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Almutairi M, Alharbi A, Almutairi H, Shemis MF, Almutairi MS, Almutairi F. Management of Osteomyelitis in Autosomal Dominant Osteopetrosis: A Rare Case Report. Cureus 2024; 16:e62660. [PMID: 39036270 PMCID: PMC11258530 DOI: 10.7759/cureus.62660] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/18/2024] [Indexed: 07/23/2024] Open
Abstract
Albers-Schönberg disease, also known as osteopetrosis or marble bone disease, is a rare genetic disorder characterised by increased cortical bone mass due to dysfunctional osteoclast cells. This case report presents a 34-year-old male with autosomal dominant osteopetrosis (ADO), who was referred for evaluation and treatment of a chronic mandibular abscess with associated osteomyelitis and fistula. The patient's medical history included multiple fractures necessitating open reduction and internal fixation. Radiological examinations revealed the presence of chronic osteomyelitis in the mandible, marked by an increase in bone density and obliteration of medullary spaces. The treatment approach included surgical debridement, extraction of adjacent teeth, sequestrectomy, and antibiotic therapy. Notably, Enterobacter cloacae bacteria were identified through culture, leading to a tailored antibiotic regimen. Follow-up assessments, including clinical photographs and postoperative CT scans, were conducted to monitor the patient's progress. Histopathological examination confirmed osteomyelitis showing both viable and non-viable bone, surrounded by significant inflammatory infiltrate. This case underscores the complexity of managing osteomyelitis in patients with osteopetrosis and highlights the importance of early diagnosis, particularly before dental extractions, to prevent disease exacerbation. The rarity of this condition emphasises the need for further research and awareness among healthcare providers for optimal patient care.
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Affiliation(s)
| | | | | | - Mohamed F Shemis
- Oral and Maxillofacial Surgery, Qassim University, Buraydah, SAU
| | | | - Faris Almutairi
- Oral and Maxillofacial Surgery, Qassim University, Buraydah, SAU
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Song XL, Peng LY, Wang DW, Wang H. Autosomal dominant osteopetrosis type II resulting from a de novo mutation in the CLCN7 gene: A case report. World J Clin Cases 2022; 10:6936-6943. [PMID: 36051116 PMCID: PMC9297392 DOI: 10.12998/wjcc.v10.i20.6936] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Revised: 12/01/2021] [Accepted: 05/28/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Osteopetrosis is a family of extremely rare diseases caused by failure of osteoclasts and impaired bone resorption. Among them, autosomal dominant osteopetrosis type II (ADO II), related to the chloride channel 7 (CLCN7) gene, is the most frequent form of osteopetrosis. In this study, we report a de novo mutation of CLCN7 in a patient without the family history of ADO II.
CASE SUMMARY A 5-year-old Chinese boy with ADO II was found to have a de novo mutation in the CLCN7 gene [c.746C>T (p.P249L)]. Typical clinical manifestations, including thickening of the cortex of spinal bones and long bones, non-traumatic fracture of the femoral neck, and femoral head necrosis, were found in this patient. The patient is the first reported case of ADO II with the missense mutation c.746C>T (p.P249L) of the CLCN7 gene reported in China. We also review the available literature on ADO II-related CLCN7 mutations, including baseline patient clinical features, special clinical significance, and common mutations.
CONCLUSION Our report will enrich the understanding of mutations in ADO II patients. The possibility of a de novo mutation should be considered in individuals who have no family history of osteopetrosis.
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Affiliation(s)
- Xiu-Li Song
- Genetic Diagnostic Centre, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Li-Yuan Peng
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Dao-Wen Wang
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Hong Wang
- Genetic Diagnostic Centre, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
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Rajendran AK, Amirthalingam S, Hwang NS. A brief review of mRNA therapeutics and delivery for bone tissue engineering. RSC Adv 2022; 12:8889-8900. [PMID: 35424872 PMCID: PMC8985089 DOI: 10.1039/d2ra00713d] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Accepted: 03/15/2022] [Indexed: 11/21/2022] Open
Abstract
The therapeutics for bone tissue regeneration requires constant advancements owing to the steady increase in the number of patients suffering from bone-related disorders, and also to find efficient and cost-effective treatment modalities. One of the major advancements in the field of therapeutics is the development of mRNAs. mRNAs, which have been extensively tested for the vaccines, could be very well utilized as a potential inducer for bone regeneration. The ability of mRNAs to enter the cells and instruct the cellular machinery to produce the required native proteins such as BMP or VEGF is a great way to avoid the issues faced with growth factor deliveries such as the production cost, loss of biological function etc. However, there have been a few hurdles for using mRNAs as an effective therapeutic agent, such as proper dosing, tolerating the degradation by RNases, improving the half-life, controlling the spatio-temporal release and reducing the off-target effects. This brief review discusses the various developments in the field of mRNA therapeutics especially for bone tissue engineering, how nano-formulations are being developed to effectively deliver the mRNAs into the cells by evading the immune responses, how researchers have developed certain strategies to increase the half-life, to successfully deliver the mRNAs to specific bone defect area and bring about effective bone regeneration.
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Affiliation(s)
- Arun Kumar Rajendran
- School of Chemical and Biological Engineering, The Institute of Chemical Processes, Seoul National University Seoul 08826 Republic of Korea
| | - Sivashanmugam Amirthalingam
- School of Chemical and Biological Engineering, The Institute of Chemical Processes, Seoul National University Seoul 08826 Republic of Korea
| | - Nathaniel S Hwang
- School of Chemical and Biological Engineering, The Institute of Chemical Processes, Seoul National University Seoul 08826 Republic of Korea
- Interdisciplinary Program in Bioengineering, Seoul National University Seoul 08826 Republic of Korea
- Bio-MAX/N-Bio Institute, Institute of Bio-Engineering, Seoul National University Seoul 08826 Republic of Korea
- Institute for Engineering Research, Seoul National University Seoul 08826 Republic of Korea
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Wang Z, Li X, Wang Y, Fu W, Liu Y, Zhang Z, Wang C. Natural History of Type II Autosomal Dominant Osteopetrosis: A Single Center Retrospective Study. Front Endocrinol (Lausanne) 2022; 13:819641. [PMID: 35370969 PMCID: PMC8970046 DOI: 10.3389/fendo.2022.819641] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Accepted: 02/23/2022] [Indexed: 12/05/2022] Open
Abstract
BACKGROUND Autosomal dominant osteopetrosis II (ADO II, MIM166600) is a sclerosing bone disorder caused by CLCN7 mutation. The main clinical characteristics include minor trauma-related fracture and hip osteoarthritis, whereas cranial nerve palsy and bone marrow failure rarely develop. Although it is generally believed that ADO II has a relatively benign course, the natural course of the disease in Chinese patients remains unclear. MATERIALS AND METHODS Thirty-six patients diagnosed with ADO II in Shanghai Jiao Tong University Affiliated Sixth People's Hospital from 2008 to 2021 were studied retrospectively. Among them, 15 patients were followed for an average of 6.3 years (1-14 years). RESULTS In this study, minor trauma-related fractures of the limb were the most typical clinical manifestations. Visual loss (1/36) and bone marrow failure (2/36), was rare in this study. The condition of ADO II seems to be stable in most patients. There were no correlations between markedly elevated bone mineral density (BMD) and minor trauma-related fractures. In total, 21 diseases causing mutations were detected. Among them, the mutation c.2299C>T (p.Arg767Trp) was the most common (16.67%), and mutation c.937G>A [p.(Glu313Lys)] was associated with severe fractures, haematological defects and cranial palsy. CONCLUSIONS Minor trauma-related fracture is the most typical clinical manifestation of ADO II and always occurs in. The mutation c.2299C>T (p.Arg767Trp) is in general a relatively common variant, while the mutation c.937G>A [p.(Glu313Lys)] seems to be associated with severe phenotype. In our study, ADO II seems to remain stable over time.
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Affiliation(s)
| | | | | | | | | | | | - Chun Wang
- *Correspondence: Chun Wang, ; Zhenlin Zhang,
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Gresky J, Dellú E, Favia M, Ferorelli D, Radina F, Scardapane A, Petiti E. A critical review of the anthropological and paleopathological literature on osteopetrosis as an ancient rare disease (ARD). INTERNATIONAL JOURNAL OF PALEOPATHOLOGY 2021; 33:280-288. [PMID: 34082191 DOI: 10.1016/j.ijpp.2021.05.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Revised: 05/17/2021] [Accepted: 05/17/2021] [Indexed: 06/12/2023]
Abstract
OBJECTIVE A reappraisal of the available evidence of osteopetrosis in the archaeological record as first step in promoting new approaches to rare diseases in paleopathology. MATERIALS AND METHODS Three different approaches are combined: a survey of the last 50 years of bioarchaeological publications; an online search addressing six of the more widely used search engines; macroscopic and radiographic analyses of the human remains from the Neolithic site of Palata 2 (Italy). RESULTS The combined results of the literature survey and the online search identified six cases of osteopetrosis. The majority of search hits place this disease into differential diagnoses. The investigation of the remains from Palata 2, one of the six cases in literature, indicates a non-specific sclerosis of the cranial vault. CONCLUSIONS Of the six cases of osteopetrosis, only two, one of the autosomal-recessive type (ARO) and one of the autosomal-dominant type (ADO), are supported by direct osteoarchaeological evidence. Therefore, inaccurate differential diagnoses generate an inflated number of cases in the paleopathological record. SIGNIFICANCE This reappraisal calls for a more informed and evidence-based approach to osteopetrosis and, more generally, to rare diseases in paleopathology. LIMITATIONS Lack of specific publications on osteopetrosis; more case studies may be present in "gray literature". SUGGESTIONS FOR FURTHER RESEARCH Cases of osteopetrosis from archaeological and historical collections as well as medical literature are needed to increase knowledge about this rare disease. More precise differential diagnoses are required, particularly when dealing with rare diseases.
