Journal of Bone and Mineral Research最新文献

{"title":"GNA11 Variants Identified in Patients with Hypercalcemia or Hypocalcemia","authors":"Sarah A. Howles,&nbsp;Caroline M. Gorvin,&nbsp;Treena Cranston,&nbsp;Angela Rogers,&nbsp;Anna K. Gluck,&nbsp;Hannah Boon,&nbsp;Kate Gibson,&nbsp;Mushtaqur Rahman,&nbsp;Allen Root,&nbsp;M. Andrew Nesbit,&nbsp;Fadil M. Hannan,&nbsp;Rajesh V. Thakker","doi":"10.1002/jbmr.4803","DOIUrl":"https://doi.org/10.1002/jbmr.4803","url":null,"abstract":"<p>Familial hypocalciuric hypercalcemia type 2 (FHH2) and autosomal dominant hypocalcemia type 2 (ADH2) are due to loss- and gain-of-function mutations, respectively, of the <i>GNA11</i> gene that encodes the G protein subunit Gα11, a signaling partner of the calcium-sensing receptor (CaSR). To date, four probands with FHH2-associated Gα11 mutations and eight probands with ADH2-associated Gα11 mutations have been reported. In a 10-year period, we identified 37 different germline <i>GNA11</i> variants in &gt;1200 probands referred for investigation of genetic causes for hypercalcemia or hypocalcemia, comprising 14 synonymous, 12 noncoding, and 11 nonsynonymous variants. The synonymous and noncoding variants were predicted to be benign or likely benign by in silico analysis, with 5 and 3, respectively, occurring in both hypercalcemic and hypocalcemic individuals. Nine of the nonsynonymous variants (Thr54Met, Arg60His, Arg60Leu, Gly66Ser, Arg149His, Arg181Gln, Phe220Ser, Val340Met, Phe341Leu) identified in 13 probands have been reported to be FHH2- or ADH2-causing. Of the remaining nonsynonymous variants, Ala65Thr was predicted to be benign, and Met87Val, identified in a hypercalcemic individual, was predicted to be of uncertain significance. Three-dimensional homology modeling of the Val87 variant suggested it was likely benign, and expression of Val87 variant and wild-type Met87 Gα11 in CaSR-expressing HEK293 cells revealed no differences in intracellular calcium responses to alterations in extracellular calcium concentrations, consistent with Val87 being a benign polymorphism. Two noncoding region variants, a 40bp-5'UTR deletion and a 15bp-intronic deletion, identified only in hypercalcemic individuals, were associated with decreased luciferase expression in vitro but no alterations in <i>GNA11</i> mRNA or Gα11 protein levels in cells from the patient and no abnormality in splicing of the <i>GNA11</i> mRNA, respectively, confirming them to be benign polymorphisms. Thus, this study identified likely disease-causing <i>GNA11</i> variants in &lt;1% of probands with hypercalcemia or hypocalcemia and highlights the occurrence of <i>GNA11</i> rare variants that are benign polymorphisms. © 2023 The Authors. <i>Journal of Bone and Mineral Research</i> published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":"38 6","pages":"907-917"},"PeriodicalIF":6.2,"publicationDate":"2023-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jbmr.4803","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5851901","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Issue Information - Declaration of Helsinki","authors":"","doi":"10.1002/jbmr.4583","DOIUrl":"https://doi.org/10.1002/jbmr.4583","url":null,"abstract":"1. The World Medical Association has developed the Declaration of Helsinki as a statement of ethical principles to provide guidance to physicians and other participants in medical research involving human subjects. Medical research involving human subjects includes research on identifiable human material or identifiable data. 2. It is the duty of the physician to promote and safeguard the health of the people. The physician’s knowledge and conscience are dedicated to the fulfillment of this duty. 3. The Declaration of Geneva of the World Medical Association binds the physician with the words, “The health of my patient will be my first consideration,” and the International Code of Medical Ethics declares that, “A physician shall act only in the patient’s interest when providing medical care which might have the effect of weakening the physical and mental condition of the patient.” 