Spinal ligament ossification is a frequently observed phenomenon stemming from progressive calcification of ligaments surrounding the spinal column. While the causes and severity vary amongst patients, it can lead to spinal canal stenosis, resulting in symptoms reminiscent of spinal cord injury or myelopathy. Consequently, drug treatment or corrective surgery is usually indicated in these patients. To date, the pathogenesis of spinal ligament ossification is still unclear. We previously showed the existence of mesenchymal stem cells (MSCs) in these ossified ligaments [1]. Building on these findings, here we sought to identify the source of MSCs in ossified (OLF) and non-ossified ligament flavum (non-OLF) from thoracic vertebrae.We found that MSCs were localized to blood vessel perivascular regions and within the collagenous matrix of spinal ligament sections, with a higher prevalence of MSCs and neovascularization found in OLF tissues than in non-OLF tissues. In addition, MSCs colocalized with markers of pericytes, not endothelial cells. In OLF tissues, chondrocytes at the ossification front also expressed MSC-specific markers. Together, these results suggest that MSCs may be involved in chondrocyte differentiation and/or endochondral ossification during the pathogenesis of OLF.Understanding stem cell involvement in the progression of various diseases is becoming an important consideration in tissue repair and regeneration. The link between stem cells and the progression of spinal ligament ossification will provide important insight into the treatment of spinal diseases. As such, we believe that our manuscript will be of significance to the broad readership of Biochemical and Biophysical Research Communications, particularly those in the stem cell field.We confirm that this manuscript has not been published elsewhere and is not under consideration by another journal.
After osteogenic induction, BMP-2 expression increased in the OPLL continuous and segmental groups. Osterix expression increased in the OPLL continuous group only. Tumor necrosis factor-α-stimulated gene-6 expression was suppressed in the OPLL continuous and segmental groups. ALP expression as well as ALP activity staining was higher in the OPLL continuous group than in the OPLL segmental group. CONCLUSION.: The study revealed genetic differences in the osteogenic differentiation potency between the OPLL continuous and segmental groups. We propose to distinguish OPLL continuous group from segmental group in biochemical studies on OPLL.
Study Design.Basic experiments in a mouse model of ossification of the posterior longitudinal ligament (OPLL).Objective.To assess the osteogenic potential of mesenchymal stem cells (MSCs) obtained from muscle and adipose tissue in Tiptoe-walking (ttw) mice, in which cervical OPLL compresses the spinal cord and causes motor and sensory dysfunction.Summary of Background Data.In humans, MSCs have been implicated in the pathogenesis of cervical OPLL. Cervical OPLL in ttw mice causes chronic compression of the spinal cord. Few studies have compared the MSC osteogenic potential with behavioral changes in an OPLL animal model.Methods.We compared the osteogenic potential and behavioral characteristics of MSCs from ttw mice (4 to 20 weeks old) with those from control wild-type mice (without hyperostosis). Ligament ossification was monitored by micro-computed tomography and pathology; tissues were double stained with fluorescent antibodies against markers for MSCs (CD45 and CD105), at 8 weeks. The Basso Mouse Scale was used to assess motor function, and heat and mechanical tests to assess sensory function. The osteogenic potential of adipose and muscle MSCs was assessed by Alizarin Red S absorbance, staining for osteogenic mineralization, and real-time quantitative polymerase chain reaction for osteogenesis-related genes.Results.Spinal-ligament ossification began in ttw mice at 8 weeks of age, and the ossified area increased with age. Immunofluorescence staining identified MSCs in the ossification area. The ttw mice became hyposensitive at 8 weeks of age, and Basso Mouse Scale scores showed motor-function deficits starting at 12 weeks of age. Alizarin Red S staining for mineralization showed a higher osteogenic potential in the adipose- and muscle-derived MSCs from ttw mice than from wild-type mice at 4, 8, and 20 weeks of age. Real-time quantitative polymerase chain reaction showed that ttw MSCs strongly expressed osteogenesis-related genes.Conclusion.MSCs derived from muscle and adipose tissue in ttw mice had a high osteogenic potential.Level of Evidence: N/A
Ectopic bone formation is thought to be responsible for ossification of the posterior longitudinal ligament of the spine (OPLL). Mesenchymal stem cells (MSCs) were isolated from spinal ligaments and shown to play a key role in the process of ectopic ossification. The purpose of this study was to explore the capacity of these MSCs to undergo lineage commitment and to assess the gene expression changes between these committed and uncommitted MSCs between OPLL and non-OPLL patients. Spinal ligament-derived cells were obtained from OPLL patients or patients with cervical spondylotic myelopathy (non-ossified) for comparison (n=8 in each group). MSCs from the two patient cohorts were evaluated for changes in colony forming ability; osteogenic, adipogenic and chondrogenic differentiation potential; and changes in gene expression following induction with lineage-specific conditions. We show that the osteogenic differentiation potential was significantly higher in MSCs from OPLL patients than in those from non-OPLL patients. In addition, alkaline phosphatase activity and several osteogenic-related genes expressions (bone morphogenetic protein 2, runt-related transcription factor 2 and alkaline phosphatase) were significantly higher in the OPLL group than in the non-OPLL group. However, single cell cloning efficiency, adipogenic and chondrogenic differentiation, and the expression of adipogenic and 2 chondrogenic-related genes were equivalent between MSCs harvested from OPLL and non-OPLL patient samples. These findings suggest an increase in the osteogenic differentiation potential of MSCs from OPLL patients and that this propensity toward the osteogenic lineage may be a causal factor in the ossification in these ligaments.
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