Julia Eazer, Mina‐Michael Barsoum, Cole Smith, Kazuki Hotta, Brad Behnke, Christina Holmes, Jacob Caldwell, Payal Ghosh, Emily Reid‐Foley, Hyerim Park, Michael Delp, Judy Muller-Delp
The magnitude of bone formation and remodeling is linked to both the magnitude of strain placed on the bone and the perfusion of bone. It was previously reported that an increase in bone perfusion and bone density occurs in the femur of old rats with moderate aerobic exercise training. This study determined the acute and chronic effects of static muscle stretching on bone blood flow and remodeling. Old male Fischer 344 rats were randomized to either a naïve or stretch-trained group. Static stretching of ankle flexor muscles was achieved by placement of a dorsiflexion splint on the left ankle for 30 min/day, 5d/wk for 4wks. The opposite hindlimb served as a contralateral control (nonstretched) limb. Bone blood flow was assessed during and after acute stretching in naïve rats, and at rest and during exercise in stretch-trained rats. Vascular reactivity of the nutrient artery of the proximal tibia was also assessed in stretch-trained rats. MicroCT analysis was used to assess bone volume and micro-architecture of the trabecular bone of both tibias near that growth plate. In naïve rats, static stretching increased blood flow to the proximal tibial metaphasis. Blood flow to the proximal tibial metaphysis during treadmill exercise was higher in the stretched limb after 4 weeks of daily stretching. Daily stretching also increased tibial bone weight and increased total volume in both the proximal and distal tibial metaphyses. In the trabecular bone immediately below the proximal tibial growth plate, total volume and bone volume increased, but bone volume/total volume was unchanged and trabecular connectivity decreased. In contrast, intravascular volume increased in this region of the bone. These data suggest that blood flow to the tibia increases during bouts of static stretching of the hindlimb muscles, and that 4 weeks of daily muscle stretching leads to bone remodeling and an increase in intravascular volume of the tibial bone.
{"title":"Adaptations of bone and bone vasculature to muscular stretch training","authors":"Julia Eazer, Mina‐Michael Barsoum, Cole Smith, Kazuki Hotta, Brad Behnke, Christina Holmes, Jacob Caldwell, Payal Ghosh, Emily Reid‐Foley, Hyerim Park, Michael Delp, Judy Muller-Delp","doi":"10.1093/jbmrpl/ziad019","DOIUrl":"https://doi.org/10.1093/jbmrpl/ziad019","url":null,"abstract":"\u0000 The magnitude of bone formation and remodeling is linked to both the magnitude of strain placed on the bone and the perfusion of bone. It was previously reported that an increase in bone perfusion and bone density occurs in the femur of old rats with moderate aerobic exercise training. This study determined the acute and chronic effects of static muscle stretching on bone blood flow and remodeling. Old male Fischer 344 rats were randomized to either a naïve or stretch-trained group. Static stretching of ankle flexor muscles was achieved by placement of a dorsiflexion splint on the left ankle for 30 min/day, 5d/wk for 4wks. The opposite hindlimb served as a contralateral control (nonstretched) limb. Bone blood flow was assessed during and after acute stretching in naïve rats, and at rest and during exercise in stretch-trained rats. Vascular reactivity of the nutrient artery of the proximal tibia was also assessed in stretch-trained rats. MicroCT analysis was used to assess bone volume and micro-architecture of the trabecular bone of both tibias near that growth plate. In naïve rats, static stretching increased blood flow to the proximal tibial metaphasis. Blood flow to the proximal tibial metaphysis during treadmill exercise was higher in the stretched limb after 4 weeks of daily stretching. Daily stretching also increased tibial bone weight and increased total volume in both the proximal and distal tibial metaphyses. In the trabecular bone immediately below the proximal tibial growth plate, total volume and bone volume increased, but bone volume/total volume was unchanged and trabecular connectivity decreased. In contrast, intravascular volume increased in this region of the bone. These data suggest that blood flow to the tibia increases during bouts of static stretching of the hindlimb muscles, and that 4 weeks of daily muscle stretching leads to bone remodeling and an increase in intravascular volume of the tibial bone.","PeriodicalId":14611,"journal":{"name":"JBMR Plus","volume":"11 5","pages":""},"PeriodicalIF":3.8,"publicationDate":"2024-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139387496","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ilka Maus, M. Dreiner, Sebastian Zetzsche, F. Metzen, Bryony C Ross, D. Mählich, M. Koch, Anja Niehoff, Brunhilde Wirth
PLS3 loss-of-function mutations in humans and mice cause X-linked primary osteoporosis. However, it remains largely unknown how PLS3 mutations cause osteoporosis and which function PLS3 plays in bone homeostasis. A recent study showed that the ubiquitous Pls3 KO in mice results in osteoporosis with decreased bone thickness and stiffness. In these mice, mainly osteoclasts were impacted in their function, exhibiting increased resorptive activity and altered podosome formation through a misregulation of the NFκB pathway. Specifically, Pls3 KO caused the decreased nuclear localization of its interaction partner NFκB repressing factor, NKRF, thereby augmenting Nfatc1 transcription. However, it has not been proven if, indeed, the osteoclasts are the major cell type affected and responsible for the osteoporosis development in ubiquitous Pls3 KO mice. Here, we generated osteoclast-specific Pls3 KO female (Pls3fl/fl; LysMCretg/0) and male (Pls3fl;LysMCretg/0) mice and demonstrate specific PLS3 loss in cultured osteoclasts. In addition, we developed a novel polyclonal PLS3 antibody that showed for the first time specific PLS3 loss in immunofluorescence staining of osteoclasts in contrast to previously available antibodies against PLS3 that failed to show PLS3-specificity in mouse cells. Moreover, we demonstrate that the osteoclast-specific Pls3 KO causes a dramatic increase in the resorptive activity of osteoclasts in vitro. Despite this pronounced effect on osteoclast resorption activity, osteoclast-specific Pls3 KO in vivo failed to cause any osteoporotic phenotype in 12-, 24-, and 48-week-old mice as proven by micro-CT and three-point bending test. These results demonstrate that the pathomechanism of PLS3-associated osteoporosis is highly complex and cannot be reproduced in a system singularly focused on one cell type, leading us to conclude that the loss of PLS3 in alternative bone cell types, such as osteoblasts and osteocytes contributes to the osteoporosis phenotype in ubiquitous Pls3 KO mice.