4. Medical progress is based on research which ultimately must rest in part on experimentation involving human subjects. 5. In medical research on human subjects, considerations related to the well-being of the human subject should take precedence over the interests of science and society. 6. The primary purpose of medical research involving human subjects is to improve prophylactic, diagnostic and therapeutic procedures and the understanding of the aetiology and pathogenesis of disease. Even the best proven prophylactic, diagnostic, and therapeutic methods must continuously be challenged through research for their effectiveness, efficiency, accessibility and quality. 7. In current medical practice and in medical research, most prophylactic, diagnostic and therapeutic procedures involve risks and burdens. 8. Medical research is subject to ethical standards that promote respect for all human beings and protect their health and rights. Some research populations are vulnerable and need special protection. The particular needs of the economically and medically disadvantaged must be recognized. Special attention is also required for those who cannot give or refuse consent for themselves, for those who may be subject to giving consent under duress, for those who will not benefit personally from the research and for those for whom the research is combined with care. 9. Research investigators should be aware of the ethical, legal and regulatory requirements for research on human subjects in their own countries as well as applicable international requirements. No national ethical, legal or regulatory requirement should be allowed to reduce or eliminate any of the protections for human subjects set forth in this Declaration.","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":"38 3","pages":"BMi-BMii"},"PeriodicalIF":6.2,"publicationDate":"2023-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jbmr.4583","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5673714","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ed Bd, Masthead, Comm List and TOC","authors":"","doi":"10.1002/jbmr.4584","DOIUrl":"https://doi.org/10.1002/jbmr.4584","url":null,"abstract":"Cheryl Ackert-Bicknell, USA Xiaochun Bai, China Murat Bastepe, USA Robert Blank, USA Joel Boerckel, USA Steve Boyd, Canada Elizabeth Bradley, USA Frederic Cailotto, France Blaine Christiansen, USA Cristiana Cipriani, Italy Bart Clarke, USA Celine Colnot, France Beth Curtis, UK Roman Eliseev, USA Mathieu Ferron, Canada Antonella Forlino, Italy Seiji Fukumoto, Japan Claudia Goettsch, USA Natalia Gouskova, USA Fadil Hannan, UK Christopher Hernandez, USA Matthew Hilton, USA Yuuki Imai, Japan Alex Ireland, UK Katharina Jähn-Rickert, Germany M Kassim Javaid, UK Rachelle Johnson, USA Ivo Kalajzic, USA Courtney Karner, USA Jung-Min Koh, South Korea Lisa Langsetmo, USA Michaël Laurent, Belgium Eva Liu, USA Gabriela Loots, USA Outi Makitie, Finland Laura McCabe, USA Michael McClung, USA Carolina Medina-Gómez, Netherlands Haakon Meyer, Norway Petar Milovanovic, Serbia Deborah Mitchell, USA Tom Nickolas, USA Jeffry Nyman, USA Ralf Oheim, Germany Noriaki Ono, USA Kyung-Hyun Park-Min, USA John Pettifor, South Africa Lilian Plotkin, USA Martina Rauner, Germany Ian Reid, New Zealand Erica Scheller, USA Ernestina Schipani, USA David Scott, Australia Joseph Stains, USA Hannah Taipaleenmaki, Germany Tingting Tang, China Thach Tran, Australia Elena Tsourdi, Germany Peter Vestergaard, Denmark Annika vom Scheidt, Austria Robert Wermers, USA Bettina Willie, Canada Timur Yorgan, Germany Elaine Yu, USA Babette Zemel, USA Xiaolei Zhang, China Elizabeth Zimmermann, Canada","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":"38 