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Affiliation(s)
- Julia Gresky
- Department of Natural Sciences, German Archaeological Institute, Berlin, Germany.
| | - Elena Dellú
- Superintendence Archaeology, Fine Arts and Landscape for the Metropolitan City of Bari, Italy
| | - Matteo Favia
- Interdisciplinary Department of Medicine, University of Bari, Italy
| | - Davide Ferorelli
- Interdisciplinary Department of Medicine, University of Bari, Italy
| | - Francesca Radina
- Superintendence Archaeology, Fine Arts and Landscape for the Metropolitan City of Bari, Italy
| | | | - Emmanuele Petiti
- Department of Natural Sciences, German Archaeological Institute, Berlin, Germany
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Case report of osteomyelitis of the mandible in osteopetrosis and management considerations. Int J Surg Case Rep 2021; 81:105813. [PMID: 33887866 PMCID: PMC8050717 DOI: 10.1016/j.ijscr.2021.105813] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 03/04/2021] [Accepted: 03/20/2021] [Indexed: 02/04/2023] Open
Abstract
Management guidelines in mandibular osteomyelitis in Osteopetrosis. A female patient with osteopetrosis presented osteomyelitis after teeth extraction. Our case suggests the importance to maintain at maximum existing mandibular bone. Dental prevention could reduce occurrence of osteomyelitis in Osteopetrosis. Introduction and importance Osteopetrosis is a poorly known and probably underdiagnosed pathology. It is caused by various genetic abnormalities resulting in osteoclast dysfunction. Functional and aesthetic consequences have a major impact on the patient’s quality of life. Ten percent of osteopetrosis cases develop osteomyelitis that usually involves the mandible. Management of this complication remains complex and often unsatisfactory. Case presentation We report a case of a 62-year-old woman with osteopetrosis, complicated by mandibular osteomyelitis with intra-oral bone exposure and submental fistulas. Management was performed with antibiotic therapy and surgical necrotic resection. This cured the fistulas but the bone exposure persisted. Discussion This case report highlights the difficulty of achieving complete healing of osteomyelitis in osteopetrosis. Antibiotic therapy, surgical management, or even hyperbaric oxygen therapy are required, but must be adapted to the case. A free flap procedure is undesirable but, when it is necessary, a bone marrow transplant could be considered to restore osteoclast function. Conclusion The management of mandibular osteomyelitis in patients with osteopetrosis must adapt to the situation and severity. To avoid most cases of osteomyelitic complications in patients suffering from osteopetrosis, we propose that a preventive strategy of better dental care should be considered.
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Computed Tomography Diagnostic of Uncommon Case of Osteopetrosis in 80-Year-Old Man-Case Report. MEDICINA-LITHUANIA 2020; 56:medicina56100518. [PMID: 33023136 PMCID: PMC7601162 DOI: 10.3390/medicina56100518] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Revised: 09/28/2020] [Accepted: 09/29/2020] [Indexed: 11/16/2022]
Abstract
Background and Objectives: During osteopetrosis course, impaired bone remodeling induces skeletal osteosclerosis and abnormally dense bones, which, however, are brittle and susceptible to low-energy fractures. In this study, radiological evaluation and densitometric measurements of several bones of the skeleton in one of the oldest patients in the world suffering from osteopetrosis was presented. Materials and Methods: Volumetric bone mineral density measurements of the examined bones in an 80-year-old man were performed using two different quantitative computed tomography techniques. Results: The obtained results show higher values of the volumetric bone mineral density of the trabecular bone in lumbar spine than in the cortical bone compartment. T-score and Z-score in this patient reached values of 27–28 and 31–32, respectively. Conclusions: The obtained densitometric data may serve for further diagnostic purposes of osteopetrosis. As documented, the severity of the osteosclerotic changes of bones were higher in this patient than in most other described cases. Moreover, radiological signs diagnosed in this patient were characteristic for all types of osteopetrosis making this case very uncommon.
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Kang S, Kang YK, Lee JA, Kim DH, Lim JS. A Case of Autosomal Dominant Osteopetrosis Type 2 with a CLCN7 Gene Mutation. J Clin Res Pediatr Endocrinol 2019; 11:439-443. [PMID: 30759959 PMCID: PMC6878338 DOI: 10.4274/jcrpe.galenos.2019.2018.0229] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Osteopetrosis is a rare genetic disease characterized by increased bone density and bone fractures due to defective osteoclast function. Autosomal dominant osteopetrosis type 2 (ADO-2), Albers-Schonberg disease, is characterized by the sclerosis of bones, predominantly involving the spine, pelvis and the base of the skull. Here, we report a typical case of osteopetrosis in a 17.7-year-old male who carries a heterozygous c.746C>T mutation in exon 9 in the chloride voltage-gated channel 7 (CLCN7) gene. The patient’s spine showed multiple sclerotic changes including sandwich vertebra. His father had the same mutation but his skeletal radiographs were normal. This is the first reported case of ADO-2, confirmed by genetic testing in a Korean patient.
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Affiliation(s)
- Sol Kang
- Korea Cancer Center Hospital, Clinic of Pediatrics, Seoul, Republic of Korea
| | - Young Kyung Kang
- Korea Cancer Center Hospital, Clinic of Pediatrics, Seoul, Republic of Korea
| | - Jun Ah Lee
- Korea Cancer Center Hospital, Clinic of Pediatrics, Seoul, Republic of Korea
| | - Dong Ho Kim
- Korea Cancer Center Hospital, Clinic of Pediatrics, Seoul, Republic of Korea
| | - Jung Sub Lim
- Korea Cancer Center Hospital, Clinic of Pediatrics, Seoul, Republic of Korea,* Address for Correspondence: Korea Cancer Center Hospital, Clinic of Pediatrics, Seoul, Republic of Korea Phone: +82-2-970-1224 E-mail:,
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9
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Dedic C, Hung TS, Shipley AM, Maeda A, Gardella T, Miller AL, Divieti Pajevic P, Kunkel JG, Rubinacci A. Calcium fluxes at the bone/plasma interface: Acute effects of parathyroid hormone (PTH) and targeted deletion of PTH/PTH-related peptide (PTHrP) receptor in the osteocytes. Bone 2018; 116:135-143. [PMID: 30053608 PMCID: PMC6158063 DOI: 10.1016/j.bone.2018.07.020] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2018] [Revised: 07/20/2018] [Accepted: 07/24/2018] [Indexed: 01/10/2023]
Abstract
Calcium ion concentration ([Ca2+]) in the systemic extracellular fluid, ECF-[Ca2+], is maintained around a genetically predetermined set-point, which combines the operational level of the kidney and bone/ECF interfaces. The ECF-[Ca2+] is maintained within a narrow oscillation range by the regulatory action of Parathyroid Hormone (PTH), Calcitonin, FGF-23, and 1,25(OH)2D3. This model implies two correction mechanisms, i.e. tubular Ca2+ reabsorption and osteoclast Ca2+ resorption. Although their alterations have an effect on the ECF-[Ca2+] maintenance, they cannot fully account for rapid correction of the continuing perturbations of plasma [Ca2+], which occur daily in life. The existence of Ca2+ fluxes at quiescent bone surfaces fulfills the role of a short-term error correction mechanism in Ca2+ homeostasis. To explore the hypothesis that PTH regulates the cell system responsible for the fast Ca2+ fluxes at the bone/ECF interface, we have performed direct real-time measurements of Ca2+ fluxes at the surface of ex-vivo metatarsal bones maintained in physiological conditions mimicking ECF, and exposed to PTH. To further characterize whether the PTH receptor on osteocytes is a critical component of the minute-to-minute ECF-[Ca2+] regulation, metatarsal bones from mice lacking the PTH receptor in these cells were tested ex vivo for rapid Ca2+ exchange. We performed direct real-time measurements of Ca2+ fluxes and concentration gradients by a scanning ion-selective electrode technique (SIET). To validate ex vivo measurements, we also evaluated acute calcemic response to PTH in vivo in mice lacking PTH receptors in osteocytes vs littermate controls. Our data demonstrated that Ca2+ fluxes at the bone-ECF interface in excised bones as well as acute calcemic response in the short-term were unaffected by PTH exposure and its signaling through its receptor in osteocytes. Rapid minute-to-minute regulation of the ECF-[Ca2+] was found to be independent of PTH actions on osteocytes. Similarly, mice lacking PTH receptor in osteocytes, responded to PTH challenge with similar calcemic increases.
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Affiliation(s)
- Christopher Dedic
- Molecular and Cell Biology, Goldman School of Dental Medicine, Boston University, Boston, MA, USA
| | - Tin Shing Hung
- Division of Life Sciences, State Key Laboratory for Molecular Neuroscience, HKUST, Hong Kong, China
| | | | - Akira Maeda
- Endocrine Unit, Massachusetts General Hospital, Boston, USA; Chugai Pharmaceutical, Japan
| | | | - Andrew L Miller
- Division of Life Sciences, State Key Laboratory for Molecular Neuroscience, HKUST, Hong Kong, China
| | - Paola Divieti Pajevic
- Molecular and Cell Biology, Goldman School of Dental Medicine, Boston University, Boston, MA, USA
| | - Joseph G Kunkel
- Pickus Center for Biomedical Research, University of New England, Biddeford, ME, USA
| | - Alessandro Rubinacci
- Bone Metabolism Unit, Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milano, Italy.
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Abstract
The group of sclerosing bone dysplasia's is a clinically and genetically heterogeneous group of rare bone disorders which, according to the latest Nosology and classification of genetic skeletal disorders (2015), can be subdivided in three subgroups; the neonatal osteosclerotic dysplasias, the osteopetroses and related disorders and the other sclerosing bone disorders. Here, we give an overview of the most important radiographic and clinical symptoms, the underlying genetic defect and potential treatment options of the different sclerosing dysplasias included in these subgroups.
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Affiliation(s)
- Eveline Boudin
- Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium
| | - Wim Van Hul
- Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium.