人类和小鼠的 PLS3 功能缺失突变会导致 X 连锁原发性骨质疏松症。然而，人们对 PLS3 突变如何导致骨质疏松症以及 PLS3 在骨稳态中发挥何种功能仍然知之甚少。最近的一项研究表明，小鼠中无处不在的 Pls3 KO 会导致骨质疏松症，骨厚度和硬度下降。在这些小鼠中，主要是破骨细胞的功能受到影响，表现出更强的吸收活性，并通过 NFκB 通路的误调改变了荚膜体的形成。具体来说，Pls3 KO导致其相互作用伙伴NFκB抑制因子NKRF的核定位减少，从而增强了Nfatc1的转录。然而，尚未证实破骨细胞是否是受影响的主要细胞类型，以及是否是导致无处不在的 Pls3 KO 小鼠发生骨质疏松症的原因。在这里，我们产生了破骨细胞特异性 Pls3 KO 雌性（Pls3fl/fl; LysMCretg/0）和雄性（Pls3fl;LysMCretg/0）小鼠，并在培养的破骨细胞中证明了特异性 PLS3 缺失。此外，我们还开发了一种新型多克隆 PLS3 抗体，该抗体首次在破骨细胞的免疫荧光染色中显示出特异性 PLS3 缺失，而之前可用的 PLS3 抗体未能在小鼠细胞中显示出 PLS3 特异性。此外，我们还证明，破骨细胞特异性 Pls3 KO 会导致体外破骨细胞的吸收活性急剧增加。尽管对破骨细胞的吸收活性有明显的影响，但通过显微 CT 和三点弯曲试验证明，体内破骨细胞特异性 Pls3 KO 在 12 周龄、24 周龄和 48 周龄的小鼠中均未导致任何骨质疏松表型。这些结果表明，与 PLS3 相关的骨质疏松症的病理机制非常复杂，无法在一个只关注一种细胞类型的系统中再现，因此我们得出结论，在其他骨细胞类型（如成骨细胞和骨细胞）中 PLS3 的缺失导致了无处不在的 Pls3 KO 小鼠的骨质疏松症表型。
{"title":"Osteoclast-specific Plastin 3 knockout in mice fail to develop osteoporosis despite dramatic increased osteoclast resorption activity","authors":"Ilka Maus, M. Dreiner, Sebastian Zetzsche, F. Metzen, Bryony C Ross, D. Mählich, M. Koch, Anja Niehoff, Brunhilde Wirth","doi":"10.1093/jbmrpl/ziad009","DOIUrl":"https://doi.org/10.1093/jbmrpl/ziad009","url":null,"abstract":"\u0000 PLS3 loss-of-function mutations in humans and mice cause X-linked primary osteoporosis. However, it remains largely unknown how PLS3 mutations cause osteoporosis and which function PLS3 plays in bone homeostasis. A recent study showed that the ubiquitous Pls3 KO in mice results in osteoporosis with decreased bone thickness and stiffness. In these mice, mainly osteoclasts were impacted in their function, exhibiting increased resorptive activity and altered podosome formation through a misregulation of the NFκB pathway. Specifically, Pls3 KO caused the decreased nuclear localization of its interaction partner NFκB repressing factor, NKRF, thereby augmenting Nfatc1 transcription. However, it has not been proven if, indeed, the osteoclasts are the major cell type affected and responsible for the osteoporosis development in ubiquitous Pls3 KO mice.\u0000 Here, we generated osteoclast-specific Pls3 KO female (Pls3fl/fl; LysMCretg/0) and male (Pls3fl;LysMCretg/0) mice and demonstrate specific PLS3 loss in cultured osteoclasts. In addition, we developed a novel polyclonal PLS3 antibody that showed for the first time specific PLS3 loss in immunofluorescence staining of osteoclasts in contrast to previously available antibodies against PLS3 that failed to show PLS3-specificity in mouse cells. Moreover, we demonstrate that the osteoclast-specific Pls3 KO causes a dramatic increase in the resorptive activity of osteoclasts in vitro. Despite this pronounced effect on osteoclast resorption activity, osteoclast-specific Pls3 KO in vivo failed to cause any osteoporotic phenotype in 12-, 24-, and 48-week-old mice as proven by micro-CT and three-point bending test. These results demonstrate that the pathomechanism of PLS3-associated osteoporosis is highly complex and cannot be reproduced in a system singularly focused on one cell type, leading us to conclude that the loss of PLS3 in alternative bone cell types, such as osteoblasts and osteocytes contributes to the osteoporosis phenotype in ubiquitous Pls3 KO mice.","PeriodicalId":14611,"journal":{"name":"JBMR Plus","volume":"39 11","pages":""},"PeriodicalIF":3.8,"publicationDate":"2024-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139450710","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Christopher de la Bastide, Lissa Soares, L. Lui, James Harrington, Peggy Cawthon, Eric Orwoll, Deborah Kado, Jaymie Meliker
Cadmium (Cd) is a heavy metal and natural element found in soil and crops with increasing concentrations linked to phosphate fertilizers and sewage sludge applied to crop lands. A large fraction of older U.S men and woman have documented Cd exposure. Cd exposure has proven health concerns such as risk of lung cancer from inhalation and impaired renal function, however, growing evidence suggests it also influences bone and muscle health. Given that low levels of Cd could affect bone and muscle, we have designed prospective studies using the two largest and most detailed U.S. studies of bone health in older men and women: The Osteoporotic Fractures in Men (MrOS) Study and the Study of Osteoporotic Fractures (SOF). We are investigating the association of urinary cadmium (U-Cd), as a surrogate for long term cadmium exposure, with bone and muscle health. Building off suggestive evidence from mechanistic and cross-sectional studies, this will be the first well-powered prospective study of incident fracture outcomes, bone loss, and muscle loss in relation to U-Cd, an established biomarker of long-term Cd exposure. The following is a proposed protocol for the intended study; if successful the proposed studies could be influential in directing future U.S policy to decrease Cd exposure in the U.S population similar to recent policies adopted by the European Union to limit Cd in fertilizers.
