The osteocyte, a terminally differentiated cell comprising 90%-95% of all bone cells 1,2 , may have multiple functions, including acting as a mechanosensor in bone (re)modeling 3 . Dentin matrix protein 1 (encoded by DMP1) is highly expressed in osteocytes 4 and, when deleted in mice, results in a hypomineralized bone phenotype 5 . We investigated the potential for this gene not only to direct skeletal mineralization but also to regulate phosphate (P i ) homeostasis. Both Dmp1-null mice and individuals with a newly identified disorder, autosomal recessive hypophosphatemic rickets, manifest rickets and osteomalacia with isolated renal phosphate-wasting associated with elevated fibroblast growth factor 23 (FGF23) levels and normocalciuria. Mutational analyses showed that autosomal recessive hypophosphatemic rickets family carried a mutation affecting the DMP1 start codon, and a second family carried a 7-bp deletion disrupting the highly conserved DMP1 C terminus. Mechanistic studies using Dmp1-null mice demonstrated that absence of DMP1 results in defective osteocyte maturation and increased FGF23 expression, leading to pathological changes in bone mineralization. Our findings suggest a bone-renal axis that is central to guiding proper mineral metabolism.Human disorders of phosphate (P i ) handling and skeletal mineralization can result from mutations in PHEX 6 , which cause X-linked hypophosphatemic rickets (XLH). A similar phenotype is also observed in Hyp mice, which have mutant Phex 7 and show increased osteocyte expression of the phosphaturic factor FGF23 (ref. 8 Individuals F1-1 and F1-3 presented with rickets and progressive lower limb deformity in late infancy, whereas sister F1-2 had rachitic changes on a chest X-ray at age 7 months. In contrast, F2-1 presented with a mild genu valgum at 8 years of age. The pre-or off-treatment age-related metabolic profiles for both kindreds were similar, characterized by hypophosphatemia owing to renal phosphate-wasting (serum P i : 0.7-0.9 mmol/l, normal: 1.2-1.8; threshold maximum for renal tubular phosphate reabsorption/glomerular filtration rate (TmP/GFR): 0.61-0.81 mmol/l, lower limit of normal: ≥1.0), high normal to moderately elevated alkaline phosphatase, normal intact parathyroid hormone (PTH) levels (4.6-6.9 pmol/l, normal: 1.6-6.9), normocalcemia (ionized calcium: 1. Resolution of rickets and normalization of alkaline phosphatase were observed during treatment with phosphate supplementation and calcitriol; however, the TmP/GFR remained low. Linear growth trajectories were heterogeneous among the affected individuals: affected individuals in F1 had a mid-parental height of 154.5 cm (5 th -10 th percentiles), with F1-1 and F1-2 measuring 153 cm (5 th percentile) and 136.5 cm (<5 th percentile) at final adult height, respectively. F1-3 had a height of 153.5 cm at 10 months post-menarche, well within the genetic target. The affected individual in F-2 had a final adult height of 172 cm (90 th -95 th percentile), 3 cm above the upper limit of her genetic ta...

Osteogenesis imperfecta is a genetic disorder of increased bone fragility, low bone mass, and other connective-tissue manifestations. The most frequently used classification outlines four clinical types, which we have expanded to seven distinct types. In most patients the disorder is caused by mutations in one of the two genes encoding collagen type 1, but in some individuals no such mutations are detectable. The most important therapeutic advance is the introduction of bisphosphonate treatment for moderate to severe forms of osteogenesis imperfecta. However, at present, the best treatment regimen and the long-term outcomes of bisphosphonate therapy are unknown. Although this treatment does not constitute a cure, it is an adjunct to physiotherapy, rehabilitation, and orthopaedic care. Gene-based therapy presently remains in the early stages of preclinical research.

Prolyl hydroxylation is a critical posttranslational modification that affects structure, function, and turnover of target proteins. Prolyl 3-hydroxylation occurs at only one position in the triple-helical domain of fibrillar collagen chains, and its biological significance is unknown. CRTAP shares homology with a family of putative prolyl 3-hydroxylases (P3Hs), but it does not contain their common dioxygenase domain. Loss of Crtap in mice causes an osteochondrodysplasia characterized by severe osteoporosis and decreased osteoid production. CRTAP can form a complex with P3H1 and cyclophilin B (CYPB), and Crtap-/- bone and cartilage collagens show decreased prolyl 3-hydroxylation. Moreover, mutant collagen shows evidence of overmodification, and collagen fibrils in mutant skin have increased diameter consistent with altered fibrillogenesis. In humans, CRTAP mutations are associated with the clinical spectrum of recessive osteogenesis imperfecta, including the type II and VII forms. Hence, dysregulation of prolyl 3-hydroxylation is a mechanism for connective tissue disease.