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Zhang X, Wei Z, He J, Wang C, Zhang Z. Novel mutations of CLCN7 cause autosomal dominant osteopetrosis type II (ADOII) and intermediate autosomal recessive osteopetrosis (ARO) in seven Chinese families. Postgrad Med 2017; 129:934-942. [PMID: 28975865 DOI: 10.1080/00325481.2017.1386529] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Affiliation(s)
- Xiaoya Zhang
- Metabolic Bone Disease and Genetic Research Unit, Department of Osteoporosis and Bone Disease, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China
| | - Zhanying Wei
- Metabolic Bone Disease and Genetic Research Unit, Department of Osteoporosis and Bone Disease, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China
| | - Jinwei He
- Metabolic Bone Disease and Genetic Research Unit, Department of Osteoporosis and Bone Disease, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China
| | - Chun Wang
- Metabolic Bone Disease and Genetic Research Unit, Department of Osteoporosis and Bone Disease, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China
| | - Zhenlin Zhang
- Metabolic Bone Disease and Genetic Research Unit, Department of Osteoporosis and Bone Disease, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China
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Ishimoto T, Sato B, Lee JW, Nakano T. Co-deteriorations of anisotropic extracellular matrix arrangement and intrinsic mechanical property in c-src deficient osteopetrotic mouse femur. Bone 2017; 103:216-223. [PMID: 28716550 DOI: 10.1016/j.bone.2017.06.023] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2017] [Revised: 06/21/2017] [Accepted: 06/28/2017] [Indexed: 01/22/2023]
Abstract
Osteopetrotic bone shows dissociation between bone mineral density (BMD) and bone strength. In this study, volumetric BMD; preferential orientation of the extracellular matrix (ECM), which is composed of collagen fibers and apatite crystals as bone material quality; and mechanical properties of the src-/- osteopetrotic and normal mouse femoral cortical bone were analyzed and compared with each other at a bone tissue level. The degree of preferential orientation of ECM along the femoral long axis was significantly decreased in the src-/- mice femur, suggesting deteriorated bone quality. Young's modulus, as a tissue-level mechanical property analyzed by nano-indentation technique along the long bone direction, also was decreased in the src-/- mice cortical femur, in spite of the similar volumetric cortical BMD. To the best of our knowledge, this is the first report to demonstrate the synchronous deterioration of Young's modulus and anisotropic ECM organization in the src-/- osteopetrotic mouse bone. These results indicate that the deterioration of the preferential ECM orientation is one major cause of the impaired mechanical property in the src-/- mouse bone.
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Affiliation(s)
- Takuya Ishimoto
- Division of Materials and Manufacturing Science, Graduate School of Engineering, Osaka University, 2-1, Yamada-Oka, Suita, Osaka 565-0871, Japan
| | - Bunji Sato
- Division of Materials and Manufacturing Science, Graduate School of Engineering, Osaka University, 2-1, Yamada-Oka, Suita, Osaka 565-0871, Japan
| | - Jee-Wook Lee
- Division of Materials and Manufacturing Science, Graduate School of Engineering, Osaka University, 2-1, Yamada-Oka, Suita, Osaka 565-0871, Japan; School of Advanced Materials Engineering, Center for Advanced Materials Technology, Kookmin University, 861-1, Jeongneung-dong, Seongbuk-gu, Seoul 136-702, Republic of Korea
| | - Takayoshi Nakano
- Division of Materials and Manufacturing Science, Graduate School of Engineering, Osaka University, 2-1, Yamada-Oka, Suita, Osaka 565-0871, Japan.
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Liu YP, Lin XH, Yan MY, Lin BQ, Zhuo MY. Debridement in chronic osteomyelitis with benign osteopetrosis: A case report. Exp Ther Med 2016; 12:2811-2814. [PMID: 27882078 PMCID: PMC5103689 DOI: 10.3892/etm.2016.3706] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2015] [Accepted: 12/23/2015] [Indexed: 01/01/2023] Open
Abstract
Osteopetrosis is a rare bone disease caused by metabolic imbalances as a result of genetic mutations. For instance, autosomal dominant osteopetrosis is caused by a missense mutation of the C1CN7 gene. This was first reported in 1904 and is thought to be caused by osteoclastic dysfunction and an impaired bone resorption ability. An accumulation of cortical bone mass during the remodeling of the medullary bone may increase the bone density and give rise to a hard marble consistency. Osteopetrosis can be divided into benign and malignant forms; however, no curative treatment exists for benign osteopetrosis. The management of complications, such as chronic osteomyelitis and fractures, serves a key role in influencing the patient survival rates. Previous studies have demonstrated that a combined treatment of hyperbaric oxygen (HBO) lavage for debridement of the necrotic region and high-dose systemic antibiotics may be effective in the management of osteopetrosis. The present study reported a case of chronic mandible osteomyelitis and fistula occurring in association with maxillary sinusitis, who was successfully treated by through nasal endoscopy, using repeated flushing and cleaning every 2 weeks as a form of debridement, in the absence of high-dose antibiotics and HBO.
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Affiliation(s)
- Yu-Ping Liu
- Department of Endocrinology and Metabolism, Xiamen Chang Gung Hospital, Xiamen, Fujian 361000, P.R. China
| | - Xiang-Hua Lin
- Department of Hematology, Xiamen Chang Gung Hospital, Xiamen, Fujian 361000, P.R. China
| | - Man-Yun Yan
- Department of Otorhinolaryngology, Xiamen Chang Gung Hospital, Xiamen, Fujian 361000, P.R. China
| | - Bao-Quan Lin
- Department of Otorhinolaryngology, Xiamen Chang Gung Hospital, Xiamen, Fujian 361000, P.R. China
| | - Ming-Ying Zhuo
- Department of Otorhinolaryngology, Xiamen Chang Gung Hospital, Xiamen, Fujian 361000, P.R. China
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Guo J, Bervoets TJM, Henriksen K, Everts V, Bronckers ALJJ. Null mutation of chloride channel 7 (Clcn7) impairs dental root formation but does not affect enamel mineralization. Cell Tissue Res 2015; 363:361-70. [PMID: 26346547 PMCID: PMC4735262 DOI: 10.1007/s00441-015-2263-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2015] [Accepted: 07/29/2015] [Indexed: 12/23/2022]
Abstract
ClC-7, located in late endosomes and lysosomes, is critical for the function of osteoclasts. Secretion of Cl(-) by the ruffled border of osteoclasts enables H(+) secretion by v-H(+)-ATPases to dissolve bone mineral. Mice lacking ClC-7 show altered lysosomal function that leads to severe lysosomal storage. Maturation ameloblasts are epithelial cells with a ruffled border that secrete Cl(-) as well as endocytose and digest large quantities of enamel matrix proteins during formation of dental enamel. We tested the hypothesis that ClC-7 in maturation ameloblasts is required for intracellular digestion of matrix fragments to complete enamel mineralization. Craniofacial bones and developing teeth in Clcn7(-/-) mice were examined by micro-CT, immunohistochemistry, quantified histomorphometry and electron microscopy. Osteoclasts and ameloblasts in wild-type mice stained intensely with anti-ClC-7 antibody but not in Clcn7(-/-) mice. Craniofacial bones in Clcn7(-/-) mice were severely osteopetrotic and contained 1.4- to 1.6-fold more bone volume, which was less mineralized than the wild-type littermates. In Clcn7(-/-) mice maturation ameloblasts and osteoclasts highly expressed Ae2 as in wild-type mice. However, teeth failed to erupt, incisors were much shorter and roots were disfigured. Molars formed a normal dental crown. In compacted teeth, dentin was slightly less mineralized, enamel did not retain a matrix and mineralized fairly normal. We concluded that ClC-7 is essential for osteoclasts to resorb craniofacial bones to enable tooth eruption and root development. Disruption of Clcn7 reduces bone and dentin mineral density but does not affect enamel mineralization.
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Affiliation(s)
- Jing Guo
- Department Oral Cell Biology, Academic Center of Dentistry Amsterdam (ACTA), University of Amsterdam and VU-University of Amsterdam, MOVE Research Institute, Gustav Mahlerlaan 3004, 1081 LA, Amsterdam, The Netherlands. .,School of Stomatology/Dental Clinic, Zhejiang Chinese Medical University, Mailbox 97, Binwen Road 548, Binjiang District, 310053, Hangzhou, China.
| | - Theodore J M Bervoets
- Department Oral Cell Biology, Academic Center of Dentistry Amsterdam (ACTA), University of Amsterdam and VU-University of Amsterdam, MOVE Research Institute, Gustav Mahlerlaan 3004, 1081 LA, Amsterdam, The Netherlands
| | - Kim Henriksen
- Nordic Bioscience Biomarkers and Research A/S, Hovedgade 207, 2730, Herlev, Denmark
| | - Vincent Everts
- Department Oral Cell Biology, Academic Center of Dentistry Amsterdam (ACTA), University of Amsterdam and VU-University of Amsterdam, MOVE Research Institute, Gustav Mahlerlaan 3004, 1081 LA, Amsterdam, The Netherlands
| | - Antonius L J J Bronckers
- Department Oral Cell Biology, Academic Center of Dentistry Amsterdam (ACTA), University of Amsterdam and VU-University of Amsterdam, MOVE Research Institute, Gustav Mahlerlaan 3004, 1081 LA, Amsterdam, The Netherlands
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Henriksen K, Thudium CS, Christiansen C, Karsdal MA. Novel targets for the prevention of osteoporosis - lessons learned from studies of metabolic bone disorders. Expert Opin Ther Targets 2015; 19:1575-84. [PMID: 25960169 DOI: 10.1517/14728222.2015.1045415] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
INTRODUCTION Osteoporosis is a major health care problem, and whereas efficacious treatments for vertebral fracture reduction are available for osteoporosis patients, these therapies are still limited with respect to capacity for restoration of bone loss, as well as efficacy on non-vertebral fractures, such as hip fractures, which are the source of morbidity and mortality. AREAS COVERED Studies of rare bone diseases in humans, such as osteopetrosis, sclerosteosis, pycnodysostosis and more, have shed light on a series of drug targets in bone that have the potential to result in therapies for osteoporosis with novel mechanisms of action, and the potential to improve the standard of care substantially. We focus on how they are separated from classic treatments for osteoporosis, in terms of novel modes of action, additional beneficial effects on bone turnover and importantly also safety. We focus on the status of anti-sclerostin antibodies, novel parathyroid hormone-related protein analogs, inhibitors of cathepsin K and ClC-7 in osteoclasts, all of which are currently in development. EXPERT OPINION There is a good possibility that the treatment of osteoporosis will be greatly improved within the coming years; however, with numerous effective and safe drugs already available careful attention to the safety of these novel candidates is crucial.
