes induce neutrophil necroptosis followed by the release of neutrophil extracellular trap-like chromatin. Sci. Rep. 7, 15003 (2017).

    PubMed  PubMed Central  Google Scholar 

  144. Desai, J. et al. PMA and crystal-induced neutrophil extracellular trap formation involves RIPK1-RIPK3-MLKL signaling. Eur. J. Immunol. 46, 223–229 (2016).

    CAS  PubMed  Google Scholar 

  145. Shi, C. et al. Crystal clots as therapeutic target in cholesterol crystal embolism. Circ. Res. 126, e37–e52 (2020).

    CAS  PubMed  Google Scholar 

  146. Mulay, S. R. & Anders, H. J. Crystal nephropathies: mechanisms of crystal-induced kidney injury. Nat. Rev. Nephrol. 13, 226–240 (2017).

    CAS  PubMed  Google Scholar 

  147. Worcester, E. M. & Coe, F. L. Clinical practice. Calcium kidney stones. N. Engl. J. Med. 363, 954–963 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Mulay, S. R. & Anders, H. J. Crystallopathies. N. Engl. J. Med. 375, e29 (2016).

    PubMed  Google Scholar 

  149. Mahajan, A. et al. Frontline science: aggregated neutrophil extracellular traps prevent inflammation on the neutrophil-rich ocular surface. J. Leukoc. Biol. 105, 1087–1098 (2019).

    CAS  PubMed  Google Scholar 

  150. Asselman, M., Verhulst, A., De Broe, M. E. & Verkoelen, C. F. Calcium oxalate crystal adherence to hyaluronan-, osteopontin-, and CD44-expressing injured/regenerating tubular epithelial cells in rat kidneys. J. Am. Soc. Nephrol 14, 3155–3166 (2003).

    CAS  PubMed  Google Scholar 

  151. Mulay, S. R. et al. Hyperoxaluria requires TNF receptors to initiate crystal adhesion and kidney stone disease. J. Am. Soc. Nephrol. 28, 761–768 (2017).

    CAS  PubMed  Google Scholar 

  152. Cochat, P. & Rumsby, G. Primary hyperoxaluria. N. Engl. J. Med. 369, 649–658 (2013).

    CAS  PubMed  Google Scholar 

  153. Kletzmayr, A. et al. Inhibitors of calcium oxalate crystallization for the treatment of oxalate nephropathies. Adv. Sci. 7, 1903337 (2020).

    CAS  Google Scholar 

  154. Marschner, J. A. et al. The long pentraxin PTX3 is an endogenous inhibitor of hyperoxaluria-related nephrocalcinosis and chronic kidney disease. Front. Immunol. 9, 2173 (2018).

    PubMed  PubMed Central  Google Scholar 

  155. Steiger, S. et al. Anti-transforming growth factor beta IgG elicits a dual effect on calcium oxalate crystallization and progressive nephrocalcinosis-related chronic kidney disease. Front. Immunol. 9, 619 (2018).

    PubMed  PubMed Central  Google Scholar 

  156. Duewell, P. et al. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature 464, 1357–1361 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  157. Mulay, S. R., Evan, A. & Anders, H. J. Molecular mechanisms of crystal-related kidney inflammation and injury. Implications for cholesterol embolism, crystalline nephropathies and kidney stone disease. Nephrol. Dialysis Transpl. 29, 507–514 (2014).

    CAS  Google Scholar 

  158. Lautenschlager, S. O. S. et al. Plasma proteins and platelets modulate neutrophil clearance of malaria-related hemozoin crystals. Cells https://doi.org/10.3390/cells9010093 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  159. Kumar, R., Tebben, P. J. & Thompson, J. R. Vitamin D and the kidney. Arch. Biochem. Biophys. 523, 77–86 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  160. Tebben, P. J., Singh, R. J. & Kumar, R. Vitamin D-mediated hypercalcemia: mechanisms, diagnosis, and treatment. Endocr. Rev. 37, 521–547 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  161. Zand, L. & Kumar, R. The use of vitamin d metabolites and analogues in the treatment of chronic kidney disease. Endocrinol. Metab. Clin. North. Am. 46, 983–1007 (2017).