3","pages":"FMi-FMv"},"PeriodicalIF":6.2,"publicationDate":"2023-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jbmr.4584","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5673704","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Journal of Bone and Mineral Research: Volume 38, Number 3, March 2023","authors":"","doi":"10.1002/jbmr.4582","DOIUrl":"https://doi.org/10.1002/jbmr.4582","url":null,"abstract":"","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":"38 3","pages":"C1"},"PeriodicalIF":6.2,"publicationDate":"2023-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jbmr.4582","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5673709","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Higenamine Promotes Osteogenesis Via IQGAP1/SMAD4 Signaling Pathway and Prevents Age- and Estrogen-Dependent Bone Loss in Mice","authors":"Hui Dong,&nbsp;Ronghan Liu,&nbsp;Ke Zou,&nbsp;Zhengxin Jin,&nbsp;Jianning Kang,&nbsp;Ying Zhang,&nbsp;Xiaodi Zhang,&nbsp;Zhengfang Sun,&nbsp;Guilian Yu,&nbsp;Nana Huang,&nbsp;Morgan Bretches,&nbsp;Shang-You Yang,&nbsp;Bin Ning","doi":"10.1002/jbmr.4800","DOIUrl":"https://doi.org/10.1002/jbmr.4800","url":null,"abstract":"<div>\u0000 \u0000 <p>Osteoporosis is a common bone disease caused by an imbalance of bone resorption and formation that results in a loss of total bone density. SMAD2/3 signal transduction is known to play a crucial role in osteogenic differentiation through transforming growth factor-beta (TGF-β). By screening a library of small-molecule compounds, the current study identifies higenamine (HG) as an active osteogenic agent that could be a therapeutic candidate for osteoporosis. In vitro data demonstrated that HG effectively induced expressions of osteogenic markers in mouse bone marrow stromal cell (BMSCs) and preosteoblastic cell cultures. Further, HG treatment resulted in enhanced bone formation and prevented accelerated bone loss on two animal models that mimic spontaneous senile osteoporosis and postmenopausal osteoporosis. IQ motif-containing GTPase-activating protein 1 (IQGAP1) was confirmed as a novel target of HG, where HG appears to bind to the Glu-1019 site of IQGAP1 to exert its osteogenic effects. Data subsequently suggested that HG promoted phosphorylation of SMAD2/3 and regulated the SMAD2/3 pathway by inhibiting SMAD4 ubiquitination. Overall, the findings highlight HG as a new small-molecule drug to promote bone formation through SMAD2/3 pathway in osteoporosis. © 2023 American Society for Bone and Mineral Research (ASBMR).</p>\u0000 </div>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":"38 5","pages":"775-791"},"PeriodicalIF":6.2,"publicationDate":"2023-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"6199048","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Al-Gazali Skeletal Dysplasia Constitutes the Lethal End of ADAMTSL2-Related Disorders","authors":"Dominyka Batkovskyte,&nbsp;Fiona McKenzie,&nbsp;Fulya Taylan,&nbsp;Pelin Ozlem Simsek-Kiper,&nbsp;Sarah M Nikkel,&nbsp;Hirofumi Ohashi,&nbsp;Roger E Stevenson,&nbsp;Thuong Ha,&nbsp;Denise P Cavalcanti,&nbsp;Hiroyuki Miyahara,&nbsp;Steven A Skinner,&nbsp;Miguel A Aguirre,&nbsp;Zühal Ak??ren,&nbsp;Gulen Eda Utine,&nbsp;Tillie Chiu,&nbsp;Kenji Shimizu,&nbsp;Anna Hammarsj?,&nbsp;Koray Boduroglu,&nbsp;Hannah W Moore,&nbsp;Raymond J Louie,&nbsp;Peer Arts,&nbsp;Allie N Merrihew,&nbsp;Milena Babic,&nbsp;Matilda R Jackson,&nbsp;Nikos Papadogiannakis,&nbsp;Anna Lindstrand,&nbsp;Ann Nordgren,&nbsp;Christopher P Barnett,&nbsp;Hamish S Scott,&nbsp;Andrei S Chagin,&nbsp;Gen Nishimura,&nbsp;Giedre Grigelioniene","doi":"10.1002/jbmr.4799","DOIUrl":"https://doi.org/10.1002/jbmr.4799","url":null,"abstract":"<p>Lethal short-limb skeletal dysplasia Al-Gazali type (OMIM %601356), also called dysplastic cortical hyperostosis, Al-Gazali type, is an ultra-rare disorder previously reported in only three unrelated individuals. The genetic etiology for Al-Gazali skeletal dysplasia has up until now been unknown. Through international collaborative efforts involving seven clinical