T Rolvien1, T A Yorgan2, U Kornak3, I Hermans-Borgmeyer4, S Mundlos3, T Schmidt2, A Niemeier5, T Schinke2, M Amling2, R Oheim2. 1. Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Lottestr. 59, 22529, Hamburg, Germany; Department of Orthopedics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Electronic address: t.rolvien@uke.de. 2. Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Lottestr. 59, 22529, Hamburg, Germany. 3. Institute of Medical Genetics and Human Genetics, Charité-Universitätsmedizin Berlin, Berlin, Germany; Berlin-Brandenburg School for Regenerative Therapies, Charité-Universitätsmedizin Berlin, Berlin, Germany; Max Planck Institute for Molecular Genetics, FG Development and Disease, Berlin, Germany. 4. Center for Molecular Neurobiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 5. Department of Orthopedics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Abstract
OBJECTIVE: Spondyloepiphyseal dysplasia, a combination of progressive arthropathy with variable signs of skeletal dysplasia, can be a result of mutations in the collagen, type II, alpha 1 (COL2A1) gene. However, the bone involvement (e.g., density, microstructure) in this disorder has hitherto not been studied. DESIGN: A 50-year-old female patient and her 8-year-old son with flattening of vertebral bodies and early-onset osteoarthritis were genetically tested using a custom designed gene bone panel including 386 genes. Bone microstructure and turnover were assessed using high-resolution peripheral quantitative computed tomography (HR-pQCT) and serum bone turnover markers, respectively. Furthermore, the bone and cartilage phenotype of male mice heterozygous for the loss-of-function mutation of Col2a1 (Col2a1+/d) was analyzed compared to wildtype littermates using μ-CT and histomorphometry. RESULTS: We identified a dominant COL2A1 mutation (c.620G > A p.(Gly207Glu)) indicating spondyloepiphyseal dysplasia in the female patient and her son, both being severely affected by skeletal deterioration. Although there was no osteoarthritis detectable at first visit, the son was affected by trabecular osteopenia, which progressed over time. In an iliac crest biopsy obtained from the mother, osteoclast indices were remarkably increased. Col2a1+/d mice developed a moderate skeletal phenotype expressed by reduced cortical and trabecular parameters at 4 weeks. Importantly, no articular defects could be observed in the knee joints at 4 weeks, while osteoarthritis was only detectable in 12-week-old mice. CONCLUSIONS: Our results indicate that collagen type II deficiency in spondyloepiphyseal dysplasia leads to skeletal deterioration with early-onset in humans and mice that occurs prior to the development of osteoarthritis.
OBJECTIVE:Spondyloepiphyseal dysplasia, a combination of progressive arthropathy with variable signs of skeletal dysplasia, can be a result of mutations in the collagen, type II, alpha 1 (COL2A1) gene. However, the bone involvement (e.g., density, microstructure) in this disorder has hitherto not been studied. DESIGN: A 50-year-old female patient and her 8-year-old son with flattening of vertebral bodies and early-onset osteoarthritis were genetically tested using a custom designed gene bone panel including 386 genes. Bone microstructure and turnover were assessed using high-resolution peripheral quantitative computed tomography (HR-pQCT) and serum bone turnover markers, respectively. Furthermore, the bone and cartilage phenotype of male mice heterozygous for the loss-of-function mutation of Col2a1 (Col2a1+/d) was analyzed compared to wildtype littermates using μ-CT and histomorphometry. RESULTS: We identified a dominant COL2A1 mutation (c.620G > A p.(Gly207Glu)) indicating spondyloepiphyseal dysplasia in the female patient and her son, both being severely affected by skeletal deterioration. Although there was no osteoarthritis detectable at first visit, the son was affected by trabecular osteopenia, which progressed over time. In an iliac crest biopsy obtained from the mother, osteoclast indices were remarkably increased. Col2a1+/dmice developed a moderate skeletal phenotype expressed by reduced cortical and trabecular parameters at 4 weeks. Importantly, no articular defects could be observed in the knee joints at 4 weeks, while osteoarthritis was only detectable in 12-week-old mice. CONCLUSIONS: Our results indicate that collagen type II deficiency in spondyloepiphyseal dysplasia leads to skeletal deterioration with early-onset in humans and mice that occurs prior to the development of osteoarthritis.
Authors: Lucia Oton-Gonzalez; Chiara Mazziotta; Maria Rosa Iaquinta; Elisa Mazzoni; Riccardo Nocini; Lorenzo Trevisiol; Antonio D'Agostino; Mauro Tognon; John Charles Rotondo; Fernanda Martini Journal: Int J Mol Sci Date: 2022-01-28 Impact factor: 5.923