    PubMed  PubMed Central  Google Scholar 

  162. Silver, J. & Levi, R. Regulation of PTH synthesis and secretion relevant to the management of secondary hyperparathyroidism in chronic kidney disease. Kidney Int. Suppl. 95, S8–S12 (2005).

    CAS  Google Scholar 

  163. Silver, J. & Levi, R. Cellular and molecular mechanisms of secondary hyperparathyroidism. Clin. Nephrol. 63, 119–126 (2005).

    CAS  PubMed  Google Scholar 

  164. Lieske, J. C. et al. Renal stone epidemiology in Rochester, Minnesota: an update. Kidney Int. 69, 760–764 (2006).

    CAS  PubMed  Google Scholar 

  165. Curhan, G. C. Epidemiology of stone disease. Urol. Clin. North. Am. 34, 287–293 (2007).

    PubMed  PubMed Central  Google Scholar 

  166. Curhan, G. C., Rimm, E. B., Willett, W. C. & Stampfer, M. J. Regional variation in nephrolithiasis incidence and prevalence among United States men. J. Urol. 151, 838–841 (1994).

    CAS  PubMed  Google Scholar 

  167. Park, S. & Pearle, M. S. Pathophysiology and management of calcium stones. Urol. Clin. North. Am. 34, 323–334 (2007).

    PubMed  Google Scholar 

  168. Broadus, A. E. et al. A consideration of the hormonal basis and phosphate leak hypothesis of absorptive hypercalciuria. J. Clin. Endocrinol. Metab. 58, 161–169 (1984).

    CAS  PubMed  Google Scholar 

  169. Cupisti, A. et al. Serum calcitriol and dietary protein intake in idiopathic calcium stone patients. Int. J. Clin. Lab. Res. 29, 85–88 (1999).

    CAS  PubMed  Google Scholar 

  170. Frick, K. K. et al. 1,25(OH)(2)D(3)-enhanced hypercalciuria in genetic hypercalciuric stone-forming rats fed a low-calcium diet. Am. J. Physiol. Ren. Physiol. 305, F1132–F1138 (2013).

    CAS  Google Scholar 

  171. Giannini, S. et al. Possible link between vitamin D and hyperoxaluria in patients with renal stone disease. Clin. Sci. 84, 51–54 (1993).

    CAS  Google Scholar 

  172. Ketha, H. et al. Altered calcium and vitamin D homeostasis in first-time calcium kidney stone-formers. PLoS One 10, e0137350 (2015).

    PubMed  PubMed Central  Google Scholar 

  173. Lieske, J. C. et al. Stone composition as a function of age and sex. Clin. J. Am. Soc. Nephrol. 9, 2141–2146 (2014).

    PubMed  PubMed Central  Google Scholar 

  174. Singh, P. et al. Stone composition among first-time symptomatic kidney stone formers in the community. Mayo Clin. Proc. 90, 1356–1365 (2015).

    PubMed  Google Scholar 

  175. Evan, A., Lingeman, J., Coe, F. L. & Worcester, E. Randall’s plaque: pathogenesis and role in calcium oxalate nephrolithiasis. Kidney Int. 69, 1313–1318 (2006).

    CAS  PubMed  Google Scholar 

  176. Evan, A. P. et al. Randall’s plaque of patients with nephrolithiasis begins in basement membranes of thin loops of Henle. J. Clin. Invest. 111, 607–616 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  177. Krambeck, A. E. et al. Current computed tomography techniques can detect duct of Bellini plugging but not Randall’s plaques. Urology 82, 301–306 (2013).

    PubMed  Google Scholar 

  178. Linnes, M. P. et al. Phenotypic characterization of kidney stone formers by endoscopic and histological quantification of intrarenal calcification. Kidney Int. 84, 818–825 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  179. Matlaga, B. R., Coe, F. L., Evan, A. P. & Lingeman, J. E. The role of Randall’s plaques in the pathogenesis of calcium stones. J. Urol. 177, 31–38 (2007).

    PubMed  Google Scholar 

  180. Lieske, J. C., Turner, S. T., Edeh, S. N., Smith, J. A. & Kardia, S. L. Heritability of urinary traits that contribute to nephrolithiasis. Clin. J. Am. Soc. Nephrol. 9, 943–950 (2014).