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Affiliation(s)
- Kim Henriksen
- a Department of Musculoskeletal Diseases, Nordic Bioscience Biomarkers and Research , Herlev Hovedgade 207, DK-2730 Herlev, Denmark
| | - Christian Schneider Thudium
- a Department of Musculoskeletal Diseases, Nordic Bioscience Biomarkers and Research , Herlev Hovedgade 207, DK-2730 Herlev, Denmark
| | - Claus Christiansen
- a Department of Musculoskeletal Diseases, Nordic Bioscience Biomarkers and Research , Herlev Hovedgade 207, DK-2730 Herlev, Denmark
| | - Morten Asser Karsdal
- a Department of Musculoskeletal Diseases, Nordic Bioscience Biomarkers and Research , Herlev Hovedgade 207, DK-2730 Herlev, Denmark
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Abdallah BM, Jafari A, Zaher W, Qiu W, Kassem M. Skeletal (stromal) stem cells: an update on intracellular signaling pathways controlling osteoblast differentiation. Bone 2015; 70:28-36. [PMID: 25138551 DOI: 10.1016/j.bone.2014.07.028] [Citation(s) in RCA: 82] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2014] [Revised: 07/22/2014] [Accepted: 07/24/2014] [Indexed: 01/06/2023]
Abstract
Skeletal (marrow stromal) stem cells (BMSCs) are a group of multipotent cells that reside in the bone marrow stroma and can differentiate into osteoblasts, chondrocytes and adipocytes. Studying signaling pathways that regulate BMSC differentiation into osteoblastic cells is a strategy for identifying druggable targets for enhancing bone formation. This review will discuss the functions and the molecular mechanisms of action on osteoblast differentiation and bone formation; of a number of recently identified regulatory molecules: the non-canonical Notch signaling molecule Delta-like 1/preadipocyte factor 1 (Dlk1/Pref-1), the Wnt co-receptor Lrp5 and intracellular kinases. This article is part of a Special Issue entitled: Stem Cells and Bone.
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Affiliation(s)
- Basem M Abdallah
- Molecular Endocrinology Laboratory (KMEB), Department of Endocrinology, Odense University Hospital & University of Southern Denmark, Odense, Denmark
| | - Abbas Jafari
- Molecular Endocrinology Laboratory (KMEB), Department of Endocrinology, Odense University Hospital & University of Southern Denmark, Odense, Denmark; DanStem (Danish Stem Cell Center), Panum Institute, University of Copenhagen, Copenhagen, Denmark
| | - Walid Zaher
- Molecular Endocrinology Laboratory (KMEB), Department of Endocrinology, Odense University Hospital & University of Southern Denmark, Odense, Denmark; Stem Cell Unit, Department of Anatomy, College of Medicine, King Saud University, Saudi Arabia
| | - Weimin Qiu
- Molecular Endocrinology Laboratory (KMEB), Department of Endocrinology, Odense University Hospital & University of Southern Denmark, Odense, Denmark
| | - Moustapha Kassem
- Molecular Endocrinology Laboratory (KMEB), Department of Endocrinology, Odense University Hospital & University of Southern Denmark, Odense, Denmark; DanStem (Danish Stem Cell Center), Panum Institute, University of Copenhagen, Copenhagen, Denmark; Stem Cell Unit, Department of Anatomy, College of Medicine, King Saud University, Saudi Arabia.
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Bollerslev J, Henriksen K, Nielsen MF, Brixen K, Van Hul W. Autosomal dominant osteopetrosis revisited: lessons from recent studies. Eur J Endocrinol 2013; 169:R39-57. [PMID: 23744590 DOI: 10.1530/eje-13-0136] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Systematic studies of autosomal dominant osteopetrosis (ADO) were followed by the identification of underlying mutations giving unique possibilities to perform translational studies. What was previously designated ADO1 turned out to be a high bone mass phenotype caused by a missense mutation in the first propeller of LRP5, a region of importance for binding inhibitory proteins. Thereby, ADO1 cannot be regarded as a classical form of osteopetrosis but must now be considered a disease of LRP5 activation. ADO (Albers-Schönberg disease, or previously ADO2) is characterized by increased number of osteoclasts and a defect in the chloride transport system (ClC-7) of importance for acidification of the resorption lacuna (a form of Chloride Channel 7 Deficiency Osteopetrosis). Ex vivo studies of osteoclasts from ADO have shown that cells do form normally but have reduced resorption capacity and an expanded life span. Bone formation seems normal despite decreased osteoclast function. Uncoupling of formation from resorption makes ADO of interest for new strategies for treatment of osteoporosis. Recent studies have integrated bone metabolism in whole-body energy homeostasis. Patients with ADO may have decreased insulin levels indicating importance beyond bone metabolism. There seems to be a paradigm shift in the treatment of osteoporosis. Targeting ClC-7 might introduce a new principle of dual action. Drugs affecting ClC-7 could be antiresorptive, still allowing ongoing bone formation. Inversely, drugs affecting the inhibitory site of LRP5 might stimulate bone formation and inhibit resorption. Thereby, these studies have highlighted several intriguing treatment possibilities, employing novel modes of action, which could provide benefits to the treatment of osteoporosis.
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Affiliation(s)
- Jens Bollerslev
- Section of Specialized Endocrinology, Medical Clinic B, Rikshospitalet, Oslo University Hospital, N-0027 Oslo, Norway.
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18
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García CM, García MAP, García RG, Gil FM. Osteomyelitis of the mandible in a patient with osteopetrosis. Case report and review of the literature. J Maxillofac Oral Surg 2013; 12:94-9. [PMID: 24431821 PMCID: PMC3589508 DOI: 10.1007/s12663-011-0196-y] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2009] [Accepted: 03/03/2011] [Indexed: 10/18/2022] Open
Abstract
Osteopetrosis is a rare hereditary bone disorder presenting with variable clinical features and is characterized by an increase in bone density and reduction of marrow spaces that result from a defect in the function of osteoclasts and, consequently, a decrease in bone turnover. This disease is generally divided into three types: severe infantile malignant autosomal recessive, intermediate mild autosomal recessive, and benign autosomal dominant. The prognosis of the first two types is very poor and is characterized by an early onset, usually within the first decade of life, and early death. The benign-type is characterized by a later onset and a longer life span. Ten percent of osteopetrosis cases develop osteomyelitis that usually involves the mandible. The osteomyelitis is generally caused by tooth extraction or pulpal necrosis. The leading cause of the increased rate of infection is thought to be a lack of adequate bone vasculature. Treatment of osteomyelitis secondary to osteopetrosis is controversial. Treatment regimens include high-dose systemic antibiotics coupled with thorough debridement of necrotic bone and primary closure of soft tissues, if possible. Hyperbaric oxygen has been used for the treatment of chronic osteomyelitis.
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Affiliation(s)
- Carlos Moreno García
- />Department of Oral and Maxillofacial Surgery-Head and Neck Surgery, University Hospital Infanta Cristina, Badajoz, Spain
| | | | - Raúl González García
- />Department of Oral and Maxillofacial Surgery-Head and Neck Surgery, University Hospital Infanta Cristina, Badajoz, Spain
| | - Florencio Monje Gil
- />Department of Oral and Maxillofacial Surgery-Head and Neck Surgery, University Hospital Infanta Cristina, Badajoz, Spain
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Henriksen K, Flores C, Thomsen JS, Brüel AM, Thudium CS, Neutzsky-Wulff AV, Langenbach GEJ, Sims N, Askmyr M, Martin TJ, Everts V, Karsdal MA, Richter J. Dissociation of bone resorption and bone formation in adult mice with a non-functional V-ATPase in osteoclasts leads to increased bone strength. PLoS One 2011; 6:e27482. [PMID: 22087326 PMCID: PMC3210177 DOI: 10.1371/journal.pone.0027482] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2011] [Accepted: 10/17/2011] [Indexed: 01/23/2023] Open
Abstract
Osteopetrosis caused by defective acid secretion by the osteoclast, is characterized by defective bone resorption, increased osteoclast numbers, while bone formation is normal or increased. In contrast the bones are of poor quality, despite this uncoupling of formation from resorption.To shed light on the effect of uncoupling in adult mice with respect to bone strength, we transplanted irradiated three-month old normal mice with hematopoietic stem cells from control or oc/oc mice, which have defective acid secretion, and followed them for 12 to 28 weeks.Engraftment levels were assessed by flow cytometry of peripheral blood. Serum samples were collected every six weeks for measurement of bone turnover markers. At termination bones were collected for µCT and mechanical testing. An engraftment level of 98% was obtained. From week 6 until termination bone resorption was significantly reduced, while the osteoclast number was increased when comparing oc/oc to controls. Bone formation was elevated at week 6, normalized at week 12, and reduced onwards. µCT and mechanical analyses of femurs and vertebrae showed increased bone volume and bone strength of cortical and trabecular bone.In conclusion, these data show that attenuation of acid secretion in adult mice leads to uncoupling and improves bone strength.
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20
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Henriksen K, Bollerslev J, Everts V, Karsdal MA. Osteoclast activity and subtypes as a function of physiology and pathology--implications for future treatments of osteoporosis. Endocr Rev 2011; 32:31-63. [PMID: 20851921 DOI: 10.1210/er.2010-0006] [Citation(s) in RCA: 164] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Osteoclasts have traditionally been associated exclusively with catabolic functions that are a prerequisite for bone resorption. However, emerging data suggest that osteoclasts also carry out functions that are important for optimal bone formation and bone quality. Moreover, recent findings indicate that osteoclasts have different subtypes depending on their location, genotype, and possibly in response to drug intervention. The aim of the current review is to describe the subtypes of osteoclasts in four different settings: 1) physiological, in relation to turnover of different bone types; 2) pathological, as exemplified by monogenomic disorders; 3) pathological, as identified by different disorders; and 4) in drug-induced situations. The profiles of these subtypes strongly suggest that these osteoclasts belong to a heterogeneous cell population, namely, a diverse macrophage-associated cell type with bone catabolic and anabolic functions that are dependent on both local and systemic parameters. Further insight into these osteoclast subtypes may be important for understanding cell-cell communication in the bone microenvironment, treatment effects, and ultimately bone quality.
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Affiliation(s)
- K Henriksen
- Nordic Bioscience A/S, Herlev Hovedgade 207, DK-2730 Herlev, Denmark.
