1.
Early‐Onset Osteoporosis: Rare Monogenic Forms Elucidate the Complexity of Disease Pathogenesis Beyond Type I Collagen
Costantini, Alice; Mäkitie, Riikka E.; Hartmann, Markus A. ...
Journal of bone and mineral research,
September 2022, Letnik:
37, Številka:
9
Journal Article
ABSTRACT
Early‐onset osteoporosis (EOOP), characterized by low bone mineral density (BMD) and fractures, affects children, premenopausal women and men aged <50 years. EOOP may be secondary to a ...
chronic illness, long‐term medication, nutritional deficiencies, etc. If no such cause is identified, EOOP is regarded primary and may then be related to rare variants in genes playing a pivotal role in bone homeostasis. If the cause remains unknown, EOOP is considered idiopathic. The scope of this review is to guide through clinical and genetic diagnostics of EOOP, summarize the present knowledge on rare monogenic forms of EOOP, and describe how analysis of bone biopsy samples can lead to a better understanding of the disease pathogenesis. The diagnostic pathway of EOOP is often complicated and extensive assessments may be needed to reliably exclude secondary causes. Due to the genetic heterogeneity and overlapping features in the various genetic forms of EOOP and other bone fragility disorders, the genetic diagnosis usually requires the use of next‐generation sequencing to investigate several genes simultaneously. Recent discoveries have elucidated the complexity of disease pathogenesis both regarding genetic architecture and bone tissue‐level pathology. Two rare monogenic forms of EOOP are due to defects in genes partaking in the canonical WNT pathway: LRP5 and WNT1. Variants in the genes encoding plastin‐3 (PLS3) and sphingomyelin synthase 2 (SGMS2) have also been found in children and young adults with skeletal fragility. The molecular mechanisms leading from gene defects to clinical manifestations are often not fully understood. Detailed analysis of patient‐derived transiliac bone biopsies gives valuable information to understand disease pathogenesis, distinguishes EOOP from other bone fragility disorders, and guides in patient management, but is not widely available in clinical settings. Despite the great advances in this field, EOOP remains an insufficiently explored entity and further research is needed to optimize diagnostic and therapeutic approaches. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
več
2.
Bone Matrix Mineralization and Response to Burosumab in Adult Patients With X‐Linked Hypophosphatemia: Results From the Phase 3, Single‐Arm International Trial
Fratzl‐Zelman, Nadja; Hartmann, Markus A.; Gamsjaeger, Sonja ...
Journal of bone and mineral research,
September 2022, Letnik:
37, Številka:
9
Journal Article
ABSTRACT
X‐linked hypophosphatemia (XLH) is characterized by excess fibroblast growth factor 23 (FGF23) secretion, renal phosphate wasting, and low 1,25(OH)2D3. Adult patients present with ...
osteomalacia, hypomineralized periosteocytic lesions, bone fragility, and pain. Burosumab is a fully human monoclonal FGF23 antibody approved for XLH treatment. UX023‐CL304 was an open‐label, phase 3 study investigating the effects of burosumab on osteomalacia in adults with XLH, who remained untreated at least 2 years prior enrollment. Here, we present the effect of burosumab on bone material properties. We analyzed transiliac bone biopsy samples from 11 individuals before and after 48 weeks of subcutaneous burosumab treatment (1.0 mg/kg administered every 4 weeks). We used quantitative backscattered electron imaging (qBEI) and Fourier transform infrared imaging (FTIRI) to assess bone mineralization density distribution (BMDD), mineralized bone volume, properties of the organic matrix, and size of periosteocytic lesions. The outcomes were compared with reference values from healthy adults and with four XLH patients either untreated or treated by conventional therapy. Prior to burosumab, the average mineralization in cancellous bone was lower than in healthy reference. CaLow, the fraction of lowly mineralized matrix, and CaHigh, the fraction of highly mineralized matrix, were both elevated resulting in a broad heterogeneity in mineralization (CaWidth). Burosumab resulted in a decrease of CaHigh toward normal range, whereas CaLow and CaWidth remained elevated. The mineralized bone volume was notably increased (+35.9%). The size of the periosteocytic lesions was variable but lower than in untreated XLH patients. FTIRI indicated decreased enzymatic collagen crosslink ratio heterogeneity. In summary, matrix mineralization in XLH is very heterogeneous. Highly mineralized regions represent old bone packets, probably protected from osteoclastic resorption by osteoid seams. The concomitant decrease of highly mineralized matrix, persistence of lowly mineralized matrix, and increase in mineralized bone volume after burosumab suggest a boost in mineralization of preexisting unmineralized or very lowly mineralized matrix, providing a potential explanation for previously observed improved osteomalacia. © 2022 American Society for Bone and Mineral Research (ASBMR).
več
3.