    PubMed  PubMed Central  Google Scholar 

  181. Lieske, J. C. et al. Heritability of dietary traits that contribute to nephrolithiasis in a cohort of adult sibships. J. Nephrol. 29, 45–51 (2016).

    CAS  PubMed  Google Scholar 

  182. Lieske, J. C. & Wang, X. Heritable traits that contribute to nephrolithiasis. Urolithiasis 47, 5–10 (2019).

    PubMed  Google Scholar 

  183. Arcidiacono, T. et al. Idiopathic calcium nephrolithiasis: a review of pathogenic mechanisms in the light of genetic studies. Am. J. Nephrol. 40, 499–506 (2014).

    CAS  PubMed  Google Scholar 

  184. Gudbjartsson, D. F. et al. Association of variants at UMOD with chronic kidney disease and kidney stones-role of age and comorbid diseases. PLoS Genet. 6, e1001039 (2010).

    PubMed  PubMed Central  Google Scholar 

  185. Howles, S. A. et al. Genetic variants of calcium and vitamin D metabolism in kidney stone disease. Nat. Commun. 10, 5175 (2019).

    PubMed  PubMed Central  Google Scholar 

  186. Okada, A. et al. Genome-wide analysis of genes related to kidney stone formation and elimination in the calcium oxalate nephrolithiasis model mouse: detection of stone-preventive factors and involvement of macrophage activity. J. Bone Min. Res. 24, 908–924 (2009).

    CAS  Google Scholar 

  187. Palsson, R., Indridason, O. S., Edvardsson, V. O. & Oddsson, A. Genetics of common complex kidney stone disease: insights from genome-wide association studies. Urolithiasis 47, 11–21 (2019).

    PubMed  Google Scholar 

  188. Rungroj, N. et al. A whole genome SNP genotyping by DNA microarray and candidate gene association study for kidney stone disease. BMC Med. Genet. 15, 50 (2014).

    PubMed  PubMed Central  Google Scholar 

  189. Taguchi, K. et al. Genome-wide gene expression profiling of Randall’s plaques in calcium oxalate stone formers. J. Am. Soc. Nephrol. 28, 333–347 (2017).

    CAS  PubMed  Google Scholar 

  190. Taguchi, K., Yasui, T., Milliner, D. S., Hoppe, B. & Chi, T. Genetic risk factors for idiopathic urolithiasis: a systematic review of the literature and causal network analysis. Eur. Urol. Focus 3, 72–81 (2017).

    PubMed  Google Scholar 

  191. Thorleifsson, G. et al. Sequence variants in the CLDN14 gene associate with kidney stones and bone mineral density. Nat. Genet. 41, 926–930 (2009).

    CAS  PubMed  Google Scholar 

  192. Urabe, Y. et al. A genome-wide association study of nephrolithiasis in the Japanese population identifies novel susceptible Loci at 5q35.3, 7p14.3, and 13q14.1. PLoS Genet. 8, e1002541 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  193. Vezzoli, G., Terranegra, A., Arcidiacono, T. & Soldati, L. Genetics and calcium nephrolithiasis. Kidney Int. 80, 587–593 (2011).

    CAS  PubMed  Google Scholar 

  194. O’Keeffe, D. T. et al. Clinical and biochemical phenotypes of adults with monoallelic and biallelic CYP24A1 mutations: evidence of gene dose effect. Osteoporos. Int. 27, 3121–3125 (2016).

    PubMed  Google Scholar 

  195. Tebben, P. J. et al. Hypercalcemia, hypercalciuria, and elevated calcitriol concentrations with autosomal dominant transmission due to CYP24A1 mutations: effects of ketoconazole therapy. J. Clin. Endocrinol. Metab. 97, E423–E427 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  196. Thompson, B. & Towler, D. A. Arterial calcification and bone physiology: role of the bone-vascular axis. Nat. Rev. Endocrinol. 8, 529–543 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  197. Leibowitz, J. O. The History of Coronary Heart Disease (Wellcome Institute of the History of Medicine, 1970).

  198. Towler, D. A. Commonalities between vasculature and bone: an osseocentric view of arteriosclerosis. Circulation 135, 320–322 (2017).

    PubMed  PubMed Central  Google Scholar 

  199. Stabley, J. N. & Towler, D. A. Arterial calcification in diabetes mellitus: preclinical models and translational implications. Arterioscler. Thromb. Vasc. Biol. 37, 205–217 (2017).