centers worldwide, a cohort of nine patients with clinical and radiographic features consistent with short-limb skeletal dysplasia Al-Gazali type was collected. The affected individuals presented with moderate intrauterine growth restriction, relative macrocephaly, hypertrichosis, large anterior fontanelle, short neck, short and stiff limbs with small hands and feet, severe brachydactyly, and generalized bone sclerosis with mild platyspondyly. Biallelic disease-causing variants in <i>ADAMTSL2</i> were detected using massively parallel sequencing (MPS) and Sanger sequencing techniques. Six individuals were compound heterozygous and one individual was homozygous for pathogenic variants in <i>ADAMTSL2</i>. In one of the families, pathogenic variants were detected in parental samples only. Overall, this study sheds light on the genetic cause of Al-Gazali skeletal dysplasia and identifies it as a semi-lethal part of the spectrum of <i>ADAMTSL2</i>-related disorders. Furthermore, we highlight the importance of meticulous analysis of the pseudogene region of <i>ADAMTSL2</i> where disease-causing variants might be located. © 2023 The Authors. <i>Journal of Bone and Mineral Research</i> published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":"38 5","pages":"692-706"},"PeriodicalIF":6.2,"publicationDate":"2023-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jbmr.4799","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5793201","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sostdc1 Suppression in the Absence of Sclerostin Potentiates Anabolic Action of Cortical Bone in Mice","authors":"Roy B. Choi,&nbsp;April M. Hoggatt,&nbsp;Daniel J. Horan,&nbsp;Emily Z. Rogers,&nbsp;Gabriela G. Loots,&nbsp;Alexander G. Robling","doi":"10.1002/jbmr.4798","DOIUrl":"https://doi.org/10.1002/jbmr.4798","url":null,"abstract":"<p>The development of Wnt-based osteoanabolic agents has progressed rapidly in recent years, given the potent effects of Wnt modulation on bone homeostasis. Simultaneous pharmacologic inhibition of the Wnt antagonists sclerostin and Dkk1 can be optimized to create potentiated effects in the cancellous bone compartment. We looked for other candidates that might be co-inhibited along with sclerostin to potentiate the effects in the cortical compartment. Sostdc1 (Wise), like sclerostin and Dkk1, also binds and inhibits Lrp5/6 coreceptors to impair canonical Wnt signaling, but Sostdc1 has greater effects in the cortical bone. To test this concept, we deleted Sostdc1 and Sost from mice and measured the skeletal effects in cortical and cancellous compartments individually. Sost deletion alone produced high bone mass in all compartments, whereas Sostdc1 deletion alone had no measurable effects on either envelope. Mice with codeletion of Sostdc1 and Sost had high bone mass and increased cortical properties (bone mass, formation rates, mechanical properties), but only among males. Combined administration of sclerostin antibody and Sostdc1 antibody in wild-type female mice produced potentiation of cortical bone gain despite no effect of Sostdc1 antibody alone. In conclusion, Sostdc1 inhibition/deletion can work in concert with sclerostin deficiency to improve cortical bone properties. © 2023 The Authors. <i>Journal of Bone and Mineral Research</i> published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":"38 5","pages":"765-774"},"PeriodicalIF":6.2,"publicationDate":"2023-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jbmr.4798","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"6149097","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Wnt1 Boosts Fracture Healing by Enhancing Bone Formation in the Fracture Callus","authors":"Melanie Haffner-Luntzer,&nbsp;Deniz Ragipoglu,&nbsp;Mubashir Ahmad,&nbsp;Astrid Schoppa,&nbsp;Lena Steppe,&nbsp;Verena Fischer,&nbsp;Julia Luther,&nbsp;Timur Yorgan,&nbsp;Ernesto Bockamp,&nbsp;Michael Amling,&nbsp;Thorsten Schinke,&nbsp;Anita Ignatius","doi":"10.1002/jbmr.4797","DOIUrl":"https://doi.org/10.1002/jbmr.4797","url":null,"abstract":"<p>Despite considerable improvement in fracture care, 5%–10% of all fractures still heal poorly or result in nonunion formation. Therefore, there is an urgent need to identify new molecules that can be used to improve bone fracture healing. One activator of the Wnt-signaling cascade, Wnt1, has recently gained attention for its intense osteoanabolic effect on the intact skeleton. The aim of the present study was to investigate whether Wnt1 might be a promising molecule to accelerate fracture healing both in skeletally healthy and osteoporotic mice that display a diminished healing capacity. Transgenic mice for a temporary induction of Wnt1 specifically in osteoblasts (Wnt1-tg) were subjected to femur osteotomy. Non-ovariectomized and ovariectomized Wnt1-tg mice displayed significantly accelerated fracture healing based on a strong increase in bone formation in the fracture callus. Transcriptome profiling revealed that Hippo/yes1-associated transcriptional regulator (YAP)-signaling and bone morphogenetic protein (BMP) signaling pathways were highly enriched in the fracture callus of Wnt1-tg animals. Immunohistochemical staining confirmed increased activation of YAP1 and expression of BMP2 in osteoblasts in the fracture callus. Therefore, our data indicate that Wnt1 boosts bone formation during fracture healing via YAP/BMP signaling both under healthy and osteoporotic conditions. To further test a potential translational application of Wnt1, we applied recombinant Wnt1 embedded into a collagen gel during critical-size bone-defect repair. Mice treated with Wnt1 displayed increased bone regeneration compared to control mice accompanied by increased YAP1/BMP2 expression in the defect area. These findings are of high clinical relevance because they indicate that Wnt1 could be used as a new therapeutic agent to treat orthopedic complications in the clinic. © 2023 The Authors. <i>Journal of Bone and Mineral Research</i> published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":"38 5","pages":"749-764"},"PeriodicalIF":6.2,"publicationDate":"2023-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jbmr.4797","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"6149070","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development of a First-in-Class Unimolecular Dual GIP/GLP-2 Analogue, GL-0001, for the Treatment of Bone Fragility","authors":"Benoit Gobron,&nbsp;Malory Couchot,&nbsp;Nigel Irwin,&nbsp;Erick Legrand,&nbsp;Béatrice Bouvard,&nbsp;Guillaume Mabilleau","doi":"10.1002/jbmr.4792","DOIUrl":"https://doi.org/10.1002/jbmr.4792","url":null,"abstract":"<p>Due to aging of the population, bone frailty is dramatically increasing worldwide. Although some therapeutic options exist, they do not fully protect or prevent against the occurrence of new fractures. All current drugs approved for the treatment of bone fragility target bone mass. However, bone resistance to fracture is not solely due to bone mass but relies also on bone extracellular matrix (ECM) material properties, i.e., the quality of the bone matrix component. Here, we introduce the first-in-class unimolecular dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-2 (GIP/GLP-2) analogue, GL-0001, that activates simultaneously the glucose-dependent insulinotropic polypeptide receptor (GIPr) and the glucagon-like peptide-2 receptor (GLP-2r). GL-0001 acts synergistically through a cyclic adenosine monophosphate-lysyl oxidase pathway to enhance collagen maturity. Furthermore, bilateral ovariectomy was performed in 32 BALB/c mice at 12 weeks of age prior to random allocation to either saline, dual GIP/GLP-2 analogues (GL-0001 or GL-0007) or zoledronic acid groups (<i>n</i> = 8/group). Treatment with dual GIP/GLP-2 analogues was initiated 4 weeks later for 8 weeks. At the organ level, GL-0001 modified biomechanical parameters by increasing ultimate load, postyield displacement, and energy-to-fracture of cortical bone. GL-0001 also prevented excess trabecular bone degradation at the appendicular skeleton and enhanced bone ECM material properties in cortical bone through a reduction of the mineral-to-matrix ratio and augmentation in enzymatic collagen cross-linking. These results demonstrate that targeting bone ECM material properties is a viable option to enhance bone strength and opens an innovative pathway for the treatment of patients suffering from bone fragility. © 2023 The Authors. <i>Journal of Bone and Mineral Research</i> published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":"38 5","pages":"733-748"},"PeriodicalIF":6.2,"publicationDate":"2023-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jbmr.4792","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5876214","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rare and Common Variants in GALNT3 May Affect Bone Mass Independently of Phosphate Metabolism","authors":"Neelam Hassan,&nbsp;Celia L. Gregson,&nbsp;Haotian Tang,&nbsp;Marc van der Kamp,&nbsp;Paul Leo,&nbsp;Aideen M. McInerney-Leo,&nbsp;Jie Zheng,&nbsp;Maria Luisa Brandi,&nbsp;Jonathan C. Y. Tang,&nbsp;William Fraser,&nbsp;Michael D. Stone,&nbsp;Elin Grundberg,&nbsp;Anglo-Australasian Genetics Consortium,&nbsp;Matthew A. Brown,&nbsp;Emma L. Duncan,&nbsp;Jonathan H. Tobias","doi":"10.1002/jbmr.4795","DOIUrl":"https://doi.org/10.1002/jbmr.4795","url":null,"abstract":"<p>Anabolic treatment options for osteoporosis remain limited. One approach to discovering novel anabolic drug targets is to identify genetic causes of extreme high bone mass (HBM). We investigated a pedigree with unexplained HBM within the UK HBM study, a national cohort of probands with HBM and their relatives. Whole exome sequencing (WES) in a family with HBM identified a rare heterozygous missense variant (NM_004482.4:c.1657C &gt; T, p.Arg553Trp) in <i>GALNT3</i>, segregating appropriately. Interrogation of data from the UK HBM study and the Anglo-Australasian Osteoporosis Genetics Consortium (AOGC) revealed an unrelated individual with HBM with another rare heterozygous variant (NM_004482.4:c.831 T &gt; A, p.Asp277Glu) within the same gene. In silico protein modeling predicted that p.Arg553Trp would disrupt salt-bridge interactions, causing instability of GALNT3, and that p.Asp277Glu would disrupt manganese binding and consequently GALNT3 catalytic function. Bi-allelic loss-of-function <i>GALNT3</i> mutations alter FGF23 metabolism, resulting in hyperphosphatemia and causing familial tumoral calcinosis (FTC). However, bone mineral density (BMD) in FTC cases, when reported, has been either normal or low. Common variants in the <i>GALNT3</i> locus show genome-wide significant associations with lumbar, femoral neck, and total body BMD. However, no significant associations with BMD are observed at loci coding for FGF23, its receptor FGFR1, or coreceptor klotho. Mendelian randomization analysis, using expression quantitative trait loci (eQTL) data from primary human osteoblasts and genome-wide association studies data from UK Biobank, suggested increased expression of <i>GALNT3</i> reduces total body, lumbar spine, and femoral neck BMD but has no effect on phosphate concentrations. In conclusion, rare heterozygous loss-of-function variants in <i>GALNT3</i> may cause HBM without altering phosphate concentration. These findings suggest that GALNT3 may affect BMD through pathways other than FGF23 regulation, the identification of which may yield novel anabolic drug targets for osteoporosis. © 2023 The Authors. <i>Journal of Bone and Mineral Research</i> published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":"38 5","pages":"678-691"},"PeriodicalIF":6.2,"publicationDate":"2023-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jbmr.4795","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5682488","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}