Hypermineralization and High Osteocyte Lacunar Density in Osteogenesis Imperfecta Type V Bone Indicate Exuberant Primary Bone Formation
Blouin, Stéphane; Fratzl‐Zelman, Nadja; Glorieux, Francis H ...
Journal of bone and mineral research,
September 2017, Letnik:
32, Številka:
9
Journal Article
ABSTRACT
In contrast to “classical” forms of osteogenesis imperfecta (OI) types I to IV, caused by a mutation in COL1A1/A2, OI type V is due to a gain‐of‐function mutation in the IFITM5 gene, ...
encoding the interferon‐induced transmembrane protein 5, or bone‐restricted interferon‐inducible transmembrane (IFITM)‐like protein (BRIL). Its phenotype distinctly differs from OI types I to IV by absence of blue sclerae and dentinogenesis imperfecta, by the occurrence of ossification disorders such as hyperplastic callus and forearm interosseous membrane ossification. Little is known about the impact of the mutation on bone tissue/material level in untreated and bisphosphonate‐treated patients. Therefore, investigations of transiliac bone biopsy samples from a cohort of OI type V children (n = 15, 8.7 ± 4 years old) untreated at baseline and a subset (n = 8) after pamidronate treatment (2.6 years in average) were performed. Quantitative backscattered electron imaging (qBEI) was used to determine bone mineralization density distribution (BMDD) as well as osteocyte lacunar density. The BMDD of type V OI bone was distinctly shifted toward a higher degree of mineralization. The most frequently occurring calcium concentration (CaPeak) in cortical (Ct) and cancellous (Cn) bone was markedly increased (+11.5%, +10.4%, respectively, p < 0.0001) compared to healthy reference values. Treatment with pamidronate resulted in only a slight enhancement of mineralization. The osteocyte lacunar density derived from sectioned bone area was elevated in OI type V Ct and Cn bone (+171%, p < 0.0001; +183.3%, p < 0.01; respectively) versus controls. The high osteocyte density was associated with an overall immature primary bone structure (“mesh‐like”) as visualized by polarized light microscopy. In summary, the bone material from OI type V patients is hypermineralized, similar to other forms of OI. The elevated osteocyte lacunar density in connection with lack of regular bone lamellation points to an exuberant primary bone formation and an alteration of the bone remodeling process in OI type V. © 2017 American Society for Bone and Mineral Research.
več
4.
A neomorphic variant in SP7 alters sequence specificity and causes a high-turnover bone disorder
Lui, Julian C; Raimann, Adalbert; Hojo, Hironori ...
Nature communications,
02/2022, Letnik:
13, Številka:
1
Journal Article
SP7/Osterix is a transcription factor critical for osteoblast maturation and bone formation. Homozygous loss-of-function mutations in SP7 cause osteogenesis imperfecta type XII, but neomorphic ...
(gain-of-new-function) mutations of SP7 have not been reported in humans. Here we describe a de novo dominant neomorphic missense variant (c.926 C > G:p.S309W) in SP7 in a patient with craniosynostosis, cranial hyperostosis, and long bone fragility. Histomorphometry shows increased osteoblasts but decreased bone mineralization. Mice with the corresponding variant also show a complex skeletal phenotype distinct from that of Sp7-null mice. The mutation alters the binding specificity of SP7 from AT-rich motifs to a GC-consensus sequence (typical of other SP family members) and produces an aberrant gene expression profile, including increased expression of Col1a1 and endogenous Sp7, but decreased expression of genes involved in matrix mineralization. Our study identifies a pathogenic mechanism in which a mutation in a transcription factor shifts DNA binding specificity and provides important in vivo evidence that the affinity of SP7 for AT-rich motifs, unique among SP proteins, is critical for normal osteoblast differentiation.
več
5.
