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Calcified Tissue International Jul 2021Common genetic variants at the RIN3 locus on chromosome 14q32 predispose to Paget's disease of bone (PDB) but the mechanisms by which they do so are unknown. Here, we...
Common genetic variants at the RIN3 locus on chromosome 14q32 predispose to Paget's disease of bone (PDB) but the mechanisms by which they do so are unknown. Here, we analysed the skeletal phenotype of female mice with targeted inactivation of the mouse Rin3 gene (Rin3) as compared with wild-type littermates. The Rin3 mice had higher trabecular bone volume (BV/TV%) compared with wild type. Mean ± standard deviation values at the distal femur at 8 weeks were 9.0 ± 2.5 vs. 7.0 ± 1.5 (p = 0.002) and at 52 weeks were 15.8 ± 9.5 vs. 8.5 ± 4.2 (p = 0.002). No differences were observed in femoral cortical bone parameters with the exception of marrow diameter which was significantly smaller in 52-week-old Rin3 mice compared to wild type: (0.43 mm ± 0.1 vs. 0.57 mm ± 0.2 (p = 0.001). Bone histomorphometry showed a lower osteoclast surface / bone surface (Oc.S/BS%) at 8 weeks in Rin3 mice compared to wild type (24.1 ± 4.7 vs. 29.7 ± 6.6; p = 0.025) but there were no significant differences in markers of bone formation at this time. At 52 weeks, Oc.S/BS did not differ between genotypes but single labelled perimeter (SL.Pm/B.Pm (%)) was significantly higher in Rin3 mice (24.4 ± 6.4 vs. 16.5 ± 3.8, p = 0.003). We conclude that Rin3 negatively regulates trabecular bone mass in mice by inhibiting osteoclastic bone resorption and favouring bone formation. Our observations also suggest that the variants that predispose to PDB in humans probably do so by causing a gain-in-function of RIN3.
Topics: Animals; Bone Density; Bone Resorption; Cancellous Bone; Female; Femur; Mice; Osteitis Deformans; Osteoclasts; Osteogenesis
PubMed: 33725152
DOI: 10.1007/s00223-021-00827-2 -
Journal of Bone and Mineral Research :... Jul 2021Early onset familial Paget's disease of bone (EoPDB), familial expansile osteolysis, and expansile skeletal hyperphosphatasia are related disorders caused by insertion...
Early onset familial Paget's disease of bone (EoPDB), familial expansile osteolysis, and expansile skeletal hyperphosphatasia are related disorders caused by insertion mutations in exon 1 of the TNFRSF11A gene, which encodes receptor activator of nuclear factor κB (RANK) protein. To understand the mechanisms underlying these disorders, we developed a mouse model carrying the 75dup27 mutation which causes EoPDB. Mice heterozygous for the mutation (Tnfrsf11a ) developed a PDB-like disorder with focal osteolytic lesions in the hind limbs with increasing age. Treatment of these mice with zoledronic acid completely prevented the development of lesions. Studies in vitro showed that RANK ligand (RANKL)-induced osteoclast formation and signaling was impaired in bone marrow cells from Tnfrsf11a animals, but that osteoclast survival was increased independent of RANKL stimulation. Surprisingly, Tnfrsf11a homozygotes had osteopetrosis at birth, with complete absence of osteoclasts. Bone marrow cells from these mice failed to form osteoclasts in response to RANKL and macrophage colony-stimulating factor (M-CSF) stimulation. This intriguing study has shown that in heterozygous form, the 75dup27 mutation causes focal osteolytic lesions in vivo reminiscent of the human disorder and extends osteoclast survival independently of RANKL signaling. In homozygous form, however, the mutation causes osteopetrosis due to failure of osteoclast formation and insensitivity to RANKL stimulation. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR)..
Topics: Animals; Homozygote; Humans; Mice; Mutagenesis, Insertional; Mutation; Osteitis Deformans; Osteoclasts; Osteopetrosis; Phenotype; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B
PubMed: 33724536
DOI: 10.1002/jbmr.4288 -
Journal of Bone and Mineral Research :... Jun 2021Paget's disease of bone (PDB) is a late-onset chronic progressive bone disease characterized by abnormal activation of osteoclasts that results in bone pain,...
