Browsing by Subject "osteopetrosis"

Now showing 1 - 4 of 4
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    Clcn7F318L/+ as a new mouse model of Albers-Schönberg disease
    (Elsevier, 2017-12) Caetano-Lopes, J.; Lessard, S. G.; Hann, S.; Espinoza, K.; Kang, Kyung Shin; Lim, Kyung-Eun; Horan, Dan J.; Noonan, H. R.; Hu, D.; Baron, R.; Robling, Alexander G.; Warman, M. L.; Anatomy and Cell Biology, School of Medicine
    Dominant negative mutations in CLCN7, which encodes a homodimeric chloride channel needed for matrix acidification by osteoclasts, cause Albers-Schönberg disease (also known as autosomal dominant osteopetrosis type 2). More than 25 different CLCN7 mutations have been identified in patients affected with Albers-Schönberg disease, but only one mutation (Clcn7G213R) has been introduced in mice to create an animal model of this disease. Here we describe a mouse with a different osteopetrosis-causing mutation (Clcn7F318L). Compared to Clcn7+/+ mice, 12-week-old Clcn7F318L/+ mice have significantly increased trabecular bone volume, consistent with Clcn7F318L acting as a dominant negative mutation. Clcn7F318L/F318L and Clcn7F318L/G213R mice die by 1 month of age and resemble Clcn7 knockout mice, which indicate that p.F318L mutant protein is non-functional and p.F318L and p.G213R mutant proteins do not complement one another. Since it has been reported that treatment with interferon gamma (IFN-G) improves bone properties in Clcn7G213R/+ mice, we treated Clcn7F318L/+ mice with IFN-G and observed a decrease in osteoclast number and mineral apposition rate, but no overall improvement in bone properties. Our results suggest that the benefits of IFN-G therapy in patients with Albers-Schönberg disease may be mutation-specific.
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    Interferon Gamma-1b Does Not Increase Markers of Bone Resorption in Autosomal Dominant Osteopetrosis
    (Wiley, 2019-03-19) Imel, Erik A.; Liu, Ziyue; Acton, Dena; Coffman, Melissa; Gebregziabher, Netsanet; Tong, Yan; Econs, Michael J.; Medicine, School of Medicine
    In autosomal dominant osteopetrosis type 2 (ADO2) CLCN7 mutations cause impaired osteoclast function. Severe consequences include skeletal fragility despite high bone mass, osteomyelitis, osteonecrosis, bone marrow failure, and severe cranial nerve impingement. There is no effective medical treatment for ADO2. We recruited subjects with ADO2 into a 14-week, open-label, pilot clinical trial of interferon gamma-1b. Doses were titrated based on tolerability and if fasting serum C-telopeptide (CTX) was <25% above baseline at week 8, targeting doses of 100 mcg/m2 three times a week. The primary outcomes were change from baseline in CTX and N-telopeptide/creatinine ratio (NTX/Cr) at week 14. Secondary outcomes included changes in urine calcium/creatinine ratio, bone formation markers and tolerability. Nine adults and 3 children were recruited. Severe manifestations of ADO2 included histories of fractures (100%), osteomyelitis (16.7%), vision loss (50%), and anemia (58.3%). Baseline CTX and NTX/Cr were generally low-normal. Procollagen type I N-terminal propeptide was elevated or in the upper-normal range in 11/12 (91.6%) subjects. Elevations of AST and LDH were common. One subject withdrew due to rash. Five subjects achieved doses of 50 ug/m2 three days a week, while 6 reached the full dose of 100 ug/m2 three days a week. Only 3/11 (27.3%) completing subjects achieved the primary outcome of increasing CTX ≥25% above baseline at week 14. The mean change from baseline in CTX at week 14 was +2.2% (SD 43.2%, p=0.86). Likewise, there was no significant change in NTX/Cr (mean change −2.1%, p=0.81). Interferon gamma-1b was poorly tolerated. Most subjects had adverse events, and the Mental Health and Mental Component Scales of the SF-36v2 declined slightly (p<0.05). Over 14 weeks, interferon gamma-1b failed to significantly increase bone turnover markers in ADO2 and was poorly tolerated. Consequently, interferon gamma-1b is unlikely to be effective for decreasing bone mass in ADO2.
