Diffuse idiopathic skeletal hyperostosis (DISH) is a condition where adjacent vertebrae become fused through formation of osteophytes. The genetic and epidemiological etiology of this condition is not well understood. Here, we implemented a machine learning algorithm to assess the prevalence and severity of the pathology in ~40,000 lateral DXA scans in the UK Biobank Imaging cohort. We find that DISH is highly prevalent, above the age of 45, ~20% of men and ~8% of women having multiple osteophytes. Surprisingly, we find strong phenotypic and genetic association of DISH with increased bone mineral density and content throughout the entire skeletal system. Genetic association analysis identified ten loci associated with DISH, including multiple genes involved in bone remodeling (RUNX2, IL11, GDF5, CCDC91, NOG, and ROR2). Overall, this study describes genetics of DISH and implicates the role of overactive osteogenesis as a key driver of the pathology.

Infantile cortical hyperostosis (ICH)/Caffey disease is an inflammatory collagenopathy of infancy, manifested by subperiosteal bone hyperplasia. Genetically, ICH was linked with heterozygosity for an R836C mutation in the COL1A1 gene. Although an autosomal-recessive trait is also suspected, it has not been proven thus far.

Extraspinal manifestations of diffuse idiopathic skeletal hyperostosis (DISH) have been described previously. We aimed to assess the prevalence of elbow hyperostotic spurs, to search for sites discriminating for elbow DISH and to analyze the effect of physical activities, handedness and sex.

Sclerosing bone dysplasias are a heterogeneous group of rare diseases marked by increased BMD caused by either increased bone formation or by decreased bone resorption. In this study we have focused on craniotubular hyperostoses mainly affecting the long bones and the skull. Currently, there are three causative genes identified namely LRP5, SOST and LRP4. All three genes are involved in the canonical Wnt signalling pathway. These findings support the role of this pathway in regulating bone formation. The secreted Frizzled related proteins (sFRPs) can modulate the Wnt signalling pathway by binding to Wnt ligands or Frizzled receptors. Studies using mice showed that two members of this family, sFRP1 and sFRP4, have an important effect on bone formation. Sfrp1-/- mice have increased BMD values especially after peak BMD was reached. On the contrary, sfrp4 overexpression mice exhibit reduced BMD. Therefore, we selected sFRP1 and sFRP4, two members of the secreted Frizzled related protein (sFRP) family, as candidate genes for mutation analysis in patients with craniotubular hyperostosis. Using Sanger sequencing we screened the exons and intron/exon boundaries of sFRP1 and sFRP4 in 53 patients. In all patients mutations in LRP5, SOST and LRP4 were excluded. We identified two unknown heterozygous variants both in sFRP1. The first variant in sFRP1 is an intronic variant which, according to prediction programs, does not affect the splicing of the gene. The second variant (p.Trp131Arg/-) was identified in a young boy whose healthy mother does not carry the variant. In conclusion, our studies indicate that mutations neither in sFRP1 nor in sFRP4 are a common cause of craniotubular hyperostoses. As a consequence, further research will be necessary to identify the disease causing gene(s) in this group of patients.

A high incidence of heterotopic ossification (HO) has been reported in patients with diffuse idiopathic skeletal hyperostosis (DISH), a metabolic disease characterized by calcifications of entheses at spine and peripheral sites. We performed histological and immunohistochemical analyses in five different HO sites in a patient with DISH to study a possible mutual interaction of bone morphogenetic protein 2 (BMP-2), transforming growth factor beta (TGF-β), and decorin, crucial for bone mass increasing, matrix calcification, and endochondral bone formation. We speculated that the surgical trauma triggered HO, inducing TGF-β release at the lesion site. TGF-β recruits osteoblast precursor cells and determines the overexpression of BMP-2 in the surrounding skeletal muscle, inducing a further osteogenic differentiation, contributing to HO onset.

LRP5 high bone mass (HBM) is an autosomal dominant endosteal hyperostosis caused by mutations of the low-density lipoprotein receptor-related protein 5 (LRP5) gene. Alternative names included "autosomal dominant osteosclerosis" and "Worth disease." The aim of the paper is to provide an historical overview of a disorder whose literature is complicated and confusing due to the past use of several denominations and lack of reviews.