Reversible Deterioration in Hypophosphatasia Caused by Renal Failure With Bisphosphonate Treatment
Cundy, Tim; Michigami, Toshimi; Tachikawa, Kanako ...
Journal of bone and mineral research,
September 2015, 2015-Sep, 2015-09-01, 20150901, Letnik:
30, Številka:
9
Journal Article
ABSTRACT
Hypophosphatasia is an inborn error of metabolism caused by mutations in the ALPL gene. It is characterized by low serum alkaline phosphatase (ALP) activity and defective mineralization of ...
bone, but the phenotype varies greatly in severity depending on the degree of residual enzyme activity. We describe a man with compound heterozygous mutations in ALPL, but no previous bone disease, who suffered numerous disabling fractures after he developed progressive renal failure (for which he eventually needed dialysis treatment) and was prescribed alendronate treatment. A bone biopsy showed marked osteomalacia with low osteoblast numbers and greatly elevated pyrophosphate concentrations at mineralizing surfaces. In vitro testing showed that one mutation, T117H, produced an ALP protein with almost no enzyme activity; the second, G438S, produced a protein with normal activity, but its activity was inhibited by raising the media phosphate concentration, suggesting that phosphate retention (attributable to uremia) could have contributed to the phenotypic change, although a pathogenic effect of bisphosphonate treatment is also likely. Alendronate treatment was discontinued and, while a suitable kidney donor was sought, the patient was treated for 6 months with teriparatide, which significantly reduced the osteomalacia. Eighteen months after successful renal transplantation, the patient was free of symptoms and the scintigraphic bone lesions had resolved. A third bone biopsy showed marked hyperosteoidosis but with plentiful new bone formation and a normal bone formation rate. This case illustrates how pharmacological (bisphosphonate treatment) and physiologic (renal failure) changes in the “environment” can dramatically affect the phenotype of a genetic disorder. © 2015 American Society for Bone and Mineral Research. © 2015 American Society for Bone and Mineral Research.
več
6.
Melorheostotic Bone Lesions Caused by Somatic Mutations in MAP2K1 Have Deteriorated Microarchitecture and Periosteal Reaction
Fratzl‐Zelman, Nadja; Roschger, Paul; Kang, Heeseog ...
Journal of bone and mineral research,
20/May , Letnik:
34, Številka:
5
Journal Article
ABSTRACT
Melorheostosis is a rare non‐hereditary condition characterized by dense hyperostotic lesions with radiographic “dripping candle wax” appearance. Somatic activating mutations in MAP2K1 have ...
recently been identified as a cause of melorheostosis. However, little is known about the development, composition, structure, and mechanical properties of the bone lesions. We performed a multi‐method phenotype characterization of material properties in affected and unaffected bone biopsy samples from six melorheostosis patients with MAP2K1 mutations. On standard histology, lesions show a zone with intensively remodeled osteonal‐like structure and prominent osteoid accumulation, covered by a shell formed through bone apposition, consisting of compact multi‐layered lamellae oriented parallel to the periosteal surface and devoid of osteoid. Compared with unaffected bone, melorheostotic bone has lower average mineralization density measured by quantitative backscattered electron imaging (CaMean: –4.5%, p = 0.04). The lamellar portion of the lesion is even less mineralized, possibly because the newly deposited material has younger tissue age. Affected bone has higher porosity by micro‐CT, due to increased tissue vascularity and elevated 2D‐microporosity (osteocyte lacunar porosity: +39%, p = 0.01) determined on quantitative backscattered electron images. Furthermore, nano‐indentation modulus characterizing material hardness and stiffness was strictly dependent on tissue mineralization (correlation with typical calcium concentration, CaPeak: r = 0.8984, p = 0.0150, and r = 0.9788, p = 0.0007, respectively) in both affected and unaffected bone, indicating that the surgical hardness of melorheostotic lesions results from their lamellar structure. The results suggest a model for pathophysiology of melorheostosis caused by somatic activating mutations in MAP2K1, in which the genetically induced gradual deterioration of bone microarchitecture triggers a periosteal reaction, similar to the process found to occur after bone infection or local trauma, and leads to an overall cortical outgrowth. The micromechanical properties of the lesions reflect their structural heterogeneity and correlate with local variations in mineral content, tissue age, and remodeling rates, in the same way as normal bone. © 2018 American Society for Bone and Mineral Research
Development of the melorheostotic lesion.
več
7.