{"title":"A protocol for the prospective study of urinary cadmium with risk of fracture, bone loss, and muscle loss","authors":"Christopher de la Bastide, Lissa Soares, L. Lui, James Harrington, Peggy Cawthon, Eric Orwoll, Deborah Kado, Jaymie Meliker","doi":"10.1093/jbmrpl/ziad006","DOIUrl":"https://doi.org/10.1093/jbmrpl/ziad006","url":null,"abstract":"\u0000 Cadmium (Cd) is a heavy metal and natural element found in soil and crops with increasing concentrations linked to phosphate fertilizers and sewage sludge applied to crop lands. A large fraction of older U.S men and woman have documented Cd exposure. Cd exposure has proven health concerns such as risk of lung cancer from inhalation and impaired renal function, however, growing evidence suggests it also influences bone and muscle health. Given that low levels of Cd could affect bone and muscle, we have designed prospective studies using the two largest and most detailed U.S. studies of bone health in older men and women: The Osteoporotic Fractures in Men (MrOS) Study and the Study of Osteoporotic Fractures (SOF). We are investigating the association of urinary cadmium (U-Cd), as a surrogate for long term cadmium exposure, with bone and muscle health. Building off suggestive evidence from mechanistic and cross-sectional studies, this will be the first well-powered prospective study of incident fracture outcomes, bone loss, and muscle loss in relation to U-Cd, an established biomarker of long-term Cd exposure. The following is a proposed protocol for the intended study; if successful the proposed studies could be influential in directing future U.S policy to decrease Cd exposure in the U.S population similar to recent policies adopted by the European Union to limit Cd in fertilizers.","PeriodicalId":14611,"journal":{"name":"JBMR Plus","volume":"44 24","pages":""},"PeriodicalIF":3.8,"publicationDate":"2024-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139387003","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
J. Coll, Anne-Frédérique Turcotte, William D Leslie, Laëtitia Michou, S. J. Weisnagel, Fabrice Mac-Way, Caroline Albert, Claudie Berger, Suzanne N Morin, Rémi Rabasa-Lhoret, Claudia Gagnon
It is unclear if advanced glycation end products (AGEs) are involved in the bone fragility of type 1 diabetes (T1D). We evaluated whether skin AGEs by skin autofluorescence and serum AGEs (pentosidine, carboxymethyl-lysine [CML]) are independently associated with BMD by DXA (lumbar spine, hip, distal radius), trabecular bone score (TBS), serum bone turnover markers (BTMs: C-terminal crossed-linked telopeptide of type 1 collagen, CTX; procollagen type 1 N-terminal propeptide, P1NP; osteocalcin), and sclerostin in participants with and without T1D. Linear regression models were used, with interaction terms to test effect modification by T1D status. In participants with T1D, correlations between skin and serum AGEs as well as between AGEs and 3-year HbA1C were evaluated using Spearman’s correlations. Data are mean±SD or median(interquartile range). We included individuals who participated in a cross-sectional study and had BMD and TBS assessment (106 T1D/65 controls, 53.2% women, age 43±15 years, BMI 26.6±5.5 kg/m2). Participants with T1D had diabetes for 27.6±12.3 years, a mean 3-year HbA1C of 7.5±0.9% and skin AGEs of 2.15±0.54 arbitrary units. A subgroup of 65 T1D/57 controls had BTMs and sclerostin measurements, and those with T1D also had serum pentosidine (16.8[8.2-32.0] ng/mL) and CML [48.0±16.8] ng/mL) measured. Femoral neck BMD, TBS, and BTMs were lower while sclerostin levels were similar in participants with T1D vs controls. T1D status did not modify the associations between AGEs and bone outcomes. Skin AGEs were significantly associated with total hip and femoral neck BMD, TBS, BTMs, and sclerostin before, but not after adjustment for confounders. Serum AGEs were not associated with any bone outcome. There were no significant correlations between skin and serum AGEs, or between AGEs and 3-year HbA1C. In conclusion, skin and serum AGEs are not independently associated with BMD, TBS, BTMs, and sclerostin in participants with relatively well-controlled T1D and participants without diabetes.
{"title":"Advanced Glycation End Products Are Not Associated With Bone Mineral Density, Trabecular Bone Score and Bone Turnover Markers in Adults With and Without Type 1 Diabetes: A Cross-Sectional Study","authors":"J. Coll, Anne-Frédérique Turcotte, William D Leslie, Laëtitia Michou, S. J. Weisnagel, Fabrice Mac-Way, Caroline Albert, Claudie Berger, Suzanne N Morin, Rémi Rabasa-Lhoret, Claudia Gagnon","doi":"10.1093/jbmrpl/ziad018","DOIUrl":"https://doi.org/10.1093/jbmrpl/ziad018","url":null,"abstract":"\u0000 It is unclear if advanced glycation end products (AGEs) are involved in the bone fragility of type 1 diabetes (T1D). We evaluated whether skin AGEs by skin autofluorescence and serum AGEs (pentosidine, carboxymethyl-lysine [CML]) are independently associated with BMD by DXA (lumbar spine, hip, distal radius), trabecular bone score (TBS), serum bone turnover markers (BTMs: C-terminal crossed-linked telopeptide of type 1 collagen, CTX; procollagen type 1 N-terminal propeptide, P1NP; osteocalcin), and sclerostin in participants with and without T1D. Linear regression models were used, with interaction terms to test effect modification by T1D status. In participants with T1D, correlations between skin and serum AGEs as well as between AGEs and 3-year HbA1C were evaluated using Spearman’s correlations. Data are mean±SD or median(interquartile range). We included individuals who participated in a cross-sectional study and had BMD and TBS assessment (106 T1D/65 controls, 53.2% women, age 43±15 years, BMI 26.6±5.5 kg/m2). Participants with T1D had diabetes for 27.6±12.3 years, a mean 3-year HbA1C of 7.5±0.9% and skin AGEs of 2.15±0.54 arbitrary units. A subgroup of 65 T1D/57 controls had BTMs and sclerostin measurements, and those with T1D also had serum pentosidine (16.8[8.2-32.0] ng/mL) and CML [48.0±16.8] ng/mL) measured. Femoral neck BMD, TBS, and BTMs were lower while sclerostin levels were similar in participants with T1D vs controls. T1D status did not modify the associations between AGEs and bone outcomes. Skin AGEs were significantly associated with total hip and femoral neck BMD, TBS, BTMs, and sclerostin before, but not after adjustment for confounders. Serum AGEs were not associated with any bone outcome. There were no significant correlations between skin and serum AGEs, or between AGEs and 3-year HbA1C. In conclusion, skin and serum AGEs are not independently associated with BMD, TBS, BTMs, and sclerostin in participants with relatively well-controlled T1D and participants without diabetes.","PeriodicalId":14611,"journal":{"name":"JBMR Plus","volume":"57 7","pages":""},"PeriodicalIF":3.8,"publicationDate":"2024-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139450656","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
A. Asavamongkolkul, N. Adulkasem, P. Chotiyarnwong, Ekasame Vanitcharoenkul, Chandhanarat Chandhanayingyong, Panai Laohaprasitiporn, Krabkaew Soparat, A. Unnanuntana
