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

Riikka E Mäkitie; Stéphane Blouin; Ville-Valtteri Välimäki; Sandra Pihlström; Kirsi Määttä; Minna Pekkinen; Nadja Fratzl-Zelman; Outi Mäkitie; Markus A Hartmann

doi:10.1002/jbm4.10537

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

JBMR Plus. 2021 Aug 20;5(11):e10537. doi: 10.1002/jbm4.10537. eCollection 2021 Nov.

Authors

Riikka E Mäkitie^{1

2

3}, Stéphane Blouin^{4

5}, Ville-Valtteri Välimäki⁶, Sandra Pihlström^{1

2}, Kirsi Määttä^{1

2}, Minna Pekkinen^{1

2

7}, Nadja Fratzl-Zelman^{4

5}, Outi Mäkitie^{1

2

7

8}, Markus A Hartmann^{4

5}

Affiliations

¹ Folkhälsan Institute of Genetics Helsinki Finland.
² Research Program for Clinical and Molecular Metabolism, Faculty of Medicine University of Helsinki Helsinki Finland.
³ Department of Otorhinolaryngology-Head and Neck Surgery Helsinki University Hospital and University of Helsinki Helsinki Finland.
⁴ Ludwig Boltzmann Institute of Osteology at Hanusch Hospital of OEGK and AUVA Trauma Centre Meidling, 1st Medical Department Hanusch Hospital Vienna Austria.
⁵ Vienna Bone and Growth Center Vienna Austria.
⁶ Pohjola Hospital Helsinki Finland.
⁷ Children's Hospital, University of Helsinki and Helsinki University Hospital Helsinki Finland.
⁸ Department of Molecular Medicine and Surgery and Center for Molecular Medicine Karolinska Institutet Stockholm Sweden.

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.

Keywords: BONE HISTOMORPHOMETRY; CONFOCAL LASER SCANNING MICROSCOPY; EARLY‐ONSET OSTEOPOROSIS; QUANTITATIVE BACKSCATTERED ELECTRON IMAGING; SPHINGOMYELIN METABOLISM; SPHINGOMYELIN SYNTHASE 2.