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21
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Fotiadou A, Arvaniti M, Kiriakou V, Tsitouridis I. Type II autosomal dominant osteopetrosis: radiological features in two families containing five members with asymptomatic and uncomplicated disease. Skeletal Radiol 2009; 38:1015-21. [PMID: 19547970 DOI: 10.1007/s00256-009-0718-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2009] [Revised: 03/27/2009] [Accepted: 05/07/2009] [Indexed: 02/02/2023]
Abstract
In this study we analysed the imaging patterns in two families containing five members with asymptomatic and uncomplicated autosomal dominant osteopetrosis (ADO II), and we report new and uncommon radiological manifestations. These findings might be useful in the context of reducing the incidence of fractures and other orthopaedic complications. Diffuse pelvic sclerosis on radiographs was observed incidentally in two patients. Both cases were asymptomatic, and the patients had never suffered a fracture. The suggestion of ADO II was raised. A detailed medical history, an imaging survey, and a haematological study were obtained so that other rare causes of osteosclerosis could be ruled out. No genetic study was conducted. All their first-degree relatives were also examined. Bony sclerosis was observed in five patients, and the radiological findings were analysed. A not previously reported thickening of the skull base without cranial nerve palsy or optic nerve atrophy was revealed in all patients. Scoliosis was present in three of them. This has been reported previously only once in ADO II. No lower limb deformity was detected. This study provided information on the pattern of radiological features in familial asymptomatic ADO II. These data on new and rare imaging findings will increase the diagnostic awareness of physicians and will guide a thorough investigation of the entire family. This might result in a consequent decrease in the incidence of fractures and other orthopaedic complications.
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22
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Kajiya H, Okamoto F, Ohgi K, Nakao A, Fukushima H, Okabe K. Characteristics of ClC7 Cl− channels and their inhibition in mutant (G215R) associated with autosomal dominant osteopetrosis type II in native osteoclasts and hClcn7 gene-expressing cells. Pflugers Arch 2009; 458:1049-59. [DOI: 10.1007/s00424-009-0689-4] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2008] [Accepted: 05/29/2009] [Indexed: 10/20/2022]
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23
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Henriksen K, Neutzsky-Wulff AV, Bonewald LF, Karsdal MA. Local communication on and within bone controls bone remodeling. Bone 2009; 44:1026-33. [PMID: 19345750 DOI: 10.1016/j.bone.2009.03.671] [Citation(s) in RCA: 175] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2008] [Revised: 03/16/2009] [Accepted: 03/18/2009] [Indexed: 02/04/2023]
Abstract
Bone remodeling is required for healthy calcium homeostasis and for repair of damage occurring with stress and age. Osteoclasts resorb bone and osteoblasts form bone. These processes normally occur in a tightly regulated sequence of events, where the amount of formed bone equals the amount of resorbed bone, thereby restoring the removed bone completely. Osteocytes are the third cell type playing an essential role in bone turnover. They appear to regulate activation of bone remodeling, and they exert both positive and negative regulation on both osteoclasts and osteoblasts. In this review, we consider the intricate communication between these bone cells in relation to bone remodeling, reviewing novel data from patients with mutations rendering different cell populations inactive, which have shown that these interactions are more complex than originally thought. We highlight the high probability that a detailed understanding of these processes will aid in the development of novel treatments for bone metabolic disorders, i.e. we discuss the possibility that bone resorption can be attenuated pharmacologically without a secondary reduction in bone formation.
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Affiliation(s)
- Kim Henriksen
- Nordic Bioscience A/S, Herlev Hovedgade 207, DK-2730 Herlev, Denmark.
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Abstract
BACKGROUND Bisphosphonates decrease bone resorption and are commonly used to treat or prevent osteoporosis. However, the effect of bisphosphonates on their target cells remains enigmatic, since in patients benefiting from therapy, little change, if any, has been observed in the number of osteoclasts, which are the cells responsible for bone resorption. METHODS We examined 51 bone-biopsy specimens obtained after a 3-year, double-blind, randomized, placebo-controlled, dose-ranging trial of oral alendronate to prevent bone resorption among healthy postmenopausal women 40 through 59 years of age. The patients were assigned to one of five groups: those receiving placebo for 3 years; alendronate at a dose of 1, 5, or 10 mg per day for 3 years; or alendronate at a dose of 20 mg per day for 2 years, followed by placebo for 1 year. Formalin-fixed, undecalcified planar sections were assessed by bone histomorphometric methods. RESULTS The number of osteoclasts was increased by a factor of 2.6 in patients receiving 10 mg of alendronate per day for 3 years as compared with the placebo group (P<0.01). Moreover, the number of osteoclasts increased as the cumulative dose of the drug increased (r=0.50, P<0.001). Twenty-seven percent of these osteoclasts were giant cells with pyknotic nuclei that were adjacent to superficial resorption cavities. Furthermore, giant, hypernucleated, detached osteoclasts with 20 to 40 nuclei were found after alendronate treatment had been discontinued for 1 year. Of these large cells, 20 to 37% were apoptotic, according to both their morphologic features and positive findings from in situ end labeling. CONCLUSIONS Long-term alendronate treatment is associated with an increase in the number of osteoclasts, which include distinctive giant, hypernucleated, detached osteoclasts that are undergoing protracted apoptosis.
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Affiliation(s)
- Robert S Weinstein
- Division of Endocrinology and Metabolism, the Center for Osteoporosis and Metabolic Bone Diseases, and the Central Arkansas Veterans Healthcare System, University of Arkansas for Medical Sciences, Little Rock 72205-7199, USA.
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Characterization of acid flux in osteoclasts from patients harboring a G215R mutation in ClC-7. Biochem Biophys Res Commun 2009; 378:804-9. [DOI: 10.1016/j.bbrc.2008.11.145] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2008] [Accepted: 11/25/2008] [Indexed: 02/05/2023]
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Advances in osteoclast biology resulting from the study of osteopetrotic mutations. Hum Genet 2008; 124:561-77. [DOI: 10.1007/s00439-008-0583-8] [Citation(s) in RCA: 85] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2008] [Accepted: 10/28/2008] [Indexed: 02/05/2023]
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Simonelli C, Adler RA, Blake GM, Caudill JP, Khan A, Leib E, Maricic M, Prior JC, Eis SR, Rosen C, Kendler DL. Dual-Energy X-Ray Absorptiometry Technical Issues: The 2007 ISCD Official Positions. J Clin Densitom 2008; 11:109-22. [PMID: 18442756 DOI: 10.1016/j.jocd.2007.12.009] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2007] [Accepted: 12/05/2007] [Indexed: 02/06/2023]
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Qiu W, Andersen TE, Bollerslev J, Mandrup S, Abdallah BM, Kassem M. Patients with high bone mass phenotype exhibit enhanced osteoblast differentiation and inhibition of adipogenesis of human mesenchymal stem cells. J Bone Miner Res 2007; 22:1720-31. [PMID: 17680723 DOI: 10.1359/jbmr.070721] [Citation(s) in RCA: 135] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
UNLABELLED Genetic mutations in the LRP5 gene affect Wnt signaling and lead to changes in bone mass in humans. Our in vivo and in vitro results show that activated mutation T253I of LRP5 enhances osteogenesis and inhibits adipogenesis. Inactivating mutation T244M of LRP5 exerts opposite effects. INTRODUCTION Mutations in the Wnt co-receptor, LRP5, leading to decreased or increased canonical Wnt signaling, result in osteoporosis or a high bone mass (HBM) phenotype, respectively. However, the mechanisms whereby mutated LRP5 causes changes in bone mass are not known. MATERIALS AND METHODS We studied bone marrow composition in iliac crest bone biopsies from patients with the HBM phenotype and controls. We also used retrovirus-mediated gene transduction to establish three different human mesenchymal stem cell (hMSC) strains stably expressing wildtype LRP5 (hMSC-LRP5(WT)), LRP5(T244) (hMSC-LRP5(T244), inactivation mutation leading to osteoporosis), or LRP5(T253) (hMSC-LRP5(T253), activation mutation leading to high bone mass). We characterized Wnt signaling activation using a dual luciferase assay, cell proliferation, lineage biomarkers using real-time PCR, and in vivo bone formation. RESULTS In bone biopsies, we found increased trabecular bone volume and decreased bone marrow fat volume in patients with the HBM phenotype (n = 9) compared with controls (n = 5). The hMSC-LRP5(WT) and hMSC-LRP5(T253) but not hMSC-LRP5(T244) transduced high level of Wnt signaling. Wnt3a inhibited cell proliferation in hMSC-LRP5(WT) and hMSC-LRP5(T253), and this effect was associated with downregulation of DKK1. Both hMSC-LRP5(WT) and hMSC-LRP5(T253) showed enhanced osteoblast differentiation and inhibited adipogenesis in vitro, and the opposite effect was observed in hMSC-LRP5(T244). Similarly, hMSC-LRP5(WT) and hMSC-LRP5(T253) but not hMSC-LRP5(T244) formed ectopic mineralized bone when implanted subcutaneously with hydroxyapatite/tricalcium phosphate in SCID/NOD mice. CONCLUSIONS LRP5 mutations and the level of Wnt signaling determine differentiation fate of hMSCs into osteoblasts or adipocytes. Activation of Wnt signaling can thus provide a novel approach to increase bone mass by preventing the age-related reciprocal decrease in osteogenesis and increase in adipogenesis.