    CAS  PubMed  Google Scholar 

  200. Speer, M. Y. et al. Smooth muscle cells give rise to osteochondrogenic precursors and chondrocytes in calcifying arteries. Circ. Res. 104, 733–741 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  201. Bennett, M. R., Sinha, S. & Owens, G. K. Vascular smooth muscle cells in aherosclerosis. Circ. Res. 118, 692–702 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  202. Pederson, L., Ruan, M., Westendorf, J. J., Khosla, S. & Oursler, M. J. Regulation of bone formation by osteoclasts involves Wnt/BMP signaling and the chemokine sphingosine-1-phosphate. Proc. Natl Acad. Sci. USA 105, 20764–20769 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  203. Stefater, J. A. 3rd et al. Macrophage Wnt-Calcineurin-Flt1 signaling regulates mouse wound angiogenesis and repair. Blood 121, 2574–2578 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  204. Demer, L. L. & Tintut, Y. Inflammatory, metabolic, and genetic mechanisms of vascular calcification. Arterioscler. Thromb. Vasc. Biol. 34, 715–723 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  205. Cheng, S. L. et al. Targeted reduction of vascular Msx1 and Msx2 mitigates arteriosclerotic calcification and aortic stiffness in LDLR-deficient mice fed diabetogenic diets. Diabetes 63, 4326–4337 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  206. Sun, Y. et al. Smooth muscle cell-specific runx2 deficiency inhibits vascular calcification. Circ. Res. 111, 543–552 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  207. Dillon, S., Staines, K. A., Millan, J. L. & Farquharson, C. How to build a bone: PHOSPHO1, biomineralization, and beyond. JBMR 3, e10202 (2019).

    Google Scholar 

  208. Duer, M., Cobb, A. M. & Shanahan, C. M. DNA damage response: a molecular lynchpin in the pathobiology of arteriosclerotic calcification. Arterioscler. Thromb. Vasc. Biol. 40, e193–e202 (2020).

    CAS  PubMed  Google Scholar 

  209. Croft, M. & Siegel, R. M. Beyond TNF: TNF superfamily cytokines as targets for the treatment of rheumatic diseases. Nat. Rev. Rheumatol. 13, 217–233 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  210. Cheng, S. L. et al. Activation of vascular smooth muscle parathyroid hormone receptor inhibits Wnt/beta-catenin signaling and aortic fibrosis in diabetic arteriosclerosis. Circ. Res. 107, 271–282 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  211. Jilka, R. L. et al. Decreased oxidative stress and greater bone anabolism in the aged, when compared to the young, murine skeleton with parathyroid hormone administration. Aging Cell 9, 851–867 (2010).

    CAS  PubMed  Google Scholar 

  212. Behrmann, A. et al. PTH/PTHrP receptor signaling restricts arterial fibrosis in diabetic LDLR(-/-) mice by inhibiting myocardin-related transcription factor relays. Circ. Res. 126, 1363–1378 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  213. Raison, D. et al. Knockdown of parathyroid hormone related protein in smooth muscle cells alters renal hemodynamics but not blood pressure. Am. J. Physiol. Ren. Physiol. 305, F333–F342 (2013).

    CAS  Google Scholar 

  214. Yu, N. et al. Increased mortality and morbidity in mild primary hyperparathyroid patients. The Parathyroid Epidemiology and Audit Research Study (PEARS). Clin. Endocrinol. 73, 30–34 (2010).

    Google Scholar 

  215. Nyby, M. D. et al. Desensitization of vascular tissue to parathyroid hormone and parathyroid hormone-related protein. Endocrinology 136, 2497–2504 (1995).

    CAS  PubMed  Google Scholar 

  216. Shao, J. S., Cheng, S. L., Sadhu, J. & Towler, D. A. Inflammation and the osteogenic regulation of vascular calcification: a review and perspective. Hypertension 55, 579–592 (2010).

    CAS  PubMed  Google Scholar 

  217. Zheng, K. H. et al. Lipoprotein(a) and oxidized phospholipids promote valve calcification in patients with aortic stenosis. J. Am. Coll. Cardiol. 73, 2150–2162 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  218. Elmariah, S. et al. Bisphosphonate use and prevalence of valvular and vascular calcification in women MESA (The Multi-Ethnic Study of Atherosclerosis). J. Am. Coll. Cardiol. 56, 1752–1759 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  219. Xiang, Z. et al. Targeted activation of human Vgamma9Vdelta2-T cells controls Epstein-Barr virus-induced B cell lymphoproliferative disease. Cancer Cell 26, 565–576 (2014).