Thailand has transitioned from an aging society to an aged society, which implies that the prevalence of age-related disorders will increase; however, epidemiological data specific to the prevalence of age-related degenerative musculoskeletal disorders among Thai older adults remain limited. Accordingly, the aim of this study was to investigate the prevalence of age-related musculoskeletal diseases, including osteoporosis, sarcopenia, and high falls risk among healthy community-dwelling Thai older adults. This cross-sectional nationwide study enrolled Thai adults aged ≥60 years from 2 randomly selected provinces from each of the 6 regions of Thailand via stratified multistage sampling during March 2021 to August 2022. All enrolled participants were evaluated for bone mineral density, skeletal muscle mass, grip strength, and gait speed. Osteoporosis was diagnosed according to the World Health Organization definition, and sarcopenia was diagnosed according to the Asian Working Group for Sarcopenia 2019 criteria. Falls risk was determined using the self-rated Fall Risk Questionnaire (FRQ). A total of 2991 eligible participants were recruited. The mean age of participants was 69.2 ± 6.5 years (range: 60–107), and 63.1% were female. The prevalence of osteoporosis, sarcopenia, and high falls risk was 29.7%, 18.1%, and 38.5%, respectively. Approximately one-fifth of subjects (19.1%) had at least 2 of 3 risk factors (i.e., osteoporosis, sarcopenia, and high falls risk) for sustaining a fragility fracture, and 3.4% had all three risk factors. In conclusion, the results of this study revealed a high and increasing prevalence of osteoporosis, sarcopenia, and high falls risk in healthy community-dwelling Thai older adults. Since these conditions are all major risk factors for fragility fracture, modification of Thailand’s national healthcare policy is urgently needed to address the increasing prevalence of these conditions among healthy community-dwelling older adults living in Thailand.
{"title":"Prevalence of osteoporosis, sarcopenia, and high falls risk in healthy community-dwelling Thai older adults: a nationwide cross-sectional study","authors":"A. Asavamongkolkul, N. Adulkasem, P. Chotiyarnwong, Ekasame Vanitcharoenkul, Chandhanarat Chandhanayingyong, Panai Laohaprasitiporn, Krabkaew Soparat, A. Unnanuntana","doi":"10.1093/jbmrpl/ziad020","DOIUrl":"https://doi.org/10.1093/jbmrpl/ziad020","url":null,"abstract":"\u0000 Thailand has transitioned from an aging society to an aged society, which implies that the prevalence of age-related disorders will increase; however, epidemiological data specific to the prevalence of age-related degenerative musculoskeletal disorders among Thai older adults remain limited. Accordingly, the aim of this study was to investigate the prevalence of age-related musculoskeletal diseases, including osteoporosis, sarcopenia, and high falls risk among healthy community-dwelling Thai older adults. This cross-sectional nationwide study enrolled Thai adults aged ≥60 years from 2 randomly selected provinces from each of the 6 regions of Thailand via stratified multistage sampling during March 2021 to August 2022. All enrolled participants were evaluated for bone mineral density, skeletal muscle mass, grip strength, and gait speed. Osteoporosis was diagnosed according to the World Health Organization definition, and sarcopenia was diagnosed according to the Asian Working Group for Sarcopenia 2019 criteria. Falls risk was determined using the self-rated Fall Risk Questionnaire (FRQ). A total of 2991 eligible participants were recruited. The mean age of participants was 69.2 ± 6.5 years (range: 60–107), and 63.1% were female. The prevalence of osteoporosis, sarcopenia, and high falls risk was 29.7%, 18.1%, and 38.5%, respectively. Approximately one-fifth of subjects (19.1%) had at least 2 of 3 risk factors (i.e., osteoporosis, sarcopenia, and high falls risk) for sustaining a fragility fracture, and 3.4% had all three risk factors. In conclusion, the results of this study revealed a high and increasing prevalence of osteoporosis, sarcopenia, and high falls risk in healthy community-dwelling Thai older adults. Since these conditions are all major risk factors for fragility fracture, modification of Thailand’s national healthcare policy is urgently needed to address the increasing prevalence of these conditions among healthy community-dwelling older adults living in Thailand.","PeriodicalId":14611,"journal":{"name":"JBMR Plus","volume":"30 10","pages":""},"PeriodicalIF":3.8,"publicationDate":"2024-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139386472","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Leanne M. Ward, Wolfgang Högler, Francis H. Glorieux, A. Portale, Michael P. Whyte, C. Munns, Ola Nilsson, Jill H Simmons, Raja Padidela, Noriyuki Namba, H. Cheong, Etienne Sochett, Koji Muroya, Hiroyuki Tanaka, P. Pitukcheewanont, G. Gottesman, Andrew Biggin, Farzana Perwad, Angel Chen, J. Lawrence Merritt, Erik A. Imel
In a randomized, open-label phase 3 study of 61 children 1–12 years old with X-linked hypophosphatemia (XLH) previously treated with conventional therapy, changing to bi-weekly (Q2W) burosumab for 64 weeks improved phosphate metabolism, radiographic rickets, and growth compared with conventional therapy. In this open-label extension period (weeks 64–88), 21 children continued burosumab Q2W at the previous dose or crossed over from conventional therapy to burosumab starting at 0.8 mg/kg Q2W and had continued clinical radiographic assessments through week 88. Efficacy endpoints and safety observations were summarized descriptively for the treatment groups (burosumab continuation, n = 6; crossover, n = 15). At week 88 compared with baseline, improvements in the following outcomes were observed in the burosumab continuation and crossover groups, respectively: mean (SD) RGI-C rickets total score (primary outcome), +2.11 (0.27) and + 1.89 (0.35); mean (SD) RGI-C lower limb deformity score, +1.61 (0.91) and + 0.73 (0.82), and mean (SD) height Z-score + 0.41 (0.50) and + 0.08 (0.34). Phosphate metabolism normalized rapidly in the crossover group and persisted in the continuation group. Mean (SD) serum ALP decreased from 169% (43%) of the upper limit of normal (ULN) at baseline to 126% (51%) at week 88 in the continuation group, and from 157% (33%) of the ULN at baseline to 111% (23%) at week 88 in the crossover group. During the extension period, treatment-emergent adverse events (AEs) were reported in all six children in the burosumab continuation group and in 14/15 children in the cross-over group. AE profiles in the randomized and extension periods were similar, with no new safety signals identified. Thus, improvements from baseline in radiographic rickets continued in the extension period among children with XLH who remained on burosumab. Children who crossed over from conventional therapy to burosumab demonstrated rapid improvement in phosphate metabolism and improved rickets healing over the ensuing 22 weeks.