Earlier retrospective studies have suggested a relation between DISH and cardiovascular disease, including myocardial infarction. The present study assessed the association between DISH and incidence of cardiovascular events and mortality in patients with high cardiovascular risk.

The purpose of this study is to anatomically evaluate the impact on the patient intra vitam of an endocranial condition on a late 20th century skull housed in the Section of Legal Medicine of the University of Foggia (Foggia, Apulia, Italy). After performing a retrospective diagnosis, the condition is framed in the broader context of studies on this pathology. An anthropological and radiological analysis (X-ray and CT scan imaging) made it possible to confirm the preliminary information and to detail the osteological diagnosis of HFI. In order to assess the impact on the cerebral surface of the endocranial growth a 3D endocast was obtained using the Software OrtogOnBlender. The skull is demonstrated to have belonged to a female senile individual known, from limited documentary evidence, to have suffered from a psychiatric condition during her life. The final diagnosis is hyperostosis frontalis interna (HFI), Type D. Although a direct correlation between the demonstrated intracranial bony growth and the onset of the patient's psychiatric condition is difficult to retrospectively ascertain, the pressure exerted on this female individual's frontal lobe may have contributed to further degenerative behavioural changes in the last years of her life. This case adds to previous knowledge, especially from the palaeopathological literature, on this condition and, for the first time, presents a neuroanatomical approach to assess the global impact of the disease.

A 73-year-old woman with type 2 diabetes mellitus was referred to our department for glycaemic control. Physical examination revealed two subcutaneous hard masses around the left shoulder and the right hip joint. The patient could not fully extend her fingers because of skin sclerosis in both hands. Laboratory studies showed hyperphosphataemia and a high ratio of renal tubular maximum reabsorption of phosphate to glomerular filtration rate. There were no abnormalities in serum calcium, creatinine, alkaline phosphatase, and intact parathyroid hormone levels, whereas serum fibroblast growth factor 23 was low. Hyperphosphataemic familial tumoural calcinosis/hyperostosis-hyperphosphataemia syndrome (HFTC/HHS) was diagnosed using whole genome sequencing that revealed a novel frameshift beyond the 584th threonine located in the lectin domain of UDP-N-acetyl-alpha-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase 3 associated with a duplication of the 1748th thymine in the coding region of the corresponding gene. Furthermore, anti-nuclear, anti-centromere, and anti-cardiolipin antibodies were positive, implying that comorbid limited type scleroderma might play a role in tumoural calcinosis (TC) development. A low phosphate diet was prescribed with phosphate-lowering medications, including aluminium hydroxide, acetazolamide, and sevelamer hydrochloride. The patient displayed a decrease in serum phosphate levels from 6.5 to 5.5 mg/dL 10 months after the initiation of treatment, but her TC had not improved during treatment for more than 1 year. This case was interesting because the patient with HFTC/HHS exhibited TC despite being over her 60s, and subsequent scleroderma might contribute to the specific clinical course. When HFTC/HHS presents with elderly-onset TC, the involvement of comorbidities in exacerbating TC should be considered.

Hyperostosis Cranialis Interna (HCI) is a rare bone disorder characterized by progressive intracranial bone overgrowth at the skull. Here we identified by whole-exome sequencing a dominant mutation (L441R) in SLC39A14 (ZIP14). We show that L441R ZIP14 is no longer trafficked towards the plasma membrane and excessively accumulates intracellular zinc, resulting in hyper-activation of cAMP-CREB and NFAT signaling. Conditional knock-in mice overexpressing L438R Zip14 in osteoblasts have a severe skeletal phenotype marked by a drastic increase in cortical thickness due to an enhanced endosteal bone formation, resembling the underlying pathology in HCI patients. Remarkably, L438R Zip14 also generates an osteoporotic trabecular bone phenotype. The effects of osteoblastic overexpression of L438R Zip14 therefore mimic the disparate actions of estrogen on cortical and trabecular bone through osteoblasts. Collectively, we reveal ZIP14 as a novel regulator of bone homeostasis, and that manipulating ZIP14 might be a therapeutic strategy for bone diseases.