    CAS  PubMed  Google Scholar 

  220. Sing, C. W. et al. Association of alendronate and risk of cardiovascular events in patients with hip fracture. J. Bone Min. Res. 33, 1422–1434 (2018).

    CAS  Google Scholar 

  221. Saag, K. G. et al. Romosozumab or alendronate for fracture prevention in women with osteoporosis. N. Engl. J. Med. 377, 1417–1427 (2017).

    CAS  PubMed  Google Scholar 

  222. Shao, J. S. et al. Msx2 promotes cardiovascular calcification by activating paracrine Wnt signals. J. Clin. Invest. 115, 1210–1220 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  223. Krishna, S. M. et al. Wnt signaling pathway inhibitor sclerostin inhibits angiotensin II-induced aortic aneurysm and atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 37, 553–566 (2017).

    CAS  PubMed  Google Scholar 

  224. Shoback, D. et al. Pharmacological management of osteoporosis in postmenopausal women: an endocrine society guideline update. J. Clin. Endocrinol. Metab. 105, dgaa048 (2020).

    PubMed  Google Scholar 

  225. Lanske, B. et al. Ablation of the PTHrP gene or the PTH/PTHrP receptor gene leads to distinct abnormalities in bone development. J. Clin. Invest. 104, 399–407 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  226. Gardinier, J. D., Daly-Seiler, C., Rostami, N., Kundal, S. & Zhang, C. Loss of the PTH/PTHrP receptor along the osteoblast lineage limits the anabolic response to exercise. PLoS One 14, e0211076 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  227. Whyte, M. P. et al. New explanation for autosomal dominant high bone mass: mutation of low-density lipoprotein receptor-related protein 6. Bone 127, 228–243 (2019).

    CAS  PubMed  Google Scholar 

  228. Li, C. et al. Disruption of LRP6 in osteoblasts blunts the bone anabolic activity of PTH. J. Bone Min. Res. 28, 2094–2108 (2013).

    CAS  Google Scholar 

  229. Cheng, S. L. et al. Vascular smooth muscle LRP6 limits arteriosclerotic calcification in diabetic LDLR-/- mice by restraining noncanonical Wnt signals. Circ. Res. 117, 142–156 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  230. Cauley, J. A. Public health impact of osteoporosis. J. Gerontol. A Biol. Sci. Med. Sci. 68, 1243–1251 (2013).

    PubMed  PubMed Central  Google Scholar 

  231. American Heart Association. Heart and Stroke Statistics. www.heart.org. https://www.heart.org/en/about-us/heart-and-stroke-association-statistics (2020).

  232. Veronese, N. et al. Relationship between low bone mineral density and fractures with incident cardiovascular disease: a systematic review and meta-analysis. J. Bone Min. Res. 32, 1126–1135 (2017).

    Google Scholar 

  233. Chiang, C. H. et al. Hip fracture and risk of acute myocardial infarction: a nationwide study. J. Bone Min. Res. 28, 404–411 (2013).

    Google Scholar 

  234. Zhou, R., Zhou, H., Cui, M., Chen, L. & Xu, J. The association between aortic calcification and fracture risk in postmenopausal women in China: the prospective Chongqing osteoporosis study. PLoS One 9, e93882 (2014).

    PubMed  PubMed Central  Google Scholar 

  235. Szulc, P. et al. Abdominal aortic calcification and risk of fracture among older women — the SOF study. Bone 81, 16–23 (2015).

    PubMed  PubMed Central  Google Scholar 

  236. Chan, J. J. et al. QCT volumetric bone mineral density and vascular and valvular calcification: the Framingham study. J. Bone Min. Res. 30, 1767–1774 (2015).

    Google Scholar 

  237. Wei, D., Zheng, G., Gao, Y., Guo, J. & Zhang, T. Abdominal aortic calcification and the risk of bone fractures: a meta-analysis of prospective cohort studies. J. Bone Min. Metab. 36, 439–446 (2018).