{"title":"Burosumab versus conventional therapy in children with X-linked hypophosphatemia: results of the open-label, phase 3 extension period","authors":"Leanne M. Ward, Wolfgang Högler, Francis H. Glorieux, A. Portale, Michael P. Whyte, C. Munns, Ola Nilsson, Jill H Simmons, Raja Padidela, Noriyuki Namba, H. Cheong, Etienne Sochett, Koji Muroya, Hiroyuki Tanaka, P. Pitukcheewanont, G. Gottesman, Andrew Biggin, Farzana Perwad, Angel Chen, J. Lawrence Merritt, Erik A. Imel","doi":"10.1093/jbmrpl/ziad001","DOIUrl":"https://doi.org/10.1093/jbmrpl/ziad001","url":null,"abstract":"\u0000 In a randomized, open-label phase 3 study of 61 children 1–12 years old with X-linked hypophosphatemia (XLH) previously treated with conventional therapy, changing to bi-weekly (Q2W) burosumab for 64 weeks improved phosphate metabolism, radiographic rickets, and growth compared with conventional therapy. In this open-label extension period (weeks 64–88), 21 children continued burosumab Q2W at the previous dose or crossed over from conventional therapy to burosumab starting at 0.8 mg/kg Q2W and had continued clinical radiographic assessments through week 88. Efficacy endpoints and safety observations were summarized descriptively for the treatment groups (burosumab continuation, n = 6; crossover, n = 15). At week 88 compared with baseline, improvements in the following outcomes were observed in the burosumab continuation and crossover groups, respectively: mean (SD) RGI-C rickets total score (primary outcome), +2.11 (0.27) and + 1.89 (0.35); mean (SD) RGI-C lower limb deformity score, +1.61 (0.91) and + 0.73 (0.82), and mean (SD) height Z-score + 0.41 (0.50) and + 0.08 (0.34). Phosphate metabolism normalized rapidly in the crossover group and persisted in the continuation group. Mean (SD) serum ALP decreased from 169% (43%) of the upper limit of normal (ULN) at baseline to 126% (51%) at week 88 in the continuation group, and from 157% (33%) of the ULN at baseline to 111% (23%) at week 88 in the crossover group. During the extension period, treatment-emergent adverse events (AEs) were reported in all six children in the burosumab continuation group and in 14/15 children in the cross-over group. AE profiles in the randomized and extension periods were similar, with no new safety signals identified. Thus, improvements from baseline in radiographic rickets continued in the extension period among children with XLH who remained on burosumab. Children who crossed over from conventional therapy to burosumab demonstrated rapid improvement in phosphate metabolism and improved rickets healing over the ensuing 22 weeks.","PeriodicalId":14611,"journal":{"name":"JBMR Plus","volume":"77 7","pages":""},"PeriodicalIF":3.8,"publicationDate":"2024-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139387189","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Hsiao H Sung, Wyatt Spresser, Joseph P Hoffmann, Zongrui Dai, Peter M Van der Kraan, M. Caird, Esmeralda Blaney Davidson, K. Kozloff
Craniofacial and dentoalveolar abnormalities are present in all types of Osteogenesis Imperfecta (OI). Mouse models of the disorder are critical to understanding these abnormalities and underlying OI pathogenesis. Previous studies on severely affected OI mice report a broad spectrum of craniofacial phenotypes, exhibiting some similarities to the human disorder. Brtl/+ and G610c/+ are moderately severe and mild type IV OI, respectively. Little is known about the aging effects on the craniofacial bones of these models and their homology to human OI. This study aimed to analyze the Brtl/+ and G610c/+ craniofacial morphometries during aging to establish suitability for further OI craniofacial bone intervention studies. We performed morphological measurements on the micro-CT scanned heads of 3-week-old, 3-month-old, and 6-month-old female Brtl/+ and G610c/+ mice. We observed that Brtl/+ skulls are shorter in length than WT (p < 0.05), whereas G610c/+ skulls are similar in length to their WT counterparts. Brtl/+ mice exhibit alveolar bone with a porotic-like appearance that is not observed in G610c/+. As they age, Brtl/+ mice show severe bone resorption in both the maxilla and mandible (p < 0.05). In contrast, G610c/+ mice experience mandibular resorption consistently across all ages, but maxillary resorption is only evident at 6 months (p < 0.05). Western blot shows high osteoclastic activities in the Brtl/+ maxilla. Both models exhibit delayed pre-functional eruptions of the third molars (p < 0.05), similar to those observed in some bisphosphonate-treated OI subjects. Our study shows that the Brtl/+ and G610c/+ mice display clear features found in type IV OI patients; both show age-related changes in craniofacial growth phenotype. Therefore, understanding the craniofacial features of these models and how they age will allow us to select the most accurate mouse model, mouse age, and bone structure for the specific craniofacial bone treatment of differing OI groups.