Paget's disease of bone (PDB) is a late-onset chronic progressive bone disease characterized by abnormal activation of osteoclasts that results in bone pain, deformities, and fractures. PDB is very rare in Asia. A subset of PDB patients have early onset and can develop malignant giant cell tumors (GCTs) of the bone (PDB/GCTs), which arise within Paget bone lesions; the result is a significantly higher mortality rate. SQSTM1, TNFRSF11A, OPG, VCP, and HNRNPA2B1 have been identified as pathogenic genes of PDB, and ZNF687 is the only confirmed gene to date known to cause PDB/GCT. However, the molecular mechanism underlying PDB/GCT has not been fully elucidated. Here, we investigate an extended Chinese pedigree with eight individuals affected by early-onset and polyostotic PDB, two of whom developed GCTs. We identified a heterozygous 4-bp deletion in the Profilin 1 (PFN1) gene (c.318_321delTGAC) by genetic linkage analysis and exome sequencing for the family. Sanger sequencing revealed another heterozygous 1-bp deletion in PFN1 (c.324_324delG) in a sporadic early-onset PDB/GCT patient, further proving its causative role. Interestingly, a heterozygous missense mutation of PFN1 (c.335 T > C) was identified in another PDB/GCT family, revealing that not only deletion but also missense mutations in PFN1 can cause PDB/GCT. Furthermore, we established a Pfn1-mutated mouse model (C57BL/6J mice) and successfully obtained Pagetic phenotypes in heterozygous mice, verifying loss of function of PFN1 as the cause of PDB/GCT development. In conclusion, our findings reveal mutations in PFN1 as the pathological mechanism in PDB/GCT, and we successfully established Pfn1-mutated mice as a suitable animal model for studying PDB-associated pathological mechanisms. The identification of PFN1 mutations has great diagnostic value for identifying PDB individuals predisposed toward developing GCTs. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
Topics: Animals; Giant Cell Tumors; Humans; Mice; Mice, Inbred C57BL; Mutation; Osteitis Deformans; Profilins; Sequestosome-1 Protein
PubMed: 33599011
DOI: 10.1002/jbmr.4275 -
Calcified Tissue International Jun 2021Bisphosphonates are the first-choice treatment of osteoporosis and Paget's disease of bone. Among the bisphosphonates, the non-amino-bisphosphonates, such as clodronic...
Bisphosphonates are the first-choice treatment of osteoporosis and Paget's disease of bone. Among the bisphosphonates, the non-amino-bisphosphonates, such as clodronic acid, are intracellular converted into toxic analogues of ATP and induce cellular apoptosis whereas the amino-bisphosphonates, such as zoledronic acid, inhibit the farnesyl-diphosphate-synthase, an enzyme of the mevalonate pathway. This pathway regulates cholesterol and glucose homeostasis and is a target for statins. In this retrospective cohort study, we evaluated the effects of an intravenous infusion of zoledronic acid (5 mg) or clodronic acid (1500 mg) on blood lipid (i.e. total cholesterol, low-density lipoprotein-cholesterol, high-density lipoprotein-cholesterol and triglycerides) and glucose levels in patients with osteoporosis and Paget's disease of bone. All patients were evaluated before, 1 and 6 months after bisphosphonate treatment. Pagetic and osteoporotic patients treated with zoledronic acid showed a significant reduction in glucose and atherogenic lipids during follow-up whereas these phenomena were not observed after clodronic treatment. The effect on circulating lipid levels was similar in naïve and re-treated Pagetic patients. Zoledronic acid treatment was associated with a reduction in blood glucose and atherogenic lipids in patients with metabolic bone disorders. The extent of change was similar to that obtained with the regular assumption of a low-intensity statin. Further studies are warranted to better evaluate the clinical implications of these observations.
Topics: Bone Density Conservation Agents; Diphosphonates; Glucose; Humans; Lipids; Osteitis Deformans; Retrospective Studies; Zoledronic Acid
PubMed: 33559705
DOI: 10.1007/s00223-021-00811-w -
Australian Journal of General Practice 2021Paget's disease of bone (PDB) is a common destructive condition of bone that affects 1-2% of the population, most typically those over the age of 55 years. It is...
BACKGROUND
Paget's disease of bone (PDB) is a common destructive condition of bone that affects 1-2% of the population, most typically those over the age of 55 years. It is usually asymptomatic.
OBJECTIVE
The aim of this article is to describe the clinical presentation, diagnosis and management of patients with PDB.