Mutations in the GJA1 gene that encodes connexin43 (Cx43) cause several rare genetic disorders, including diseases affecting the epidermis. Here, we examined the in vitro functional consequences of a Cx43 mutation, Cx43-G38E, linked to a novel human phenotype of hypotrichosis, follicular keratosis and hyperostosis. We found that Cx43-G38E was efficiently translated in Xenopus oocytes and localized to gap junction plaques in transfected HeLa cells. Cx43-G38E formed functional gap junction channels with the same efficiency as wild-type Cx43 in Xenopus oocytes, although voltage gating of the gap junction channels was altered. Notably, Cx43-G38E significantly increased membrane current flow through the formation of active hemichannels when compared to wild-type Cx43. These data demonstrate the association of increased hemichannel activity to a connexin mutation linked to a skeletal-cutaneous phenotype, suggesting that augmented hemichannel activity could play a role in skin and skeletal disorders caused by human Cx43 mutations.

Diffuse idiopathic skeletal hyperostosis (DISH) is characterized by progressive calcification of spinal tissues; however, the impact of calcification on pain and function is poorly understood. This study examined the association between progressive ectopic spine calcification in mice lacking equilibrative nucleoside transporter 1 (ENT1-/-), a preclinical model of DISH, and behavioral indicators of pain.

Bone morphogenetic protein (BMP) signaling regulates the physiological and pathological development of skeletal tissues. Activin receptor-like kinase 2 (ALK2) is a BMP type I transmembrane serine/threonine kinase receptor. Recently, a p.K400E mutation was found in ALK2 in a patient with diffuse idiopathic skeletal hyperostosis (DISH), which is a disorder characterized by calcification and ossification of spinal ligaments and entheses. We report here the functional characterization of ALK2 p.K400E in vitro. Cells overexpressing ALK2 p.K400E activated BMP signaling in response to osteogenic BMP ligands. However, ALK2 p.K400E was not activated by a nonosteogenic ligand, Activin A. BMP signaling through ALK2 p.K400E was further enhanced by the coexpression of a BMP type II receptor. The type II receptor increased the phosphorylation level of ALK2 p.K400E, suggesting that ALK2 p.K400E is a hypersensitive mutant to the BMP type II receptor kinases. Our findings suggest that pathological calcification and ossification in DISH are caused by overactivated BMP signaling through ALK2 p.K400E enhanced by type II receptors in response to osteogenic BMPs rather than Activin A.

Retrospective multicenter.

A working group was established to develop a core domain set (CDS) for Chronic Nonbacterial Osteomyelitis (CNO) and Synovitis, Acne, Pustulosis, Hyperostosis, Osteitis (SAPHO) following the OMERACT filter 2.1.

The SIBLINGs are a subfamily of the secreted calcium-binding phosphoproteins and comprise five small integrin-binding ligand N-linked glycoproteins [dentin matrix protein-1 (DMP1), secreted phosphoprotein-1 (SPP1) also called osteopontin (OPN), integrin-binding sialoprotein (IBSP) also called bone sialoprotein (BSP), matrix extracellular phosphoglycoprotein (MEPE), and dentin sialophosphoprotein (DSPP)]. Each SIBLING has at least one "acidic, serine- and aspartic acid-rich motif" (ASARM) and multiple Ser-x-Glu/pSer sequences that when phosphorylated promote binding of the protein to hydroxyapatite for regulation of biomineralization. Mendelian disorders from loss-of-function mutation(s) of the genes that encode the SIBLINGs thus far involve DSPP causing various autosomal dominant dysplasias of dentin but without skeletal disease, and DMP1 causing autosomal recessive hypophosphatemic rickets, type 1 (ARHR1). No diseases have been reported from gain-of-function mutation(s) of DSPP or DMP1 or from alterations of SPP1, IBSP, or MEPE. Herein, we describe severe hypophosphatemic osteosclerosis and hyperostosis associated with skeletal deformity, short stature, enthesopathy, tooth loss, and high circulating FGF23 levels in a middle-aged man and young woman from an endogamous family living in southern India. Both shared novel homozygous mutations within two genes that encode a SIBLING protein: stop-gain ("nonsense") DMP1 (c.556G>T,p.Glu186Ter) and missense SPP1 (c.769C>T,p.Leu266Phe). The man alone also carried novel heterozygous missense variants within two additional genes that condition mineral homeostasis and are the basis for autosomal recessive disorders: CYP27B1 underlying vitamin D dependent rickets, type 1, and ABCC6 underlying both generalized arterial calcification of infancy, type 2 and pseudoxanthoma elasticum (PXE). By immunochemistry, his bone contained high amounts of OPN, particularly striking surrounding osteocytes. We review how our patients' disorder may represent the first digenic SIBLING protein osteopathy.