所有类型的成骨不全症（OI）都存在颅面和牙槽骨异常。该疾病的小鼠模型对于了解这些异常和潜在的 OI 发病机制至关重要。以前对严重受影响的 OI 小鼠进行的研究报告了广泛的颅面表型，与人类疾病有一些相似之处。Brtl/+ 和 G610c/+ 分别属于中度严重和轻度 IV 型 OI。人们对这些模型对颅面部骨骼的老化影响及其与人类 OI 的同源性知之甚少。本研究旨在分析Brtl/+和G610c/+在衰老过程中的颅面形态，以确定是否适合进一步的OI颅面骨骼干预研究。我们对 3 周大、3 个月大和 6 个月大的雌性 Brtl/+ 和 G610c/+ 小鼠的头部进行了微计算机断层扫描形态测量。我们观察到 Brtl/+ 头骨的长度比 WT 小鼠短（p < 0.05），而 G610c/+ 头骨的长度与 WT 小鼠相似。Brtl/+ 小鼠的牙槽骨呈现出多孔状外观，而 G610c/+ 则没有这种现象。随着年龄的增长，Brtl/+小鼠的上颌骨和下颌骨都出现了严重的骨吸收现象（p < 0.05）。相比之下，G610c/+ 小鼠在所有年龄段都会出现下颌骨吸收，但上颌骨吸收只在 6 个月时才明显（p < 0.05）。Western 印迹显示 Brtl/+ 上颌骨的破骨活性很高。两种模型都表现出第三磨牙功能前萌出延迟（p < 0.05），这与在一些接受过双磷酸盐治疗的 OI 受试者身上观察到的情况类似。我们的研究表明，Brtl/+ 和 G610c/+ 小鼠表现出 IV 型 OI 患者的明显特征；两者的颅面生长表型都出现了与年龄相关的变化。因此，了解这些模型的颅面特征及其如何衰老将使我们能够选择最准确的小鼠模型、小鼠年龄和骨结构，以针对不同的 OI 群体进行特定的颅面骨治疗。
{"title":"Collagen mutation and age contribute to differential craniofacial phenotypes in mouse models of osteogenesis imperfecta","authors":"Hsiao H Sung, Wyatt Spresser, Joseph P Hoffmann, Zongrui Dai, Peter M Van der Kraan, M. Caird, Esmeralda Blaney Davidson, K. Kozloff","doi":"10.1093/jbmrpl/ziad004","DOIUrl":"https://doi.org/10.1093/jbmrpl/ziad004","url":null,"abstract":"\u0000 Craniofacial and dentoalveolar abnormalities are present in all types of Osteogenesis Imperfecta (OI). Mouse models of the disorder are critical to understanding these abnormalities and underlying OI pathogenesis. Previous studies on severely affected OI mice report a broad spectrum of craniofacial phenotypes, exhibiting some similarities to the human disorder. Brtl/+ and G610c/+ are moderately severe and mild type IV OI, respectively. Little is known about the aging effects on the craniofacial bones of these models and their homology to human OI. This study aimed to analyze the Brtl/+ and G610c/+ craniofacial morphometries during aging to establish suitability for further OI craniofacial bone intervention studies. We performed morphological measurements on the micro-CT scanned heads of 3-week-old, 3-month-old, and 6-month-old female Brtl/+ and G610c/+ mice. We observed that Brtl/+ skulls are shorter in length than WT (p < 0.05), whereas G610c/+ skulls are similar in length to their WT counterparts. Brtl/+ mice exhibit alveolar bone with a porotic-like appearance that is not observed in G610c/+. As they age, Brtl/+ mice show severe bone resorption in both the maxilla and mandible (p < 0.05). In contrast, G610c/+ mice experience mandibular resorption consistently across all ages, but maxillary resorption is only evident at 6 months (p < 0.05). Western blot shows high osteoclastic activities in the Brtl/+ maxilla. Both models exhibit delayed pre-functional eruptions of the third molars (p < 0.05), similar to those observed in some bisphosphonate-treated OI subjects. Our study shows that the Brtl/+ and G610c/+ mice display clear features found in type IV OI patients; both show age-related changes in craniofacial growth phenotype. Therefore, understanding the craniofacial features of these models and how they age will allow us to select the most accurate mouse model, mouse age, and bone structure for the specific craniofacial bone treatment of differing OI groups.","PeriodicalId":14611,"journal":{"name":"JBMR Plus","volume":"38 8","pages":""},"PeriodicalIF":3.8,"publicationDate":"2024-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139385780","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
A. Leerling, F. Smit, Zita Spӓth, Ana Navas Cañete, L. de Geus-Oei, A. van de Burgt, Olaf M Dekkers, W. van der Bruggen, Natasha M Appelman-Dijkstra, D. Vriens, Elizabeth M Winter
Chronic nonbacterial osteitis (CNO) is a rare disease spectrum, which lacks biomarkers for disease activity. Sodium fluoride positron emission tomography ([18F]NaF-PET/CT) is a sensitive imaging tool for bone diseases and yields quantitative data on bone turnover. We evaluate the capacities of [18F]NaF-PET/CT to provide structural and functional assessment in adult CNO. Cross-sectional study among 43 adult CNO patients and 16 controls (patients referred for suspected, but not diagnosed as CNO) undergoing [18F]NaF-PET/CT at our expert clinic. Structural features were compared between patients and controls, and maximal standardized uptake values (SUVmax (g/ml)) were calculated for bone lesions, soft tissue/joint lesions, and reference bone. SUVmax was correlated with clinical disease activity in patients. Manubrial and costal sclerosis/hyperostosis, and calcification of the costoclavicular ligament emerged core structural features associated with CNO as visualized by [18F]NaF-PET/CT. SUVmax of CNO lesions was higher compared to in-patient reference bone (mean paired difference 11.4, 95%CI9.4–13.5, p < 0.001) and controls (mean difference 12.4, 95%CI9.1–15.8, p < 0.001). Highest SUVmax values were found in soft tissue and joint areas like the costoclavicular ligament and manubriosternal joint, and these correlated with erythrocyte sedimentation rate in patients (correlation coefficient 0.546, p < 0.002). [18F]NaF-PET/CT is a promising imaging tool for adult CNO, allowing for detailed structural evaluation of its typical bone, soft-tissue and joint features. At the same time, [18F]NaF-PET/CT yields quantitative bone remodeling data that represent the pathologically increased bone turnover and the process of new bone formation. Further studies should investigate the application of quantified [18F]NaF-uptake as a novel biomarker for disease activity in CNO, and its utility to steer clinical decision-making.