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Affiliation(s)
- Weimin Qiu
- Laboratory for Molecular Endocrinology (KMEB), Department of Endocrinology and Metabolism, University Hospital of Odense, Odense C, Denmark
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Sørensen MG, Henriksen K, Neutzsky-Wulff AV, Dziegiel MH, Karsdal MA. Diphyllin, a novel and naturally potent V-ATPase inhibitor, abrogates acidification of the osteoclastic resorption lacunae and bone resorption. J Bone Miner Res 2007; 22:1640-8. [PMID: 17576165 DOI: 10.1359/jbmr.070613] [Citation(s) in RCA: 90] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
UNLABELLED Dissolution of the inorganic phase of bone by the osteoclasts mediated by V-ATPase and ClC-7 is a prerequisite for bone resorption. Inhibitors of osteoclastic V-ATPase or ClC-7 are novel approaches for inhibition of osteoclastic bone resorption. By testing natural compounds in acidification assays, diphyllin was identified. We characterized diphyllin with respect to the pharmacological effects on osteoclasts. INTRODUCTION Osteoclastic acidification of the resorption lacuna and bone resorption requires activity of both V-ATPase and the chloride channel ClC-7. Inhibition of these processes represents a novel approach for treatment of bone metabolic disorders. We identified diphyllin, a novel inhibitor of V-ATPase, and characterized this natural compound with respect to activity in human osteoclasts. MATERIALS AND METHODS Diphyllin was tested in the acid influx assay and V-ATPase assay using bovine chromaffin granules. Human osteoclasts were generated from CD14+ monocytes cultured with macrophage-colony stimulating factor (M-CSF) and RANKL. The effect of diphyllin on lysosomal acidification in human osteoclasts was studied using acridine orange. The effect of diphyllin on bone resorption by osteoclasts was measured as release of C-terminal cross-linked telopeptide of type I collagen (CTX-I) and calcium into the supernatants and by scoring pit area. Osteoclast number, TRACP activity, and cell viability were measured. Furthermore, the effect of diphyllin on bone nodule formation was tested using the mouse osteoblast cell line MC3T3-E1. RESULTS In the acid influx assay, diphyllin potently inhibited the acid influx (IC50 = 0.6 nM). We found that diphyllin inhibited V-ATPase with an IC50 value of 17 nM, compared with 4 nM for bafilomycin A1. Moreover, diphyllin dose-dependently inhibited lysosomal acidification in human osteoclasts. Furthermore, we found that diphyllin inhibited human osteoclastic bone resorption measured by CTX-I (IC50 = 14 nM), calcium release, and pit area, despite increasing TRACP activity, numbers of osteoclasts, and cell viability. Finally, diphyllin showed no effect on bone formation in vitro, whereas bafilomycin A1 was toxic. CONCLUSIONS We identified a natural compound that potently inhibits V-ATPase and thereby lysosomal acidification in osteoclasts, which leads to abrogation of bone resorption. Because recent studies indicate that inhibition of the osteoclastic acidification leads to inhibition of resorption without inhibiting formation, we speculate that diphyllin is a potential novel treatment for bone disorders involving excessive resorption.
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Henriksen K, Gram J, Høegh-Andersen P, Jemtland R, Ueland T, Dziegiel MH, Schaller S, Bollerslev J, Karsdal MA. Osteoclasts from patients with autosomal dominant osteopetrosis type I caused by a T253I mutation in low-density lipoprotein receptor-related protein 5 are normal in vitro, but have decreased resorption capacity in vivo. THE AMERICAN JOURNAL OF PATHOLOGY 2006; 167:1341-8. [PMID: 16251418 PMCID: PMC1603785 DOI: 10.1016/s0002-9440(10)61221-7] [Citation(s) in RCA: 36] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Autosomal dominant osteopetrosis type I (ADOI) is presumably caused by gain-of-function mutations in the LRP5 gene. Patients with a T253I mutation in LRP5 have a high bone mass phenotype, characterized by increased mineralizing surface index but abnormally low numbers of small osteoclasts. To investigate the effect of the T253I mutation in LRP5 on osteoclasts, we isolated CD14+ monocytes from ADOI patients and assessed their ability to generate osteoclasts when treated with RANKL and M-CSF compared to that of age- and sex-matched control osteoclasts. We found normal osteoclastogenesis, expression of osteoclast markers, morphology, and localization of proteins involved in bone resorption, such as ClC-7 and cathepsin K. The ability to resorb bone was also normal. In vivo, we compared the bone resorption and bone formation response to T3 in ADOI patients and age- and sex-matched controls. We found attenuated resorptive response to T3 stimulation, despite a normal bone formation response, in alignment with the reduced number of osteoclasts in vivo. These data demonstrate that ADOI osteoclasts are normal with respect to all aspects investigated in vitro. We speculate that the mutations causing ADOI alter the osteoblastic phenotype toward a smaller potential for supporting osteoclastogenesis.
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Affiliation(s)
- Kim Henriksen
- Pharmos Bioscience A/S, Herlev Hovedgade 207, Herlev, DK-2730, Ribe County Hospital, Esbjerg, and the University Hospital of Copenhagen, Denmark.
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Balemans W, Van Wesenbeeck L, Van Hul W. A clinical and molecular overview of the human osteopetroses. Calcif Tissue Int 2005; 77:263-74. [PMID: 16307387 DOI: 10.1007/s00223-005-0027-6] [Citation(s) in RCA: 94] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2005] [Accepted: 04/08/2005] [Indexed: 12/15/2022]
Abstract
The osteopetroses are a heterogeneous group of bone remodeling disorders characterized by an increase in bone density due to a defect in osteoclastic bone resorption. In humans, several types can be distinguished and a classification has been made based on their mode of inheritance, age of onset, severity, and associated clinical symptoms. The best-known forms of osteopetrosis are the malignant and intermediate autosomal recessive forms and the milder autosomal dominant subtypes. In addition to these forms, a restricted number of cases have been reported in which additional clinical features unrelated to the increased bone mass occur. During the last years, molecular genetic studies have resulted in the identification of several disease-causing gene mutations. Thus far, all genes associated with a human osteopetrosis encode proteins that participate in the functioning of the differentiated osteoclast. This contributed substantially to the understanding of osteoclast functioning and the pathogenesis of the human osteopetroses and will provide deeper insights into the molecular pathways involved in other bone pathologies, including osteoporosis.
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Affiliation(s)
- W Balemans
- Department of Medical Genetics, University and University Hospital of Antwerp, Antwerp, Belgium
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33
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Karsdal MA, Henriksen K, Sørensen MG, Gram J, Schaller S, Dziegiel MH, Heegaard AM, Christophersen P, Martin TJ, Christiansen C, Bollerslev J. Acidification of the osteoclastic resorption compartment provides insight into the coupling of bone formation to bone resorption. THE AMERICAN JOURNAL OF PATHOLOGY 2005; 166:467-76. [PMID: 15681830 PMCID: PMC1602325 DOI: 10.1016/s0002-9440(10)62269-9] [Citation(s) in RCA: 121] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Patients with defective osteoclastic acidification have increased numbers of osteoclasts, with decreased resorption, but bone formation that remains unchanged. We demonstrate that osteoclast survival is increased when acidification is impaired, and that impairment of acidification results in inhibition of bone resorption without inhibition of bone formation. We investigated the role of acidification in human osteoclastic resorption and life span in vitro using inhibitors of chloride channels (NS5818/NS3696), the proton pump (bafilomycin) and cathepsin K. We found that bafilomycin and NS5818 dose dependently inhibited acidification of the osteoclastic resorption compartment and bone resorption. Inhibition of bone resorption by inhibition of acidification, but not cathepsin K inhibition, augmented osteoclast survival, which resulted in a 150 to 300% increase in osteoclasts compared to controls. We investigated the effect of inhibition of osteoclastic acidification in vivo by using the rat ovariectomy model with twice daily oral dosing of NS3696 at 50 mg/kg for 6 weeks. We observed a 60% decrease in resorption (DPYR), increased tartrate-resistant acid phosphatase levels, and no effect on bone formation evaluated by osteocalcin. We speculate that attenuated acidification inhibits dissolution of the inorganic phase of bone and results in an increased number of nonresorbing osteoclasts that are responsible for the coupling to normal bone formation. Thus, we suggest that acidification is essential for normal bone remodeling and that attenuated acidification leads to uncoupling with decreased bone resorption and unaffected bone formation.
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Affiliation(s)
- Morten A Karsdal
- Nordic Bioscience A/S, Herlev Hovedgade 207, DK-2730 Herlev, Denmark.
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Munns CFJ, Rauch F, Travers R, Glorieux FH. Three children with lower limb fractures and a mineralization defect: a novel bone fragility disorder? Bone 2004; 35:1023-8. [PMID: 15542026 DOI: 10.1016/j.bone.2004.08.004] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2004] [Revised: 06/21/2004] [Accepted: 08/02/2004] [Indexed: 02/02/2023]
Abstract
In this report, we describe three unrelated children with an apparently novel bone fragility disorder that is associated with an idiopathic mineralization defect. Recurrent lower limb fractures started with weight bearing. The patients had none of the phenotypic, radiological, or histomorphometric features classically associated with known bone fragility disorders such as osteogenesis imperfecta (OI), idiopathic juvenile osteoporosis (IJO), or mild autosomal dominant osteopetrosis. Radiologically, there was increased metaphyseal trabeculation, normal to increased cortical thickness, and no evidence of rickets or osteomalacia. Areal and volumetric bone mineral density (BMD) of the lumbar spine did not show any major alteration. Peripheral quantitative computed tomography of the radius showed elevated cortical thickness and total and trabecular volumetric bone mineral density in one patient. Qualitative histology of iliac bone biopsy specimens showed a paucity of the birefringent pattern of normal lamellar bone. Quantitative histomorphometric analysis demonstrated osteomalacia with a prolonged mineralization lag time in the presence of a decreased mineral apposition rate. There was no biochemical evidence of abnormal calcium or phosphate metabolism. Type I collagen mutation analysis was negative. We conclude that this is a bone fragility disorder of moderate severity that tends to cause fractures in the lower extremities and is associated with the accumulation of osteoid due to an intrinsic mineralization defect. The pathogenetic basis for this disorder remains to be elucidated.
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Affiliation(s)
- Craig F J Munns
- Genetics Unit, Shriners Hospital for Children, Montréal, Québec, Canada
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35
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Johnson ML, Harnish K, Nusse R, Van Hul W. LRP5 and Wnt signaling: a union made for bone. J Bone Miner Res 2004; 19:1749-57. [PMID: 15476573 DOI: 10.1359/jbmr.040816] [Citation(s) in RCA: 136] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2004] [Revised: 03/16/2004] [Accepted: 06/21/2004] [Indexed: 01/05/2023]
Affiliation(s)
- Mark L Johnson
- Osteoporosis Research Center, Creighton University School of Medicine, Omaha, Nebraska 68131, USA.
