Abnormal Bone Tissue Organization and Osteocyte Lacunocanalicular Network in Early‐Onset Osteoporosis Due to SGMS2 Mutations

Abstract Pathological variants in SGMS2, encoding sphingomyelin synthase 2 (SMS2), result in a rare autosomal dominant skeletal disorder with cranial doughnut lesions. The disease manifests as early‐onset osteoporosis or a more severe skeletal dysplasia with low bone mineral density, frequent fractu...

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Autores principales:	Riikka E. Mäkitie, Stéphane Blouin, Ville‐Valtteri Välimäki, Sandra Pihlström, Kirsi Määttä, Minna Pekkinen, Nadja Fratzl‐Zelman, Outi Mäkitie, Markus A. Hartmann
Formato:	article
Lenguaje:	EN
Publicado:	Wiley 2021
Materias:	BONE HISTOMORPHOMETRY CONFOCAL LASER SCANNING MICROSCOPY EARLY‐ONSET OSTEOPOROSIS QUANTITATIVE BACKSCATTERED ELECTRON IMAGING SPHINGOMYELIN METABOLISM SPHINGOMYELIN SYNTHASE 2 Orthopedic surgery RD701-811 Diseases of the musculoskeletal system RC925-935
Acceso en línea:	https://doaj.org/article/acebc817b0f14b70aa54dc378913b30f
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spelling	oai:doaj.org-article:acebc817b0f14b70aa54dc378913b30f2021-11-04T12:00:57ZAbnormal Bone Tissue Organization and Osteocyte Lacunocanalicular Network in Early‐Onset Osteoporosis Due to SGMS2 Mutations2473-403910.1002/jbm4.10537https://doaj.org/article/acebc817b0f14b70aa54dc378913b30f2021-11-01T00:00:00Zhttps://doi.org/10.1002/jbm4.10537https://doaj.org/toc/2473-4039Abstract Pathological variants in SGMS2, encoding sphingomyelin synthase 2 (SMS2), result in a rare autosomal dominant skeletal disorder with cranial doughnut lesions. The disease manifests as early‐onset osteoporosis or a more severe skeletal dysplasia with low bone mineral density, frequent fractures, long‐bone deformities, and multiple sclerotic cranial lesions. The exact underlying molecular features and skeletal consequences, however, remain elusive. This study investigated bone tissue characteristics in two adult males with a heterozygous SGMS2 mutation p.Arg50* and significant bone fragility. Transiliac bone biopsy samples from both (patient 1: 61 years; patient 2: 29 years) were analyzed by bone histomorphometry, confocal laser scanning microscopy, and quantitative backscattered electron imaging (qBEI). Bone histomorphometry portrayed largely normal values for structural and turnover parameters, but in both patient 1 and patient 2, respectively, osteoid thickness (−1.80 SD, −1.37 SD) and mineralizing surface (−1.03 SD, −2.73 SD) were reduced and osteoid surface increased (+9.03 SD, +0.98 SD), leading to elevated mineralization lag time (+8.16 SD, +4.10 SD). qBEI showed low and heterogeneous matrix mineralization (CaPeak −2.41 SD, −3.72 SD; CaWidth +7.47 SD, +4.41 SD) with a chaotic arrangement of collagenous fibrils under polarized light. Last, osteocyte lacunae appeared abnormally large and round in shape and the canalicular network severely disturbed with short‐spanned canaliculi lacking any orderliness or continuity. Taken together, these data underline a central role for functional SMS2 in bone matrix organization and mineralization, lacunocanalicular network, and in maintaining skeletal strength and integrity. These data bring new knowledge on changes in bone histology resulting from abnormal sphingomyelin metabolism and aid en route to better understanding of sphingolipid‐related skeletal disorders. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.Riikka E. MäkitieStéphane BlouinVille‐Valtteri VälimäkiSandra PihlströmKirsi MäättäMinna PekkinenNadja Fratzl‐ZelmanOuti MäkitieMarkus A. HartmannWileyarticleBONE HISTOMORPHOMETRYCONFOCAL LASER SCANNING MICROSCOPYEARLY‐ONSET OSTEOPOROSISQUANTITATIVE BACKSCATTERED ELECTRON IMAGINGSPHINGOMYELIN METABOLISMSPHINGOMYELIN SYNTHASE 2Orthopedic surgeryRD701-811Diseases of the musculoskeletal systemRC925-935ENJBMR Plus, Vol 5, Iss 11, Pp n/a-n/a (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	BONE HISTOMORPHOMETRY CONFOCAL LASER SCANNING MICROSCOPY EARLY‐ONSET OSTEOPOROSIS QUANTITATIVE BACKSCATTERED ELECTRON IMAGING SPHINGOMYELIN METABOLISM SPHINGOMYELIN SYNTHASE 2 Orthopedic surgery RD701-811 Diseases of the musculoskeletal system RC925-935