{"title":"18F-sodium fluoride PET-CT visualizes disease activity in adult chronic nonbacterial osteitis (CNO)","authors":"A. Leerling, F. Smit, Zita Spӓth, Ana Navas Cañete, L. de Geus-Oei, A. van de Burgt, Olaf M Dekkers, W. van der Bruggen, Natasha M Appelman-Dijkstra, D. Vriens, Elizabeth M Winter","doi":"10.1093/jbmrpl/ziad007","DOIUrl":"https://doi.org/10.1093/jbmrpl/ziad007","url":null,"abstract":"\u0000 \u0000 \u0000 Chronic nonbacterial osteitis (CNO) is a rare disease spectrum, which lacks biomarkers for disease activity. Sodium fluoride positron emission tomography ([18F]NaF-PET/CT) is a sensitive imaging tool for bone diseases and yields quantitative data on bone turnover. We evaluate the capacities of [18F]NaF-PET/CT to provide structural and functional assessment in adult CNO.\u0000 \u0000 \u0000 \u0000 Cross-sectional study among 43 adult CNO patients and 16 controls (patients referred for suspected, but not diagnosed as CNO) undergoing [18F]NaF-PET/CT at our expert clinic. Structural features were compared between patients and controls, and maximal standardized uptake values (SUVmax (g/ml)) were calculated for bone lesions, soft tissue/joint lesions, and reference bone. SUVmax was correlated with clinical disease activity in patients.\u0000 \u0000 \u0000 \u0000 Manubrial and costal sclerosis/hyperostosis, and calcification of the costoclavicular ligament emerged core structural features associated with CNO as visualized by [18F]NaF-PET/CT. SUVmax of CNO lesions was higher compared to in-patient reference bone (mean paired difference 11.4, 95%CI9.4–13.5, p < 0.001) and controls (mean difference 12.4, 95%CI9.1–15.8, p < 0.001). Highest SUVmax values were found in soft tissue and joint areas like the costoclavicular ligament and manubriosternal joint, and these correlated with erythrocyte sedimentation rate in patients (correlation coefficient 0.546, p < 0.002).\u0000 \u0000 \u0000 \u0000 [18F]NaF-PET/CT is a promising imaging tool for adult CNO, allowing for detailed structural evaluation of its typical bone, soft-tissue and joint features. At the same time, [18F]NaF-PET/CT yields quantitative bone remodeling data that represent the pathologically increased bone turnover and the process of new bone formation. Further studies should investigate the application of quantified [18F]NaF-uptake as a novel biomarker for disease activity in CNO, and its utility to steer clinical decision-making.\u0000","PeriodicalId":14611,"journal":{"name":"JBMR Plus","volume":"26 5","pages":""},"PeriodicalIF":3.8,"publicationDate":"2024-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139450722","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-04eCollection Date: 2024-02-01DOI: 10.1093/jbmrpl/ziae007
Andreea Teodora Dinescu, Bin Zhou, Yizhong Jenny Hu, Sanchita Agarwal, Elizabeth Shane, Xiang-Dong Edward Guo
High-resolution peripheral quantitative computed tomography (HR-pQCT) has been used for in vivo 3D visualization of trabecular microstructure. Second-generation HR-pQCT (HR-pQCT II) has been shown to have good agreement with first generation HR-pQCT (HR-pQCT I). Advanced Individual Trabecula Segmentation (ITS) decomposes the trabecula network into individual plates and rods. ITS based on HR-pQCT I showed a strong correlation to ITS based on micro-computed tomography (μCT) and identified trabecular changes in metabolic bone diseases. ITS based on HR-pQCT II has new potential because of the enhanced resolution but has yet to be validated. The objective of this study was to assess the agreement between ITS based on HR-pQCT I, HR-pQCT II, and μCT to assess the capability of ITS on HR-pQCT images as a tool for studying bone structure. Freshly frozen tibia and radius bones were scanned in the distal region using HR-pQCT I at 82 μm, HR-pQCT II at 60.7 μm, and μCT at 37 μm. Images were registered, binarized, and ITS analysis was performed. Bone volume fraction (pBV/TV, rBV/TV), number density (pTb.N, rTb.N), thickness (pTb.Th, rTb.Th), and plate-to-rod (PR) ratio (pBV/rBV) of trabecular plates and rods were obtained. Paired Student's t-tests with post hoc Bonferroni analysis were used to examine the differences. Linear regression was used to determine the correlation coefficient. The HR-pQCT I parameters were different from the μCT measurements. The HR-pQCT II parameters were different from the μCT measurements except for rTb.N, and the HR-pQCT I parameters were different from the HR-pQCT II measurements except for pTb.Th. The strong correlation between HR-pQCT II and μCT microstructural analysis (R2 = 0.55-0.94) suggests that HR-pQCT II can be used to assess changes in plate and rod microstructure and that values from HR-pQCT I can be corrected.