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36
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Or R, Aker M, Shapira MY, Resnick I, Bitan M, Samuel S, Slavin S. Allogeneic stem cell transplantation for the treatment of diseases associated with a deficiency in bone marrow products. ACTA ACUST UNITED AC 2004; 26:133-42. [PMID: 15549305 DOI: 10.1007/s00281-004-0169-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2004] [Accepted: 06/14/2004] [Indexed: 10/26/2022]
Abstract
Our understanding of the pathophysiology of hematopoietic failure associated syndromes led to the developmental of potentially curative procedures for the treatment of many diseases including Severe aplastic anemia, Fanconi's anemia, Primary immunodeficiency, Osteopetrosis, and Metabolic diseases. Although the number of patients that were transplanted for bone marrow deficiency diseases is relatively low as compared to patients with hematological malignancies, the impact on the knowledge of hematopoiesis and transplantation biology is tremendous. Moreover, the patient's average young age suffering from these diseases further encourage searching for curative approaches. Lucking a fully MHC matched donor, remained a significant obstacle in stem cell transplantation for non-malignant hematological disorders. Lessons from attempts to cure aplasic anemia with bone marrow transplantation guided us to the improvement of pretransplant conditioning regimens and prevention of graft versus host reactions after transplantation. Furthermore, in recent years optimization of disease specific protocol have been successfully designed and clinically applied.
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Affiliation(s)
- Reuven Or
- Department of Bone Marrow Transplantation, Cancer Immunotherapy and Immunobiology Research Center, Hadassah University Hospital, P.O.B 12000, 91120 Jerusalem, Israel.
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37
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Henriksen K, Gram J, Schaller S, Dahl BH, Dziegiel MH, Bollerslev J, Karsdal MA. Characterization of osteoclasts from patients harboring a G215R mutation in ClC-7 causing autosomal dominant osteopetrosis type II. THE AMERICAN JOURNAL OF PATHOLOGY 2004; 164:1537-45. [PMID: 15111300 PMCID: PMC1615650 DOI: 10.1016/s0002-9440(10)63712-1] [Citation(s) in RCA: 95] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
Autosomal dominant osteopetrosis II (ADOII) is a relatively benign disorder caused by a missense mutation in the ClCN7 gene. In this study, we characterize the osteoclasts from patients with ADOII, caused by a G215R mutation, and investigate the effect on osteoclast function in vitro. Osteoclasts from ADOII patients and healthy age- and sex-matched controls, were used to evaluate osteoclastogenesis, cell fusion, acidification, and resorptive activity. ADOII osteoclasts in vivo have increased number and size. However, in vitro we observed no significant changes in the osteoclast formation rate, the morphology, and the expression of markers, such as cathepsin K and tartrate-resistant acid phosphatase. When mature ADOII osteoclasts were investigated on mineralized bone, they degraded the bone material, however only to 10 to 20% of the level in controls. We show by acridine orange, that the reduced chloride transport leads to reduced acidification. We show that the residual activity is sensitive to inhibitors of cathepsins and chloride channels, confirming that resorption is reduced but present. In conclusion, this is the first functional in vitro study of human ADOII osteoclasts. We show normal osteoclastogenesis in ADOII osteoclasts. However, the residual activity of the ClC-7 channel in ADOII osteoclasts does not allow sufficient acidification and thereby resorption.
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Abstract
Osteoporosis is a common multifactorial disorder of reduced bone mass. The disorder in its most common form is generalized, affecting the elderly, both sexes, and all racial groups. Multiple environmental factors are involved in the pathogenesis. Genes also play a major role as reflected by heritability of many components of bone strength. Quantitative phenotypes in bone strength in the normal population do not conform to a monogenetic mode of inheritance. The common form of osteoporosis is generally considered to be a polygenic disorder arising from the interaction of common polymorphic alleles at quantitative trait loci, with multiple environmental factors. Finding the susceptibility genes underlying osteoporosis requires identifying specific alleles that coinherit with key heritable phenotypes in bone strength. Because of the close correspondence among mammalian genomes, identification of the genes underlying bone strength in mammals such as the mouse is likely to be of major assistance in human studies. Identification of susceptibility genes for osteoporosis is one of several important approaches toward the long-term goal of understanding the molecular biology of the normal variation in bone strength and how it may be modified to prevent osteoporosis. As with all genetic studies in humans, these scientific advances will need to be made in an environment of legal and ethical safeguards that are acceptable to the general public.
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Affiliation(s)
- Munro Peacock
- Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
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39
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Van Hul E, Gram J, Bollerslev J, Van Wesenbeeck L, Mathysen D, Andersen PE, Vanhoenacker F, Van Hul W. Localization of the gene causing autosomal dominant osteopetrosis type I to chromosome 11q12-13. J Bone Miner Res 2002; 17:1111-7. [PMID: 12054167 DOI: 10.1359/jbmr.2002.17.6.1111] [Citation(s) in RCA: 67] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The osteopetroses are a heterogeneous group of genetic conditions characterized by increased bone density due to impaired bone resorption by osteoclasts. Within the autosomal dominant form of osteopetrosis, the radiological type I (ADOI) is characterized by a generalized osteosclerosis, most pronounced at the cranial vault. The patients are often asymptomatic but some suffer from pain and hearing loss. ADOI is the only type of osteopetrosis not associated with an increased fracture rate. Linkage analysis in two families with ADOI from Danish origin enabled us to assign the disease-causing gene to chromosome 11q12-13. A summated maximum lod score of +6.54 was obtained with marker D11S1889 and key recombinants allowed delineation of a candidate region of 6.6 cM between markers D11S1765 and D11S4113. Previously, genes causing other conditions with abnormal bone density have been identified from this chromosomal region. The TCIRG1 gene was shown to underly autosomal recessive osteopetrosis (ARO), and, recently, mutations in the LRP5 gene were found both in the osteoporosis-pseudoglioma syndrome and the high bone mass trait. Because both genes map within the candidate region for ADOI, it can not be excluded that ADOI is caused by mutations in either the TCIRG1 or the LRP5 gene.
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Affiliation(s)
- Els Van Hul
- Department of Medical Genetics, University of Antwerp, Belgium
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40
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Jämsä T, Rho JY, Fan Z, MacKay CA, Marks SC, Tuukkanen J. Mechanical properties in long bones of rat osteopetrotic mutations. J Biomech 2002; 35:161-5. [PMID: 11784534 DOI: 10.1016/s0021-9290(01)00203-2] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Osteopetrosis is a metabolic bone disease with increased skeletal density radiographically and increased risk of fracture. Experimental studies with rat osteopetrotic mutations have shown increased bone density and decreased bone strength. However, it is not known if this reduction in bone strength is only due to changes in structure and geometry or if the tissue properties of bone material itself are changed as well. We have evaluated bone tissue properties with nanoindentation in three osteopetrotic mutations in the rat (incisors-absent ia/ia, osteopetrosis op/op and toothless tl/tl) to test the hypothesis that reduced bone resorption in these mutations results in reduced tissue properties of bone material. No significant differences in elastic modulus or hardness were found between osteopetrotic mutants and their normal littermates (NLMs) in any of the three stocks. This indicates that the tissue properties of bone material are not changed significantly in osteopetrosis, even if the mechanical strength is decreased at the macroscopic level.
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Affiliation(s)
- Timo Jämsä
- Department of Medical Technology, University of Oulu, P.O. Box 5000, 90014 Oulu, Finland.
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41
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Greenfield JR, Center JR, Freund J, Eisma JA. Treatment of an atraumatic fracture: the importance of establishing a definitive diagnosis. J Bone Miner Res 2001; 16:2362-4. [PMID: 11760854 DOI: 10.1359/jbmr.2001.16.12.2362] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Affiliation(s)
- J R Greenfield
- Department of Endocrinology, St Vincent's Hospital, Darlinghurst, Sydney NSW, Australia
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42
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Van Hul W, Vanhoenacker F, Balemans W, Janssens K, De Schepper AM. Molecular and radiological diagnosis of sclerosing bone dysplasias. Eur J Radiol 2001; 40:198-207. [PMID: 11731208 DOI: 10.1016/s0720-048x(01)00400-4] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Bone mineral density (BMD) is a quantitative trait for which the heritability of the variance is estimated to be up to 80%, based on epidemiological and twin studies. Further illustration of the involvement of genetic factors in bone homeostasis, is the existence of an extended group of genetic conditions associated with an abnormal bone density. The group of conditions with increased bone density has long been poorly studied and understood at the molecular genetic level but recently, thanks to recent developments in molecular genetics and genomics, for some of them major breakthroughs have been made. These findings will make the molecular analysis of such patients an additional tool in diagnostics and in genetic counseling. However, the initial identification of affected patients is still largely dependent upon recognition of clinical and radiological stigmata of the disease. Therefore, in this overview of sclerosing bone dysplasias, the classical clinical and radiological signs of this group of disorders will be discussed along with the new molecular insights.
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Affiliation(s)
- W Van Hul
- Department of Medical Genetics, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Antwerp, Belgium.
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Bénichou O, Cleiren E, Gram J, Bollerslev J, de Vernejoul MC, Van Hul W. Mapping of autosomal dominant osteopetrosis type II (Albers-Schönberg disease) to chromosome 16p13.3. Am J Hum Genet 2001; 69:647-54. [PMID: 11468688 PMCID: PMC1235505 DOI: 10.1086/323132] [Citation(s) in RCA: 57] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2001] [Accepted: 07/03/2001] [Indexed: 12/15/2022] Open
Abstract
The osteopetroses are a heterogeneous group of conditions characterized by a bone-density increase due to impaired bone resorption. As well as the two or more autosomal recessive types, two autosomal dominant forms of osteopetrosis, differentiated by clinical and radiological signs, are described. Autosomal dominant osteopetrosis (ADO) type II, also known as "Albers-Schönberg disease," is characterized by sclerosis, predominantly involving the spine (vertebral end-plate thickening, or Rugger-Jersey spine), the pelvis ("bone-within-bone" structures), and the skull base. An increased fracture rate can be observed in these patients. By linkage analysis, the presence, on chromosome 1p21, of a gene causing ADO type II was previously suggested. However, analysis of further families with ADO type II indicated genetic heterogeneity within ADO type II, with the chromosome 1p21 locus being only a minor locus. We now perform a genomewide linkage scan of a French extended family with ADO type II, which allows us to localize an ADO type II gene on chromosome 16p13.3. Analysis of microsatellite markers in five further families with ADO type II could not exclude this chromosomal region. A summed maximum LOD score of 12.70 was generated with marker D16S3027, at a recombination fraction (straight theta) of 0. On the basis of the key recombinants in the families, a candidate region of 8.4 cM could be delineated, flanked by marker D16S521, on distal side, and marker D16S423, on the proximal side. Surprisingly, one of the families analyzed is the Danish family previously suggested to have linkage to chromosome 1p21. Linkage to chromosome 16p13.3 clearly cannot be excluded in this family, since a maximum LOD score of 4.21 at theta=0 is generated with marker D16S3027. Because at present no other family with ADO type II has proved to have linkage to chromosome 1p21, we consider the most likely localization of the disease-causing gene in this family to be to chromosome 16p13.3. This thus reopens the possibility that ADO type II is genetically homogeneous because of a single gene on chromosome 16p13.3.
