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.
Highlights
I n recent years, several new forms of monogenic osteoporosis have been identified, each contributing to our understanding of the genetic factors and molecular pathomechanisms governing skeletal health.[1]. In 2019, we identified mutations in sphingomyelin synthase 2 (SGMS2), encoding SMS2, to cause a previously clinically described disorder—osteoporosis with calvarial doughnut lesions (OP-CDL; OMIM #126550).(2) Depending on the underlying SGMS2 variant, affected subjects present
Sphingomyelin (SM) is an essential structural component in the plasma membrane, and the catalytic role of SMS2 in the phosphate-yielding sphingolipid metabolism suggests a key role in matrix mineralization.[2,3] Our previous basic histomorphometric evaluation of patients’ bone biopsy samples depicted an overall decrease in bone volume with a disorganized collagenous network, overall reduced mineral content, and increased heterogeneity in matrix mineralization.[2] the findings suggested increased osteoclast numbers, further functional analyses found no differences in osteoclast morphology or their resorptive capacity.[2]. Sgms2 was highly expressed in osteoblasts and osteoclasts in murine cortical bone
We have expanded the characterization of the tissue-level bone pathology in patients with primary osteoporosis due to a pathogenic variant in the SGMS2 gene
Summary
I n recent years, several new forms of monogenic osteoporosis have been identified, each contributing to our understanding of the genetic factors and molecular pathomechanisms governing skeletal health.[1]. Sphingomyelin (SM) is an essential structural component in the plasma membrane, and the catalytic role of SMS2 in the phosphate-yielding sphingolipid metabolism suggests a key role in matrix mineralization.[2,3] Our previous basic histomorphometric evaluation of patients’ bone biopsy samples depicted an overall decrease in bone volume with a disorganized collagenous network, overall reduced mineral content, and increased heterogeneity in matrix mineralization.[2] the findings suggested increased osteoclast numbers, further functional analyses found no differences in osteoclast morphology or their resorptive capacity.[2] Sgms was highly expressed in osteoblasts and osteoclasts in murine cortical bone In light of these results and the patients’ clinical manifestations, we concluded that sphingolipid metabolism has an evident role in bone health and its disturbance a damaging effect on bone material properties. The results reveal severe material defects in bone matrix mineralization, osteocyte orientation and the canalicular network
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