spellingShingle	BONE HISTOMORPHOMETRY CONFOCAL LASER SCANNING MICROSCOPY EARLY‐ONSET OSTEOPOROSIS QUANTITATIVE BACKSCATTERED ELECTRON IMAGING SPHINGOMYELIN METABOLISM SPHINGOMYELIN SYNTHASE 2 Orthopedic surgery RD701-811 Diseases of the musculoskeletal system RC925-935 Riikka E. Mäkitie Stéphane Blouin Ville‐Valtteri Välimäki Sandra Pihlström Kirsi Määttä Minna Pekkinen Nadja Fratzl‐Zelman Outi Mäkitie Markus A. Hartmann Abnormal Bone Tissue Organization and Osteocyte Lacunocanalicular Network in Early‐Onset Osteoporosis Due to SGMS2 Mutations
description	Abstract Pathological variants in SGMS2, encoding sphingomyelin synthase 2 (SMS2), result in a rare autosomal dominant skeletal disorder with cranial doughnut lesions. The disease manifests as early‐onset osteoporosis or a more severe skeletal dysplasia with low bone mineral density, frequent fractures, long‐bone deformities, and multiple sclerotic cranial lesions. The exact underlying molecular features and skeletal consequences, however, remain elusive. This study investigated bone tissue characteristics in two adult males with a heterozygous SGMS2 mutation p.Arg50* and significant bone fragility. Transiliac bone biopsy samples from both (patient 1: 61 years; patient 2: 29 years) were analyzed by bone histomorphometry, confocal laser scanning microscopy, and quantitative backscattered electron imaging (qBEI). Bone histomorphometry portrayed largely normal values for structural and turnover parameters, but in both patient 1 and patient 2, respectively, osteoid thickness (−1.80 SD, −1.37 SD) and mineralizing surface (−1.03 SD, −2.73 SD) were reduced and osteoid surface increased (+9.03 SD, +0.98 SD), leading to elevated mineralization lag time (+8.16 SD, +4.10 SD). qBEI showed low and heterogeneous matrix mineralization (CaPeak −2.41 SD, −3.72 SD; CaWidth +7.47 SD, +4.41 SD) with a chaotic arrangement of collagenous fibrils under polarized light. Last, osteocyte lacunae appeared abnormally large and round in shape and the canalicular network severely disturbed with short‐spanned canaliculi lacking any orderliness or continuity. Taken together, these data underline a central role for functional SMS2 in bone matrix organization and mineralization, lacunocanalicular network, and in maintaining skeletal strength and integrity. These data bring new knowledge on changes in bone histology resulting from abnormal sphingomyelin metabolism and aid en route to better understanding of sphingolipid‐related skeletal disorders. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
format	article
author	Riikka E. Mäkitie Stéphane Blouin Ville‐Valtteri Välimäki Sandra Pihlström Kirsi Määttä Minna Pekkinen Nadja Fratzl‐Zelman Outi Mäkitie Markus A. Hartmann
author_facet	Riikka E. Mäkitie Stéphane Blouin Ville‐Valtteri Välimäki Sandra Pihlström Kirsi Määttä Minna Pekkinen Nadja Fratzl‐Zelman Outi Mäkitie Markus A. Hartmann
author_sort	Riikka E. Mäkitie
title	Abnormal Bone Tissue Organization and Osteocyte Lacunocanalicular Network in Early‐Onset Osteoporosis Due to SGMS2 Mutations
title_short	Abnormal Bone Tissue Organization and Osteocyte Lacunocanalicular Network in Early‐Onset Osteoporosis Due to SGMS2 Mutations
title_full	Abnormal Bone Tissue Organization and Osteocyte Lacunocanalicular Network in Early‐Onset Osteoporosis Due to SGMS2 Mutations
title_fullStr	Abnormal Bone Tissue Organization and Osteocyte Lacunocanalicular Network in Early‐Onset Osteoporosis Due to SGMS2 Mutations
title_full_unstemmed	Abnormal Bone Tissue Organization and Osteocyte Lacunocanalicular Network in Early‐Onset Osteoporosis Due to SGMS2 Mutations
title_sort	abnormal bone tissue organization and osteocyte lacunocanalicular network in early‐onset osteoporosis due to sgms2 mutations
publisher	Wiley
publishDate	2021
url	https://doaj.org/article/acebc817b0f14b70aa54dc378913b30f
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_version_	1718444920650334208

Abnormal Bone Tissue Organization and Osteocyte Lacunocanalicular Network in Early‐Onset Osteoporosis Due to SGMS2 Mutations

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