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    Osteopetroses, emphasizing potential approaches to treatment
    (Elsevier, 2017-09) Teti, Anna; Econs, Michael J.; Medicine, School of Medicine
    Osteopetroses are a heterogeneous group of rare genetic bone diseases sharing the common hallmarks of reduced osteoclast activity, increased bone mass and high bone fragility. Osteoclasts are bone resorbing cells that contribute to bone growth and renewal through the erosion of the mineralized matrix. Alongside the bone forming activity by osteoblasts, osteoclasts allow the skeleton to grow harmonically and maintain a healthy balance between bone resorption and formation. Osteoclast impairment in osteopetroses prevents bone renewal and deteriorates bone quality, causing atraumatic fractures. Osteopetroses vary in severity and are caused by mutations in a variety of genes involved in bone resorption or in osteoclastogenesis. Frequent signs and symptoms include osteosclerosis, deformity, dwarfism and narrowing of the bony canals, including the nerve foramina, leading to hematological and neural failures. The disease is autosomal, with only one extremely rare form associated so far to the X-chromosome, and can have either recessive or dominant inheritance. Recessive ostepetroses are generally lethal in infancy or childhood, with a few milder forms clinically denominated intermediate osteopetroses. Dominant osteopetrosis is so far associated only with mutations in the CLCN7 gene and, although described as a benign form, it can be severely debilitating, although not at the same level as recessive forms, and can rarely result in reduced life expectancy. Severe osteopetroses due to osteoclast autonomous defects can be treated by Hematopoietic Stem Cell Transplant (HSCT), but those due to deficiency of the pro-osteoclastogenic cytokine, RANKL, are not suitable for this procedure. Likewise, it is unclear as to whether HSCT, which has high intrinsic risks, results in clinical improvement in autosomal dominant osteopetrosis. Therefore, there is an unmet medical need to identify new therapies and studies are currently in progress to test gene and cell therapies, small interfering RNA approach and novel pharmacologic treatments.
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    The PDE4 Inhibitors Roflumilast and Rolipram Rescue ADO2 Osteoclast Resorption Dysfunction
    (Springer, 2024-03-14) Hong, Jung Min; Gerard-O’Riley, Rita L.; Acton, Dena; Alam, Imranul; Econs, Michael J.; Bruzzaniti, Angela; Biomedical and Applied Sciences, School of Dentistry
    Autosomal Dominant Osteopetrosis type II (ADO2) is a rare bone disease of impaired osteoclastic bone resorption caused by heterozygous missense mutations in the chloride channel 7 (CLCN7). Adenylate cyclase, which catalyzes the formation of cAMP, is critical for lysosomal acidification in osteoclasts. We found reduced cAMP levels in ADO2 osteoclasts compared to wild-type (WT) osteoclasts, leading us to examine whether regulating cAMP would improve ADO2 osteoclast activity. Although forskolin, a known activator of adenylate cyclase and cAMP levels, negatively affected osteoclast number, it led to an overall increase in ADO2 and WT osteoclast resorption activity in vitro. Next, we examined cAMP hydrolysis by the phosphodiesterase 4 (PDE4) proteins in ADO2 versus WT osteoclasts. QPCR analysis revealed higher expression of the three major PDE4 subtypes (4a, 4b, 4d) in ADO2 osteoclasts compared in WT, consistent with reduced cAMP levels in ADO2 osteoclasts. In addition, we found that the PDE4 antagonists, rolipram and roflumilast, stimulated ADO2 and WT osteoclast formation in a dose-dependent manner. Importantly, roflumilast and rolipram displayed a concentration-dependent increase in osteoclast resorption activity which was greater in ADO2 than WT osteoclasts. Moreover, treatment with roflumilast rescued cAMP levels in ADO2 OCLs. The key findings from our studies demonstrate that osteoclasts from ADO2 mice exhibit reduced cAMP levels and PDE4 inhibition rescues cAMP levels and ADO2 osteoclast activity dysfunction in vitro. The mechanism of action of PDE4 inhibitors and their ability to reduce the high bone mass of ADO2 mice in vivo are currently under investigation. Importantly, these studies advance the understanding of the mechanisms underlying the ADO2 osteoclast dysfunction which is critical for the development of therapeutic approaches to treat clinically affected ADO2 patients.