Distinct Clinical and Pathological Features of Melorheostosis Associated With Somatic MAP2K1 Mutations
Jha, Smita; Fratzl‐Zelman, Nadja; Roschger, Paul ...
Journal of bone and mineral research,
January 2019, Letnik:
34, Številka:
1
Journal Article
ABSTRACT
Melorheostosis is a rare hyperostotic disease of the long bones classically characterized by a “dripping candle‐wax” radiographic appearance. We recently described somatic activating ...
mutations in MAP2K1 as a cause of melorheostosis. Here, we report distinguishing characteristics of patients with MAP2K1‐positive melorheostosis. Fifteen unrelated patients with radiographic appearance of melorheostosis underwent paired biopsies of affected and unaffected bone for whole‐exome sequencing, histology, and cell culture. Eight patients with mutations in MAP2K1 in affected bone were compared to the seven MAP2K1‐negative patients to identify distinguishing characteristics. Patients with MAP2K1‐positive melorheostosis had a distinct phenotype with classic “dripping candle‐wax” appearance on radiographs (p = 0.01), characteristic vascular lesions on skin overlying affected bone (p = 0.01), and higher prevalence of extraosseous mineralization and joint involvement (p = 0.04 for both). Melorheostotic bone from both MAP2K1‐positive and MAP2K1‐negative patients showed two zones of distinct morphology—an outer segment of parallel layers of primary lamellar bone and a deeper zone of intensely remodeled highly porous osteonal‐like bone. Affected bone from MAP2K1‐positive patients showed excessive osteoid (p = 0.0012), increased number of osteoblasts (p = 0.012) and osteoclasts (p = 0.04), and increased vascularity on histology in comparison to paired unaffected bone which was not seen in affected bone in most MAP2K1‐negative patients. The identification of a distinct phenotype of patients with MAP2K1‐positive melorheostosis demonstrates clinical and genetic heterogeneity among patients with the disease. Further studies are needed to better understand the underlying pathophysiology and associated skin findings. © 2018 American Society for Bone and Mineral Research.
Patients with melorheostosis associated with somatic mosaic MAP2K1 mutations (found in affected bone and skin overlying affected bone) were more likely to have cutaneous vascular changes in skin overlying affected bone, classic “dripping candle‐wax appearance” on x‐rays and increased osteoid on bone histomorphometry. Presence of these characteristics may predict association with MAP2K1 mutations.
več
8.
Fkbp10 Deletion in Osteoblasts Leads to Qualitative Defects in Bone
Lietman, Caressa D; Lim, Joohyun; Grafe, Ingo ...
Journal of bone and mineral research,
June 2017, Letnik:
32, Številka:
6
Journal Article
ABSTRACT
Osteogenesis imperfecta (OI), also known as brittle bone disease, displays a spectrum of clinical severity from mild (OI type I) to severe early lethality (OI type II), with clinical ...
features including low bone mass, fractures, and deformities. Mutations in the FK506 Binding Protein 10 (FKBP10), gene encoding the 65‐kDa protein FKBP65, cause a recessive form of OI and Bruck syndrome, the latter being characterized by joint contractures in addition to low bone mass. We previously showed that Fkbp10 expression is limited to bone, tendon, and ligaments in postnatal tissues. Furthermore, in both patients and Fkbp10 knockout mice, collagen telopeptide hydroxylysine crosslinking is dramatically reduced. To further characterize the bone specific contributions of Fkbp10, we conditionally ablated FKBP65 in Fkbp10fl/fl mice (Mus musculus; C57BL/6) using the osteoblast‐specific Col1a1 2.3‐kb Cre recombinase. Using μCT, histomorphometry and quantitative backscattered electron imaging, we found minimal alterations in the quantity of bone and no differences in the degree of bone matrix mineralization in this model. However, mass spectroscopy (MS) of bone collagen demonstrated a decrease in mature, hydroxylysine‐aldehyde crosslinking. Furthermore, bone of mutant mice exhibits a reduction in mineral‐to‐matrix ratio and in crystal size as shown by Raman spectroscopy and small‐angle X‐ray scattering, respectively. Importantly, abnormalities in bone quality were associated with impaired bone biomechanical strength in mutant femurs compared with those of wild‐type littermates. Taken together, these data suggest that the altered collagen crosslinking through Fkbp10 ablation in osteoblasts primarily leads to a qualitative defect in the skeleton. © 2017 American Society for Bone and Mineral Research.