Metformin, an effective hypoglycemic, can modulate different points of malignant mass, polycystic ovary syndrome (PCOS), cardiovascular diseases, tuberculosis, and nerve regeneration. Recently, the effect of metformin on bone metabolism has been analyzed. Metformin relies on organic cation transporters (OCT1), a polyspecific cell membrane of the solute carrier 22A (SLC22A) gene family, to facilitate its intracellular uptake and action on complex I of the respiratory chain of mitochondria. These changes activate the cellular energy sensor AMP-activated protein kinase (AMPK). Thus, the increased cellular AMP/ATP ratio causes a dramatic and progressive activation of insulin and lysosomes, resulting in a decrease in intracellular glucose level, which promotes osteoblast proliferation and differentiation. AMPK also phosphorylates runt-related transcription factor 2 (Runx2) at S118, the lineage-specific transcriptional regulators, to promote osteogenesis. Metformin phosphorylates extracellular signal-regulated kinase (ERK), stimulates endothelial and inducible nitric oxide synthases (e/iNOS), inhibits the GSK3β/Wnt/β-catenin pathway, and promotes osteogenic differentiation of osteoblasts. The effect of metformin on hyperglycemia decreases intracellular reactive oxygen species (ROS) and advanced glycation end-products (AGEs) in collagen, and reduced serum levels of insulin-like growth factors (IGF-1) were beneficial for bone formation. Metformin has a certain effect on microangiopathy and anti-inflammation, which can induce osteoporosis, activate the activity of osteoclasts, and inhibit osteoblast activity, and has demonstrated extensive alteration in bone and mineral metabolism. The aim of this review was to elucidate the mechanisms of metformin on osteoblasts in insulin-deficient diabetes.

Ossification of the posterior longitudinal ligament (OPLL) can cause severe and irreversible paralysis in not only the cervical spine but also the thoracolumbar spine. To date, however, the prevalence and distribution of OPLL in the whole spine has not been precisely evaluated in patients with cervical OPLL. Therefore, we conducted a multi-center study to comprehensively evaluate the prevalence and distribution of OPLL using multi-detector computed tomography (CT) images in the whole spine and to analyze what factors predict the presence of ossified lesions in the thoracolumbar spine in patients who were diagnosed with cervical OPLL by plain X-ray. Three hundred and twenty-two patients with a diagnosis of cervical OPLL underwent CT imaging of the whole spine. The sum of the levels in which OPLL was present in the whole spine was defined as the OP-index and used to evaluate the extent of ossification. The distribution of OPLL in the whole spine was compared between male and female subjects. In addition, a multiple regression model was used to ascertain related factors that affected the OP-index. Among patients with cervical OPLL, women tended to have more ossified lesions in the thoracolumbar spine than did men. A multiple regression model revealed that the OP-index was significantly correlated with the cervical OP-index, sex (female), and body mass index. Furthermore, the prevalence of thoracolumbar OPLL in patients with a cervical OP-index ≥ 10 was 7.8 times greater than that in patients with a cervical OP-index ≤ 5. The results of this study reveal that the extent of OPLL in the whole spine is significantly associated with the extent of cervical OPLL, female sex, and obesity.

Syndrome of synovitis acne pustulosis hyperostosis osteitis (SAPHO) and chronic recurrent multifocal osteomyelitis (CRMO) present two diseases of a dermatologic and rheumatologic spectrum that are variable in manifestation und therapeutic response. Genetic risk factors have long been assumed in both diseases, but no single reliable factor has been identified yet. Therefore, we aimed to clinically characterize a patient group with syndrome of synovitis acne pustulosis hyperostosis osteitis (SAPHO) (n = 47) and chronic recurrent multifocal osteomyelitis (CRMO)/ chronic non-bacterial osteomyelitis (CNO) (n = 9) and analyze a CRMO candidate gene.

The aim of the study was to evaluate the impact of disease activity, selected serum cytokines, and therapy on metabolic syndrome (MetS) components in patients with synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome.