Erik A. Imel

Lothar Seefried

Nathalie Bravenboer

Frontiers in Endocrinology

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Frontiers in EndocrinologyOPEN ACCESSEDITED AND REVIEWED BYJonathan H Tobias,University of Bristol, United Kingdom*CORRESPONDENCELothar Seefriedl-seefried.klh@uni-wuerzburg.deRECEIVED 02 May 2023ACCEPTED 05 May 2023PUBLISHED 24 May 2023CITATIONSeefried L, Bravenboer N and Imel EA(2023) Editorial: Rare musculoskeletaldisorders: disease mechanismsand therapies.Front. Endocrinol. 14:1215941.doi: 10.3389/fendo.2023.1215941COPYRIGHT© 2023 Seefried, Bravenboer and Imel. Thisis an open-access article distributed underthe terms of the Creative CommonsAttribution License (CC BY). The use,distribution or reproduction in otherforums is permitted, provided the originalauthor(s) and the copyright owner(s) arecredited and that the original publication inthis journal is cited, in accordance withaccepted academic practice. No use,distribution or reproduction is permittedwhich does not comply with these terms.TYPE EditorialPUBLISHED 24 May 2023DOI 10.3389/fendo.2023.1215941Editorial: Rare musculoskeletaldisorders: disease mechanismsand therapiesLothar Seefried1*, Nathalie Bravenboer2 and Erik A. Imel31Department of Osteology, Julius Maximilian University of Würzburg, Würzburg, Germany,2Department of Clinical Chemistry, Vrije Universiteit Medical Center, Amsterdam University,Amsterdam, Netherlands, 3Department of Medicine and Pediatrics, Indiana University School ofMedicine, Indianapolis, IN, United StatesKEYWORDSosteogenesis imperfecta, X-linked hypophosphataemia (XLH), ANO5 gene, rare skeletaldisorders, bone diseasesEditorial on the Research TopicRare musculoskeletal disorders: disease mechanisms and therapiesAlong with our continuously growing understanding of rare musculoskeletal disordersover recent years, clinical care concepts for affected patients could be refined and amendedincluding novel, pharmacological compounds. Thanks to ongoing scientific effortsregarding both basic sciences and clinical research in rare musculoskeletal disorders,further advances and deeper insights into disease mechanisms can be expected, paving theway for more innovative, purposive treatments. It is thus with great pleasure that we inviteyou to read the valuable contributions authors have made to this Research Topic, providingcurrent perspectives on various conditions which are contemporarily in focus with regardsto better understanding disease mechanisms as well as improving concepts for clinical care.Building on hospital admission data derived from a Nationwide Registry Study in theNetherlands, Storoni et al. report on the incidence, morbidity and mortality of patients withOsteogenesis Imperfecta (OI). Overseeing data of 674 OI patients, the authors calculated anannual birth incidence rate for OI at 6.5 per 100,000 live births which is slightly lower thanwhat has been reported previously. The analysis revealed that patients with OI had onaverage 2.9 times higher hospitalization rate as compared to the general Dutch population.Specifically in the youngest patients (<20 years), the hospitalization rate ratio was as high as8.4. In that regard, both OI type and severity appear to have an impact on extraskeletalmanifestations, which play a key role in the hospital admissions. Based on the fact that thepercentage of patients over 65 years is 2.7 times lower than in the general population, theauthors infer that life expectancy is substantially reduced in OI patients. Based on thesedeficits, more awareness is needed to better understand impact of OI on patients’ lifeexpectancy, health care burden, and to improve strategies for clinical care.Analogously, the importance of looking beyond mere bone manifestations alsobecomes evident from in the manuscript on the impact of muscular symptoms and/orpain in adult patients with hypophosphatasia (HPP) authored by Dahir et al. Building ondata from the global HPP registry, this cross-sectional analysis compared 300 patients withdocumented skeletal manifestation and 73 patients experiencing muscular symptoms and/or pain without any overt bone issues of the disease. While those with a leading bonefrontiersin.org01Seefried et al. 10.3389/fendo.2023.1215941manifestation had a lower median age at first HPP manifestation(12.3 vs 22.1 years), more signs and symptoms of the disease, and ahigher proportion of patients requiring mobility aids (22.6% vs3.5%), there weren’t any obvious differences between these groupsregarding their functional and self-perceived limitations.Specifically the results attained in the Six-Minute Walk test andthe SF-36v2 and HAQ-DI scores were similar between both groups,eventually confirming that impaired quality of life in HPP has acomplex background and is largely independent of skeletalinvolvement. It is not yet known to what extent asfotase alfatreatment could address the symptomatology of patients withoutovert bone manifestations, which was not adressed in this paper.A readily comprehensible mechanism how a skeletal dysplasiacan impact functional outcomes and eventually quality of life comesfrom the functional and structural analyses of the ankle joints of 23adolescent and young adult patients (16-50 years) with X-linkedHypophosphatemia (XLH) performed by Akta et al. The patientreported outcome measures, specifically SF36 and the WOMACscore, confirmed self-perceived functional deficits in these patients,which was paralleled by a significantly reduced gait quality, anklepower and plantar flexion when compared to a historic, unaffectedcontrol group. Even in these adolescent and young to middle-ageadult patients, the authors observed joint space narrowing alongwith a decreased range of motion and diminished power. Ankledeformities – both varus (30%) and valgus (22%) – were seen in>50% of the patients and were most likely attributable to theunderlying mineralization disorder, while no ligamentousinstabilities were detected.The pathophysiological complexity behind XLH and the pivotalrole of the osteocyte in its manifestations is concisely summarizedin the respective review manuscript by Miwa Yamazaki andMichigami. Starting with the impact of elevated osteocyte-derivedFibroblast Growth Factor 23 (FGF23) on impairing phosphatehomeostasis by increasing the renal excretion of inorganicphosphate (Pi) and decreasing the production of 1,25-dihydroxyvitamin D, the authors enlarge on the mechanisms howgenetic variants not only in PHEX but also in DMP-1, ENPP1 andFAM20C can boost the osteocyte production of FGF23. Further, theauthors collate available evidence on the involvement of the FGF-Receptor 1, how Pi sensing in osteocytes may be altered in thesediseases and why levels of sclerostin, another osteocyte derivedfactor and potent Wnt/b-catenin signaling inhibitor may beinvolved in that regulatory process.Adding to our growing understanding of how genetic alterationsin single genes eventually change the transcriptional and metabolicsignature of bone cells to eventually cause the skeletal phenotypewe’re seeing in clinical practice, Li et al., provide data on how aspecific missense variant in Ano5 results in enhanced osteogenesisUsing their previously established p.Cys360Tyr knock-in mousemodel, the authors analyzed the metabolomic and transcriptomicprofile of wildtype (Ano5+/+) and Ano5KI/KI mature mousecalvarial osteoblasts (mCOBs) in vitro. Their transcriptomicanalysis revealed 407 differentially expressed genes in Ano5KI/KIosteoblasts compared with wildtype and they identified 42 differentialFrontiers in Endocrinology 02metabolites involved in amino acid and pyrimidine metabolism,endocrine mechanisms and calcium reabsorption. Validationexperiments using qRT-PCR and CCK-8 assays largely confirmedthat Ano5KI/KI interferes with cell cycle regulating genes (Mki67,Ccnb1, and Ccna2) and calcium signaling pathways, which could bedemonstrated to cause higher calcium content in mineral nodulesthan Ano5+/+ mCOBs, paralleled by an upregulation of osteocalcin,an osteoblast-derived metabolic hormone.Rare musculoskeletal disorders represent a broad array ofphenotypes and mechanisms, affecting patients from birththrough adulthood. The manuscripts in this section furtherhighlight the breadth of research that needs to be conducted tofurther advance our understanding of these disorders, frommolecularmechanisms to skeletal structural and joint abnormalities,impairments in mobility and quality of life, health care burden andin some cases influencing life expectancy. The wide range of aspectscovered in these above publications renders this Research Topicparticularly insightful and we hope these inspire follow-up studiesbuilding on the valuable contributions these authors havemade.Withthat said, we thank all authors for their contribution and we hope allreaders will experience the same level of joy and excitement we hadwhen collating the manuscripts for this Research Topic.Author contributionsAll authors listed have made a substantial, direct, andintellectual contribution to the work and approved itfor publication.Conflict of interestLS received honoraria for lectures and advice from AstraZeneca/Alexion, Amgen, Chiesi, Gedeon-Richter, GlaxoSmithKline,Inozyme, Ipsen, KyowaKirin, medi, STADA, Theramex and UCBand support for scientific projects to the institution fromAstraZeneca/Alexion, Chiesi, KyowaKirin and Novartis. EAIreceived research funding from Ultragenyx, Kyowa Kirin, Amgen,Sanofi, Calciolytix, and has received honoraria for advising orconsulting fees from Kyowa Kirin, Ultragenyx, Inozyme, and Agios.The remaining author declares that the research was conductedin the absence of any commercial or financial relationships thatcould be construed as a potential conflict of interest.Publisher’s noteAll claims expressed in this article are solely those of the authorsand do not necessarily represent those of their affiliatedorganizations, or those of the publisher, the editors and thereviewers. Any product that may be evaluated in this article, orclaim that may be made by its manufacturer, is not guaranteed orendorsed by the publisher.frontiersin.org

Editorial: Rare musculoskeletal disorders: disease mechanisms and therapies

Seefried, Lothar

Bravenboer, Nathalie

Imel, Erik A.

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https://www.frontiersin.org/articles/10.3389/fendo.2023.1215941/pdf

Editorial: Rare musculoskeletal disorders: disease mechanisms and therapies

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