več
9.
Quantitative Backscattered Electron Imaging of Bone Using a Thermionic or a Field Emission Electron Source
Hartmann, Markus A.; Blouin, Stéphane; Misof, Barbara M. ...
Calcified tissue international,
08/2021, Letnik:
109, Številka:
2
Journal Article
Quantitative backscattered electron imaging is an established method to map mineral content distributions in bone and to determine the bone mineralization density distribution (BMDD). The method we ...
applied was initially validated for a scanning electron microscope (SEM) equipped with a tungsten hairpin cathode (thermionic electron emission) under strongly defined settings of SEM parameters. For several reasons, it would be interesting to migrate the technique to a SEM with a field emission electron source (FE-SEM), which, however, would require to work with different SEM parameter settings as have been validated for DSM 962. The FE-SEM has a much better spatial resolution based on an electron source size in the order of several 100 nanometers, corresponding to an about
10
5
to
10
6
times smaller source area compared to thermionic sources. In the present work, we compare BMDD between these two types of instruments in order to further validate the methodology. We show that a transition to higher pixel resolution (1.76, 0.88, and 0.57 μm) results in shifts of the BMDD peak and BMDD width to higher values. Further the inter-device reproducibility of the mean calcium content shows a difference of up to 1 wt% Ca, while the technical variance of each device can be reduced to
±
0.17
wt% Ca. Bearing in mind that shifts in calcium levels due to diseases, e.g., high turnover osteoporosis, are often in the range of 1 wt% Ca, both the bone samples of the patients as well as the control samples have to be measured on the same SEM device. Therefore, we also constructed new reference BMDD curves for adults to be used for FE-SEM data comparison.
več
10.
Evidence for a Role for Nanoporosity and Pyridinoline Content in Human Mild Osteogenesis Imperfecta
Paschalis, Eleftherios P; Gamsjaeger, Sonja; Fratzl‐Zelman, Nadja ...
Journal of bone and mineral research,
20/May , Letnik:
31, Številka:
5
Journal Article
ABSTRACT
Osteogenesis imperfecta (OI) is a clinically and genetically heterogeneous connective tissue disorder characterized by bone fragility that arises from decreased bone mass and abnormalities ...
in bone material quality. OI type I represents the milder form of the disease and according to the original Sillence classification is characterized by minimal skeletal deformities and near‐normal stature. Raman microspectroscopy is a vibrational spectroscopic technique that allows the determination of bone material properties in bone biopsy blocks with a spatial resolution of ∼1 µm, as a function of tissue age. In the present study, we used Raman microspectroscopy to evaluate bone material quality in transiliac bone biopsies from children with a mild form of OI, either attributable to collagen haploinsufficiency OI type I (OI‐Quant; n = 11) or aberrant collagen structure (OI‐Qual; n = 5), as a function of tissue age, and compared it against the previously published values established in a cohort of biopsies from healthy children (n = 54, ages 1 to 23 years). The results indicated significant differences in bone material compositional characteristics between OI‐Quant patients and healthy controls, whereas fewer were evident in the OI‐Qual patients. Differences in both subgroups of OI compared with healthy children were evident for nanoporosity, mineral maturity/crystallinity as determined by maxima of the v1PO4 Raman band, and pyridinoline (albeit in different direction) content. These alterations in bone material compositional properties most likely contribute to the bone fragility characterizing this disease. © 2016 American Society for Bone and Mineral Research.
več
PDF