    CAS  Google Scholar 

  238. Caffarelli, C., Montagnani, A., Nuti, R. & Gonnelli, S. Bisphosphonates, atherosclerosis and vascular calcification: update and systematic review of clinical studies. Clin. Interv. Aging 12, 1819–1828 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  239. Szulc, P., Samelson, E. J., Kiel, D. P. & Delmas, P. D. Increased bone resorption is associated with increased risk of cardiovascular events in men: the MINOS study. J. Bone Min. Res. 24, 2023–2031 (2009).

    CAS  Google Scholar 

  240. Cauley, J. A. et al. Inflammatory markers and the risk of hip and vertebral fractures in men: the osteoporotic fractures in men (MrOS). J. Bone Min. Res. 31, 2129–2138 (2016).

    CAS  Google Scholar 

  241. Barbour, K. E. et al. Inflammatory markers and risk of hip fracture in older white women: the study of osteoporotic fractures. J. Bone Min. Res. 29, 2057–2064 (2014).

    CAS  Google Scholar 

  242. Choi, H. J. et al. Risk of fractures in subjects with antihypertensive medications: a nationwide claim study. Int. J. Cardiol. 184, 62–67 (2015).

    PubMed  Google Scholar 

  243. Swanson, C. M. et al. Obstructive sleep apnea and metabolic bone disease: insights into the relationship between bone and sleep. J. Bone Min. Res. 30, 199–211 (2015).

    Google Scholar 

  244. Cauley, J. A. et al. Characteristics of self-reported sleep and the risk of falls and fractures: the Women’s Health Initiative (WHI). J. Bone Min. Res. 34, 464–474 (2019).

    CAS  Google Scholar 

  245. Cauley, J. A. et al. Hypoxia during sleep and the risk of falls and fractures in older men: the Osteoporotic Fractures in Men Sleep Study. J. Am. Geriatr. Soc. 62, 1853–1859 (2014).

    PubMed  PubMed Central  Google Scholar 

  246. Sullivan, S. D. et al. Effects of self-reported age at nonsurgical menopause on time to first fracture and bone mineral density in the Women’s Health Initiative Observational Study. Menopause 22, 1035–1044 (2015).

    PubMed  PubMed Central  Google Scholar 

  247. Muka, T. et al. Association of age at onset of menopause and time since onset of menopause with cardiovascular outcomes, intermediate vascular traits, and all-cause mortality: a systematic review and meta-analysis. JAMA Cardiol. 1, 767–776 (2016).

    PubMed  Google Scholar 

  248. D’Amelio, P. et al. Role of iron metabolism and oxidative damage in postmenopausal bone loss. Bone 43, 1010–1015 (2008).

    PubMed  Google Scholar 

  249. McLean, R. R. et al. Homocysteine as a predictive factor for hip fracture in older persons. N. Engl. J. Med. 350, 2042–2049 (2004).

    CAS  PubMed  Google Scholar 

  250. Pusceddu, I. et al. Subclinical inflammation, telomere shortening, homocysteine, vitamin B6, and mortality: the Ludwigshafen Risk and Cardiovascular Health Study. Eur. J. Nutr. 59, 1399–1411 (2019).

    PubMed  PubMed Central  Google Scholar 

  251. Wang, S. et al. Prevalence and extent of calcification over aorta, coronary and carotid arteries in patients with rheumatoid arthritis. J. Intern. Med. 266, 445–452 (2009).

    CAS  PubMed  Google Scholar 

  252. Mackey, R. H. et al. Rheumatoid arthritis, anti-cyclic citrullinated peptide positivity, and cardiovascular disease risk in the women’s health initiative. Arthritis Rheumatol. 67, 2311–2322 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  253. Singh, P., Harris, P. C., Sas, D. J. & Lieske, J. C. The genetics of kidney stone disease and nephrocalcinosis. Nat. Rev. Nephrol. 18, 224–240 (2022).

    PubMed  Google Scholar 

  254. Mizobuchi, M., Towler, D. & Slatopolsky, E. Vascular calcification: the killer of patients with chronic kidney disease. J. Am. Soc. Nephrol. 20, 1453–1464 (2009).

    CAS  PubMed  Google Scholar 

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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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Nature Reviews Endocrinology thanks Ian Reid and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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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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