| Skeletal deformity and bone fragility are the hallmarks of the brittle bone dysplasia osteogenesis imperfecta. The diagnosis of osteogenesis imperfecta usually depends on family history and clinical presentation characterized by a fracture (or fractures) during the prenatal period, at birth or in early childhood; genetic tests can confirm diagnosis. Osteogenesis imperfecta is caused by dominant autosomal mutations in the type I collagen coding genes (COL1A1 and COL1A2) in about 85% of individuals, affecting collagen quantity or structure. In the past decade, (mostly) recessive, dominant and X-linked defects in a wide variety of genes encoding proteins involved in type I collagen synthesis, processing, secretion and post-translational modification, as well as in proteins that regulate the differentiation and activity of bone-forming cells have been shown to cause osteogenesis imperfecta. The large number of causative genes has complicated the classic classification of the disease, and although a new genetic classification system is widely used, it is still debated. Phenotypic manifestations in many organs, in addition to bone, are reported, such as abnormalities in the cardiovascular and pulmonary systems, skin fragility, muscle weakness, hearing loss and dentinogenesis imperfecta. Management involves surgical and medical treatment of skeletal abnormalities, and treatment of other complications. More innovative approaches based on gene and cell therapy, and signalling pathway alterations, are under investigation. NATURE REVIEWS | DISEASE PRIMERS VOLUME 3 | ARTICLE NUMBER 17052 | 1 PRIMER © 2 0 1 7 M a c m i l l a n P u b l i s h e r s L i m i t e d , p a r t o f S p r i n g e r N a t u r e . A l l r i g h t s r e s e r v e d .In this Primer, we provide an overview of epidemio logy, genetics and pathophysiology of osteogenesis imperfecta, as well as diagnosis and management. EpidemiologyStudies from Europe and the United States have found a birth prevalence of osteogenesis imperfecta of 0.3-0.7 per 10,000 births 5,6 . These birth cohort analyses reflect more severe types of osteogenesis imperfecta and do not include more subtle types that become apparent after birth. A population based study that used the Danish National Patient Register found an annual incidence of osteogenesis imperfecta of 1.5 per 10,000 births between 1997 and 2013 (REF. 7). Population surveys in countries with comprehensive medical databases, such as Finland, estimated a prevalence of about 0.5 per 10,000 individ uals 8 , with most having phenotypically milder osteo genesis imperfecta type I and type IV (BOX 1; TABLE 1). Because these birth cohort and population surveys are based on clinical findings and tend to find mutu ally exclusive populations, a reasonable estimate of the incidence of osteogenesis imperfecta is about 1 per 10,000 individuals. Most patients are heterozygous for mutations in COL1A1 or COL1A2. No difference in the prevalence between sexes was reported.Approximately 90% of the 3,000 individuals whose mutations ha...

The mechanism of calcification in bone and related tissues is a matter of current interest. The mean size and the arrangement of the mineral crystals are important parameters difficult to obtain by electron microscopy. Furthermore, most studies have been carried out on poorly calcified model systems or chemically treated samples. In the work presented here, native bone was studied as a function of age by a quantitative small-angle X-ray scattering method (SAXS). Bone samples (calvariae and ulnae) from rats and mice were investigated. Measurements were performed on native bone immediately after dissection for samples up to 1 mm thick. The size, shape, and predominant orientation of the mineral crystals in bone were obtained for embryonal, young, and adult animals. The results indicate that the mineral nucleates as thin layers of calcium phosphate within the hole zone of the collagen fibrils. The mineral nuclei subsequently grow in thickness to about 3 nm, which corresponds to maximum space available in these holes.

Hamann C, Goettsch C, Mettelsiefen J, Henkenjohann V, Rauner M, Hempel U, Bernhardt R, Fratzl-Zelman N, Roschger P, Rammelt S, Günther KP, Hofbauer LC. Delayed bone regeneration and low bone mass in a rat model of insulin-resistant type 2 diabetes mellitus is due to impaired osteoblast function. Am J Physiol Endocrinol Metab 301: E1220 -E1228, 2011. First published September 6, 2011; doi:10.1152/ajpendo.00378.2011.-Patients with diabetes mellitus have an impaired bone metabolism; however, the underlying mechanisms are poorly understood. Here, we analyzed the impact of type 2 diabetes mellitus on bone physiology and regeneration using Zucker diabetic fatty (ZDF) rats, an established rat model of insulin-resistant type 2 diabetes mellitus. ZDF rats develop diabetes with vascular complications when fed a Western diet. In 21-wk-old diabetic rats, bone mineral density (BMD) was 22.5% (total) and 54.6% (trabecular) lower at the distal femur and 17.2% (total) and 20.4% (trabecular) lower at the lumbar spine, respectively, compared with nondiabetic animals. BMD distribution measured by backscattered electron imaging postmortem was not different between diabetic and nondiabetic rats, but evaluation of histomorphometric indexes revealed lower mineralized bone volume/tissue volume, trabecular thickness, and trabecular number. Osteoblast differentiation of diabetic rats was impaired based on lower alkaline phosphatase activity (Ϫ20%) and mineralized matrix formation (Ϫ55%). In addition, the expression of the osteoblast-specific genes bone morphogenetic protein-2, RUNX2, osteocalcin, and osteopontin was reduced by 40 -80%. Osteoclast biology was not affected based on tartrate-resistant acidic phosphatase staining, pit formation assay, and gene profiling. To validate the implications of these molecular and cellular findings in a clinically relevant model, a subcritical bone defect of 3 mm was created at the left femur after stabilization with a four-hole plate, and bone regeneration was monitored by X-ray and microcomputed tomography analyses over 12 wk. While nondiabetic rats filled the defects by 57%, diabetic rats showed delayed bone regeneration with only 21% defect filling. In conclusion, we identified suppressed osteoblastogenesis as a cause and mechanism for low bone mass and impaired bone regeneration in a rat model of type 2 diabetes mellitus. bone defect; bone matrix mineralization; bone regeneration; type 2 diabetes mellitus; osteoblast; osteoclast DIABETES MELLITUS TYPE 2 AND the associated metabolic syndrome have become epidemic clinical and economic health problems (1). Morbidity and mortality of diabetes mellitus are determined by vascular complications, including cardiovascular disease, retinopathy, nephropathy, and polyneuropathy (11). Skeletal sequelae of long-standing diabetes mellitus include Charcot neuroarthropathy and the diabetic foot syndrome, which may require amputation. More recently, osteoporosis with an increased risk of fragility fractures has emerged as a complication in patients with long-stan...