DISCUSSION
Most cases of PDB are diagnosed incidentally on radiographs or as an isolated elevation of serum alkaline phosphatase. Symptomatic patients present with bone pain, fractures, arthritis and features of compression neuropathy. Diagnosis is made on the basis of typical radiological features on plain films, while a radionuclide bone scan may be used to assess the extent of disease. The mainstay of treatment for PDB is bisphosphonate therapy, with zoledronic acid being the most effective agent. A single infusion of zoledronic acid leads to a sustained reduction in bone pain and markers of bone turnover. However, bisphosphonates should be reserved for symptomatic patients, as treatment with these agents has been associated with an increase in rates of fracture in patients with asymptomatic PDB.
Topics: Diphosphonates; Fractures, Bone; Humans; Middle Aged; Osteitis Deformans; Radiography; Zoledronic Acid
PubMed: 33543158
DOI: 10.31128/AJGP-10-20-5690 -
Nature Communications Jan 2021Missense mutations in Valosin-Containing Protein (VCP) are linked to diverse degenerative diseases including IBMPFD, amyotrophic lateral sclerosis (ALS), muscular...
Missense mutations in Valosin-Containing Protein (VCP) are linked to diverse degenerative diseases including IBMPFD, amyotrophic lateral sclerosis (ALS), muscular dystrophy and Parkinson's disease. Here, we characterize a VCP-binding co-factor (SVIP) that specifically recruits VCP to lysosomes. SVIP is essential for lysosomal dynamic stability and autophagosomal-lysosomal fusion. SVIP mutations cause muscle wasting and neuromuscular degeneration while muscle-specific SVIP over-expression increases lysosomal abundance and is sufficient to extend lifespan in a context, stress-dependent manner. We also establish multiple links between SVIP and VCP-dependent disease in our Drosophila model system. A biochemical screen identifies a disease-causing VCP mutation that prevents SVIP binding. Conversely, over-expression of an SVIP mutation that prevents VCP binding is deleterious. Finally, we identify a human SVIP mutation and confirm the pathogenicity of this mutation in our Drosophila model. We propose a model for VCP disease based on the differential, co-factor-dependent recruitment of VCP to intracellular organelles.
Topics: Amyotrophic Lateral Sclerosis; Animals; Animals, Genetically Modified; Disease Models, Animal; Drosophila Proteins; Drosophila melanogaster; Frontotemporal Dementia; Humans; Longevity; Lysosomes; Membrane Proteins; Muscular Dystrophies, Limb-Girdle; Mutation; Myositis, Inclusion Body; Neurodegenerative Diseases; Osteitis Deformans; Phosphate-Binding Proteins; Protein Binding; Valosin Containing Protein
PubMed: 33479240
DOI: 10.1038/s41467-020-20796-8 -
BMJ Case Reports Dec 2020A 60-year-old man presented to our hospital with complaints of pain and deformity on his right thigh for the past 2 days following a history of accidental slip and fall....
A 60-year-old man presented to our hospital with complaints of pain and deformity on his right thigh for the past 2 days following a history of accidental slip and fall. Radiological investigations suggested a pathological type 2 Seinsheimer subtrochanteric fracture of the right femur with a 'bone within bone' appearance, which posed a diagnostic dilemma as this radiological appearance is seen in a spectrum of conditions. Radiographic skeletal survey failed to identify a similar appearance elsewhere in the body. Laboratory investigations pointed in favour of bone mineral disease, and histopathological examination of the bone narrowed it down to Paget's disease. The fracture was fixed with a contralateral distal femur locking compression plate. The fracture site failed to show signs of union until 6 months postsurgery and hence the patient was advised for grafting procedure. The patient deferred surgery and remains without major complications until 18 months of follow-up.
Topics: Accidental Falls; Biopsy; Bone Plates; Chronic Kidney Disease-Mineral and Bone Disorder; Diagnosis, Differential; Femur; Fracture Fixation, Internal; Fractures, Spontaneous; Hip Fractures; Humans; Male; Middle Aged; Osteitis Deformans; Radiography
PubMed: 33370952
DOI: 10.1136/bcr-2020-238567 -
Clinical Medicine (London, England) Nov 2020Adult Paget's disease of bone is the second commonest metabolic bone condition after osteoporosis. The condition is characterised by increased bone cell activity, with...