高分辨率外周定量计算机断层扫描（HR-pQCT）已被用于体内小梁微结构的三维可视化。第二代高分辨外周定量计算机断层扫描（HR-pQCT II）与第一代高分辨外周定量计算机断层扫描（HR-pQCT I）具有良好的一致性。先进的单个小梁分割（ITS）将小梁网络分解为单个板和棒。基于 HR-pQCT I 的 ITS 与基于显微计算机断层扫描（μCT）的 ITS 有很强的相关性，并能识别代谢性骨病的骨小梁变化。基于 HR-pQCT II 的 ITS 由于分辨率的提高而具有新的潜力，但尚未得到验证。本研究的目的是评估基于 HR-pQCT I、HR-pQCT II 和 μCT 的 ITS 之间的一致性，以评估 HR-pQCT 图像上的 ITS 作为骨结构研究工具的能力。使用 82 μm 的 HR-pQCT I、60.7 μm 的 HR-pQCT II 和 37 μm 的 μCT 扫描新鲜冷冻的胫骨和桡骨远端区域。对图像进行注册、二值化和 ITS 分析。获得骨小梁板和骨小梁棒的骨体积分数（pBV/TV、rBV/TV）、数量密度（pTb.N、rTb.N）、厚度（pTb.Th、rTb.Th）和板棒比（PR）（pBV/rBV）。采用配对学生 t 检验和事后 Bonferroni 分析来检验差异。线性回归用于确定相关系数。HR-pQCT I参数与μCT测量结果不同。除rTb.N外，HR-pQCT II参数与μCT测量值不同；除pTb.Th外，HR-pQCT I参数与HR-pQCT II测量值不同。HR-pQCT II 与 μCT 显微结构分析之间的强相关性（R2 = 0.55-0.94）表明，HR-pQCT II 可用于评估板材和棒材显微结构的变化，HR-pQCT I 的值可进行校正。
{"title":"Individual trabecula segmentation validation in first- and second-generation high-resolution peripheral computed tomography compared to micro-computed tomography in the distal radius and tibia.","authors":"Andreea Teodora Dinescu, Bin Zhou, Yizhong Jenny Hu, Sanchita Agarwal, Elizabeth Shane, Xiang-Dong Edward Guo","doi":"10.1093/jbmrpl/ziae007","DOIUrl":"10.1093/jbmrpl/ziae007","url":null,"abstract":"<p><p>High-resolution peripheral quantitative computed tomography (HR-pQCT) has been used for in vivo 3D visualization of trabecular microstructure. Second-generation HR-pQCT (HR-pQCT II) has been shown to have good agreement with first generation HR-pQCT (HR-pQCT I). Advanced Individual Trabecula Segmentation (ITS) decomposes the trabecula network into individual plates and rods. ITS based on HR-pQCT I showed a strong correlation to ITS based on micro-computed tomography (μCT) and identified trabecular changes in metabolic bone diseases. ITS based on HR-pQCT II has new potential because of the enhanced resolution but has yet to be validated. The objective of this study was to assess the agreement between ITS based on HR-pQCT I, HR-pQCT II, and μCT to assess the capability of ITS on HR-pQCT images as a tool for studying bone structure. Freshly frozen tibia and radius bones were scanned in the distal region using HR-pQCT I at 82 μm, HR-pQCT II at 60.7 μm, and μCT at 37 μm. Images were registered, binarized, and ITS analysis was performed. Bone volume fraction (pBV/TV, rBV/TV), number density (pTb.N, rTb.N), thickness (pTb.Th, rTb.Th), and plate-to-rod (PR) ratio (pBV/rBV) of trabecular plates and rods were obtained. Paired Student's <i>t</i>-tests with post hoc Bonferroni analysis were used to examine the differences. Linear regression was used to determine the correlation coefficient. The HR-pQCT I parameters were different from the μCT measurements. The HR-pQCT II parameters were different from the μCT measurements except for rTb.N, and the HR-pQCT I parameters were different from the HR-pQCT II measurements except for pTb.Th. The strong correlation between HR-pQCT II and μCT microstructural analysis (R<sup>2</sup> = 0.55-0.94) suggests that HR-pQCT II can be used to assess changes in plate and rod microstructure and that values from HR-pQCT I can be corrected.</p>","PeriodicalId":14611,"journal":{"name":"JBMR Plus","volume":"8 3","pages":"ziae007"},"PeriodicalIF":3.8,"publicationDate":"2024-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10945717/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140174720","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ka-Young Ryu, N. K. Pokhrel, Hye-Jin Jung, Hyo Jeong Kim, Jiwon Seok, Tae-Young Kim, Hyung Joon Kim, Ji Hye Lee, Jae-Young Kim, Yong-Gun Kim, Youngkyun Lee
Bone homeostasis is maintained by tightly coordinated activities of bone-forming osteoblasts and bone-resorbing osteoclasts. In the present report, the role of Mer tyrosine kinase (MerTK) in bone metabolism was investigated. The expression of MerTK decreased upon BMP2 stimulation of osteoblast precursors. The femurs of Mertk-deficient mice showed significantly increased bone volume with concomitant increase of bone formation and reduction in bone resorption. These bone phenotypes were attributed to the increased osteoblast differentiation and mineralization accounted by the enhanced β-Catenin and Smad signaling in the absence of MerTK in osteoblast precursors. Although the Mertk-deficient bone marrow macrophages were predisposed to enhanced osteoclast differentiation via augmented Ca2+-NFATc1 signaling, the dramatic increase of Tnfsf11b/Tnfsf11 (Opg/Rankl) ratio in Mertk knockout bones and osteoblast precursors corroborated the reduction of osteoclastogenesis in Mertk deficiency. In ligature-induced periodontitis and ovariectomy models, the bone resorption was significantly attenuated in Mertk-deficient mice compared with wild type control. Taken together, these data indicate novel role of MerTK in bone metabolism and suggest a potential strategy targeting MerTK in treating bone-lytic diseases including periodontitis and osteoporosis.
{"title":"Mer tyrosine kinase regulates bone metabolism, and its deficiency partially ameliorates periodontitis- and ovariectomy-induced bone loss in mice","authors":"Ka-Young Ryu, N. K. Pokhrel, Hye-Jin Jung, Hyo Jeong Kim, Jiwon Seok, Tae-Young Kim, Hyung Joon Kim, Ji Hye Lee, Jae-Young Kim, Yong-Gun Kim, Youngkyun Lee","doi":"10.1093/jbmrpl/ziad014","DOIUrl":"https://doi.org/10.1093/jbmrpl/ziad014","url":null,"abstract":"\u0000 Bone homeostasis is maintained by tightly coordinated activities of bone-forming osteoblasts and bone-resorbing osteoclasts. In the present report, the role of Mer tyrosine kinase (MerTK) in bone metabolism was investigated. The expression of MerTK decreased upon BMP2 stimulation of osteoblast precursors. The femurs of Mertk-deficient mice showed significantly increased bone volume with concomitant increase of bone formation and reduction in bone resorption. These bone phenotypes were attributed to the increased osteoblast differentiation and mineralization accounted by the enhanced β-Catenin and Smad signaling in the absence of MerTK in osteoblast precursors. Although the Mertk-deficient bone marrow macrophages were predisposed to enhanced osteoclast differentiation via augmented Ca2+-NFATc1 signaling, the dramatic increase of Tnfsf11b/Tnfsf11 (Opg/Rankl) ratio in Mertk knockout bones and osteoblast precursors corroborated the reduction of osteoclastogenesis in Mertk deficiency. In ligature-induced periodontitis and ovariectomy models, the bone resorption was significantly attenuated in Mertk-deficient mice compared with wild type control. Taken together, these data indicate novel role of MerTK in bone metabolism and suggest a potential strategy targeting MerTK in treating bone-lytic diseases including periodontitis and osteoporosis.","PeriodicalId":14611,"journal":{"name":"JBMR Plus","volume":"63 2","pages":""},"PeriodicalIF":3.8,"publicationDate":"2024-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139385613","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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