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Osteogenesis imperfecta (OI) is most often caused by mutations in the type I procollagen genes (COL1A1/COL1A2). We identified two children with substitutions in the type I procollagen C-propeptide cleavage site, which disrupt a unique processing step in collagen maturation and define a novel phenotype within OI. The patients have mild OI caused by mutations in COL1A1 (Patient 1: p.Asp1219Asn) or COL1A2 (Patient 2: p.Ala1119Thr), respectively. Patient 1 L1-L4 DXA Z-score was 13.9 and pQCT vBMD was 13.1; Patient 2 had L1-L4 DXA Z-score of 0.0 and pQCT vBMD of À1.8. Patient BMD contrasts with radiographic osteopenia and histomorphometry without osteosclerosis. Mutant procollagen processing is impaired in pericellular and in vitro assays. Patient dermal collagen fibrils have irregular borders. Incorporation of pCcollagen into matrix leads to increased bone mineralization. FTIR imaging confirms elevated mineral/matrix ratios in both patients, along with increased collagen maturation in trabecular bone, compared to normal or OI controls. Bone mineralization density distribution revealed a marked shift toward increased mineralization density for both patients. Patient 1 has areas of higher and lower bone mineralization than controls; Patient 2's bone matrix has a mineral content exceeding even classical OI bone. These patients define a new phenotype of high BMD OI and demonstrate that procollagen C-propeptide cleavage is crucial to normal bone mineralization.

Osteogenesis imperfecta type I (OI-I) represents the mildest form of OI. The collagen I mutations underlying the disorder can be classified as quantitative mutations that lead to formation of a decreased amount of normal collagen or qualitative mutations where structurally aberrant collagen chains are generated. However, the phenotypic consequences of a particular mutation are not well understood. Transiliac bone biopsies from 19 young OI-I patients (age range 2.0-14.1 years) and 19 age-matched controls were used to assess bone histomorphometric parameters and bone mineralization density distribution, measured by quantitative backscattered electron imaging. Thirteen of the OI-I patients were affected by quantitative and six patients by qualitative mutations. Compared to age-matched controls, iliac bone samples in the OI group were smaller and had thinner cortices and less trabecular bone. Resorption parameters were similar between groups, whereas surface-based parameters of bone formation were considerably higher in OI patients than in controls with the exception of bone formation rate per osteoblast surface, which was reduced in OI. Backscattered electron imaging revealed a higher mean mineralization density (+7%, P < 0.001) in OI-I patients than in age-matched controls, which was accompanied by a reduced heterogeneity of mineralization (-13%, P < 0.001). However, the increase of mean degree of mineralization in OI did not exceed the average level of normal adult bone. No differences were found between the two mutation types. In summary, the tissue- and material-level abnormalities found in OI-I (low bone mass and increased mineral content of the matrix) seem to be independent of the collagen mutations.

Several recent results are suggesting that the collagen packing in mineralized tissues is much less regular than in the case of other nonmineralizing collagen, e.g., rat tail tendon. To clarify this question we have investigated the molecular arrangement in mineralized and unmineralized turkey leg tendon as a model for the collagen of mineralized tissues. Using a combination of diffuse x-ray scattering and computer simulation, it could be shown quantitatively that, although the collagen fibril structure is periodic in the axial direction, it is similar to a two-dimensional fluid in the lateral plane. This has important consequences for the understanding of the mineralization process, which is also discussed.

Melorheostosis is a sporadic disease of uncertain etiology characterized by asymmetric bone overgrowth and functional impairment. Using whole exome sequencing, we identify somatic mosaic MAP2K1 mutations in affected, but not unaffected, bone of eight unrelated patients with melorheostosis. The activating mutations (Q56P, K57E and K57N) cluster tightly in the MEK1 negative regulatory domain. Affected bone displays a mosaic pattern of increased p-ERK1/2 in osteoblast immunohistochemistry. Osteoblasts cultured from affected bone comprise two populations with distinct p-ERK1/2 levels by flow cytometry, enhanced ERK1/2 activation, and increased cell proliferation. However, these MAP2K1 mutations inhibit BMP2-mediated osteoblast mineralization and differentiation in vitro, underlying the markedly increased osteoid detected in affected bone histology. Mosaicism is also detected in the skin overlying bone lesions in four of five patients tested. Our data show that the MAP2K1 oncogene is important in human bone formation and implicate MEK1 inhibition as a potential treatment avenue for melorheostosis.