Adult Paget's disease of bone is the second commonest metabolic bone condition after osteoporosis. The condition is characterised by increased bone cell activity, with bone-resorbing osteoclasts often larger and containing more nuclei than normal and osteoblasts producing increased amounts of disorganised bone. This leads to expanded bone of poor quality possessing both sclerotic and lytic areas. Paget's disease of bone has a strong genetic element, with a family history being noted in 10-20% of cases. A number of genetic defects have been found to be associated with the condition. The most common disease-associated variants identified affect the gene, providing insights into disease aetiology, with the clinical value of knowledge of mutation status currently under active investigation. The diagnosis may be suggested by an isolated raised total alkaline phosphatase (ALP) without other identifiable causes. This can be confirmed on plain X-ray and the extent determined by isotope bone scan. The mainstay of treatment are the bisphosphonates, especially intravenous zoledronate which results in long-term suppression of bone turnover. ALP is the usual means of monitoring the condition, although more specific bone turnover markers can be helpful, especially in coincident liver disease. Patients should be followed up to monitor for biochemical relapse or development of complications, which may require medical or surgical intervention.
Topics: Adult; Bone Remodeling; Diphosphonates; Humans; Mutation; Osteitis Deformans; Osteoporosis
PubMed: 33199322
DOI: 10.7861/clinmed.20.6.page -
The British Journal of General Practice... Nov 2020
Topics: Adult; Humans; Osteitis Deformans
PubMed: 33122280
DOI: 10.3399/bjgp20X713369 -
Journal of Cellular Biochemistry Apr 2021Paget's disease (PD) is characterized by increased numbers of abnormal osteoclasts (OCLs) that drive exuberant bone formation, but the mechanisms responsible for the...
Paget's disease (PD) is characterized by increased numbers of abnormal osteoclasts (OCLs) that drive exuberant bone formation, but the mechanisms responsible for the increased bone formation remain unclear. We previously reported that OCLs from 70% of PD patients express measles virus nucleocapsid protein (MVNP), and that transgenic mice with targeted expression of MVNP in OCLs (MVNP mice) develop bone lesions and abnormal OCLs characteristic of PD. In this report, we examined if OCL-derived sphingosine-1-phosphate (S1P) contributed to the abnormal bone formation in PD, since OCL-derived S1P can act as a coupling factor to increase normal bone formation via binding S1P-receptor-3 (S1PR3) on osteoblasts (OBs). We report that OCLs from MVNP mice and PD patients expressed high levels of sphingosine kinase-1 (SphK-1) compared with wild-type (WT) mouse and normal donor OCLs. SphK-1 production by MVNP-OCLs was interleukin-6 (IL-6)-dependent since OCLs from MVNP/IL-6 mice expressed lower levels of SphK-1. Immunohistochemistry of bone biopsies from a normal donor, a PD patient, WT and MVNP mice confirmed increased expression levels of SphK-1 in OCLs and S1PR3 in OBs of the PD patient and MVNP mice compared with normal donor and WT mice. Further, MVNP-OCLs cocultured with OBs from MVNP or WT mice increased OB-S1PR3 expression and enhanced expression of OB differentiation markers in MVNP-OBs precursors compared with WT-OBs, which was mediated by IL-6 and insulin-like growth factor 1 secreted by MVNP-OCLs. Finally, the addition of an S1PR3 antagonist (VPC23019) to WT or MVNP-OBs treated with WT and MVNP-OCL-conditioned media (CM) blocked enhanced OB differentiation of MVNP-OBs treated with MVNP-OCL-CM. In contrast, the addition of the SIPR3 agonist, VPC24191, to the cultures enhanced osterix and Col-1A expression in MVNP-OBs treated with MVNP-OCL-CM compared with WT-OBs treated with WT-OCL-CM. These results suggest that IL-6 produced by PD-OCLs increases S1P in OCLs and S1PR3 on OBs, to increase bone formation in PD.
Topics: Animals; Enzyme-Linked Immunosorbent Assay; Female; Humans; Immunoblotting; Immunohistochemistry; Interleukin-6; Lysophospholipids; Male; Mice; Osteitis Deformans; Osteoclasts; Osteogenesis; Phosphorylation; Sphingosine; Sphingosine-1-Phosphate Receptors
PubMed: 33107091
DOI: 10.1002/jcb.29861