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Affiliation(s)
- O Bénichou
- Laboratoire INSERM U 349, Hôpital Lariboisière, Paris
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44
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Bénichou OD, Van Hul E, Van Hul W, de Vernejoul MC. Exclusion of the chromosomal 1p21 region in a large pedigree with a phenotypic variant of type II autosomal dominant osteopetrosis. Joint Bone Spine 2001. [DOI: 10.1016/s1297-319x(01)00277-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
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Frost HM. From Wolff's law to the Utah paradigm: insights about bone physiology and its clinical applications. THE ANATOMICAL RECORD 2001; 262:398-419. [PMID: 11275971 DOI: 10.1002/ar.1049] [Citation(s) in RCA: 243] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
Efforts to understand our anatomy and physiology can involve four often overlapping phases. We study what occurs, then how, then ask why, and then seek clinical applications. In that regard, in 1960 views, bone's effector cells (osteoblasts and osteoclasts) worked chiefly to maintain homeostasis under the control of nonmechanical agents, and that physiology had little to do with anatomy, biomechanics, tissue-level things, muscle, and other clinical applications. But it seems later-discovered tissue-level mechanisms and functions (including biomechanical ones, plus muscle) are the true key players in bone physiology, and homeostasis ranks below the mechanical functions. Adding that information to earlier views led to the Utah paradigm of skeletal physiology that combines varied anatomical, clinical, pathological, and basic science evidence and ideas. While it explains in a general way how strong muscles make strong bones and chronically weak muscles make weak ones, and while many anatomists know about the physiology that fact depends on, poor interdisciplinary communication left people in many other specialties unaware of it and its applications. Those applications concern 1.) healing of fractures, osteotomies, and arthrodeses; 2.) criteria that distinguish mechanically competent from incompetent bones; 3.) design criteria that should let load-bearing implants endure; 4.) how to increase bone strength during growth, and how to maintain it afterwards on earth and in microgravity situations in space; 5.) how and why healthy women only lose bone next to marrow during menopause; 6.) why normal bone functions can cause osteopenias; 7.) why whole-bone strength and bone health are different matters; 8.) why falls can cause metaphyseal and diaphyseal fractures of the radius in children, but mainly metaphyseal fractures of that bone in aged adults; 9.) which methods could best evaluate whole-bone strength, "osteopenias" and "osteoporoses"; 10.) and why most "osteoporoses" should not have bone-genetic causes and some could have extraosseous genetic causes. Clinical specialties that currently require this information include orthopaedics, endocrinology, radiology, rheumatology, pediatrics, neurology, nutrition, dentistry, and physical, space and sports medicine. Basic science specialties include absorptiometry, anatomy, anthropology, biochemistry, biomechanics, biophysics, genetics, histology, pathology, pharmacology, and cell and molecular biology. This article reviews our present general understanding of this new bone physiology and some of its clinical applications and implications. It must leave to other times, places, and people the resolution of questions about that new physiology, and to understand the many devils that should lie in its details. (Thompson D'Arcy, 1917).
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Affiliation(s)
- H M Frost
- Department of Orthopaedic Surgery, Southern Colorado Clinic, Pueblo, Colorado 81004, USA
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46
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Kapelushnik J, Shalev C, Yaniv I, Aker M, Carmi R, Cohen Z, Mozer A, Schulman C, Stein G, Or R. Osteopetrosis: a single centre experience of stem cell tranisplantation and prenatal diagnosis. Bone Marrow Transplant 2001; 27:129-32. [PMID: 11281380 DOI: 10.1038/sj.bmt.1702743] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Malignant osteopetrosis (MOP) is an autosomal recessive disease in which osteoclast dysfunction results in excessive bone deposition and early infant death. Thirteen children suffering from MOP from four related families all belonging to one Bedouin tribe, were studied. The disease was diagnosed as early as at a few days postnatal to 5 months. Nine children underwent BMT, four of whom are still alive; one is blind and two have markedly reduced vision. Four children who did not undergo BMT died between 4 and 6 months of age. Recently, the gene for MOP has been mapped for this Bedouin tribe allowing prenatal diagnosis. Seven pregnancies were subsequently prenatally diagnosed and two fetuses were found to be affected. Pregnancy was electively terminated in one case. In the other case the parents refused and after establishing the diagnosis, the newborn was transplanted at the age of 7 days.
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Affiliation(s)
- J Kapelushnik
- Hemato-Oncology Unit, Soroka University Medical Centre, Beer-Sheva, Israel
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47
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Bénichou OD, Bénichou B, Copin H, De Vernejoul MC, Van Hul W. Further evidence for genetic heterogeneity within type II autosomal dominant osteopetrosis. J Bone Miner Res 2000; 15:1900-4. [PMID: 11028441 DOI: 10.1359/jbmr.2000.15.10.1900] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Type II autosomal dominant osteopetrosis (ADO II) is characterized by an increased bone mass that contrasts with the high frequency of fractures. Linkage analysis performed in an extensive Danish family recently provided evidence for the mapping of an ADO II gene to an 8.5-cM region in chromosome 1p21 between microsatellite markers D1S486 and D1S2792. We recruited, phenotyped, and haplotyped 4F catheter ADO II families including 18 affected subjects and 29 unaffected subjects in order to narrow the candidate region and to search for genetic heterogeneity. ADO II diagnosis was ascertained by the observation of vertebral end plate thickening in at least 2 patients from successive generations. Linkage studies involved five microsatellite markers (D1S486, D1S206, D1S495, D1S248, and D1S2792) spanning 1p21. Haplotype analyses of two of our families clearly excluded the tested locus. The two remaining families gave poorly informative results. These results, combined with those previously reported in two American families, suggest that chromosomal region 1p21 is most likely a minor locus for ADO II.
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Affiliation(s)
- O D Bénichou
- INSERM Unit 349, Hôpital Lariboisière, Paris, France
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48
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Tuukkanen J, Koivukangas A, Jämsä T, Sundquist K, Mackay CA, Marks SC. Mineral density and bone strength are dissociated in long bones of rat osteopetrotic mutations. J Bone Miner Res 2000; 15:1905-11. [PMID: 11028442 DOI: 10.1359/jbmr.2000.15.10.1905] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
Bone mineral density (BMD) and mechanical strength generally show strong positive correlations. However, osteopetrosis is a metabolic bone disease with increased skeletal density radiographically and increased risk of fracture. We have evaluated mechanical strength and mineral density in three osteopetrotic mutations in the rat (incisors-absent [ia/ia], osteopetrosis [op/op], and toothless [tl/tl]) to test the hypothesis that reduced bone resorption in one or more of these mutations results in weaker bones in the presence of greater mineral density and skeletal mass. Peripheral quantitative computed tomography (pQCT) was used to analyze BMD and cross-sectional geometry in the tibial diaphysis and metaphysis as well as the femoral diaphysis and femoral neck. The bending breaking force of tibial and femoral midshafts was obtained using the three-point bending test and femoral neck strength was tested by axial loading. Osteopetrotic mutants were significantly smaller than their normal littermates (NLMs) in each stock. The pQCT analysis showed that BMD and bone mineral content (BMC) were higher than or equal to NLMs in all skeletal sites measured in the osteopetrotic mutants. However, the mechanical breaking force was equal to or lower than their NLMs in all sites. The cross-sectional structure of long bone shafts was markedly different in osteopetrotic mutants, having a thin cortex and a medullary area filled with primary trabecular bone. These results indicate that osteopetrotic mutations in the rat increase bone density and decrease bone strength. The tibial diaphysis was significantly weaker in tl/tl and ia/ia mutants and the tibial metaphysis showed the greatest increase in BMD in all mutants. These data are another illustration that an increased BMD does not necessarily lead to stronger bones.
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Affiliation(s)
- J Tuukkanen
- Department of Anatomy and Cell Biology, University of Oulu, Finland
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Abstract
In mammalian osteopetrosis the different mutations exemplify reduced bone resorption leading to net accumulation of bone. Recently, high blood levels of creatine kinase-BB have been reported in some human forms, suggesting it as a marker of osteopetrosis. In the current study serum creatine kinase-BB was evaluated in relation to known osteoclastic pathophysiology in two human types of autosomal dominant osteopetrosis at baseline and after stimulation with triiodothyronine and in four different rodent mutations. Creatine kinase-BB was increased markedly in Type 2 autosomal dominant osteopetrosis and in the incisors absent rat, both characterized by large numbers of giant osteoclasts, and did not change significantly after stimulation. Although creatine kinase-BB was unchanged in Type 1 autosomal dominant osteopetrosis at baseline and after stimulation, the rodent counterparts characterized by small osteoclasts, microphthalmic and osteopetrotic mice and toothless rats, had significantly decreased levels. Similar differences were observed in both types of autosomal dominant osteopetrosis compared with controls concerning tartrate resistant acid phosphatase. Creatine kinase-BB in mammalian osteopetrosis is related to osteoclastic number and size, where it probably reflects the differentiation and maturation of inactive bone resorbing cells. The isoenzyme does not seem to be a valuable screening marker for osteopetrosis.
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Affiliation(s)
- J Bollerslev
- Department of Medical Endocrinology, National University Hospital, Oslo, Norway
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Affiliation(s)
- R S Weinstein
- Department of Internal Medicine, University of Arkansas, Little Rock, USA
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