Three-dimensional EOS Analysis of Apical Vertebral Rotation in Adolescent Idiopathic Scoliosis.

BACKGROUND: Apical vertebral rotation (AVR) is increasingly recognized as one of the important radiographic parameters in adolescent idiopathic scoliosis (AIS). EOS enables us to precisely measure AVR by 3-dimensional reconstruction. The objective of the present study was to describe the postoperative correction and the long-term follow-up of AVR in posterior spinal fusion with direct vertebral rotation and elucidate the factors that affected the correction. METHODS: We retrospectively reviewed 153 consecutive posterior spinal fusion surgeries for AIS performed between 2009 and 2012. Among them, 55 patients who fulfilled the study inclusion criteria with complete preoperative, immediate postoperative, and last follow-up (>1 y) EOS images were included in the present study. EOS 3-dimentional reconstructions were undertaken for each patient. Postoperative AVR correction and the loss of correction were calculated. RESULTS: Preoperative AVR of the major curve averaged 19 degrees (SD=7 degrees), and AVR on immediate postoperative images averaged 9 degrees (SD=6 degrees, P<0.001). AVR at final follow-up averaged 11 degrees (SD=6 degrees, P=0.06). Postoperative correction was larger in all-screw construct than in hybrid construct (55% vs. 36%, P=0.03). CONCLUSIONS: The present study is the first study to measure AVR in a large population of AIS patients using EOS 3-dimensional reconstruction. We report the correction magnitude was significantly affected by the construct. LEVEL OF EVIDENCE: Level IV-therapeutic study (case series).

Bacterial Lipopolysaccharides Exacerbate Neurogenic Heterotopic Ossification Development.

Neurogenic heterotopic ossifications (NHO) are heterotopic bones that develop in periarticular muscles after severe central nervous system (CNS) injuries. Several retrospective studies have shown that NHO prevalence is higher in patients who suffer concomitant infections. However, it is unclear whether these infections directly contribute to NHO development or reflect the immunodepression observed in patients with CNS injury. Using our mouse model of NHO induced by spinal cord injury (SCI) between vertebrae T11 to T13 , we demonstrate that lipopolysaccharides (LPS) from gram-negative bacteria exacerbate NHO development in a toll-like receptor-4 (TLR4)-dependent manner, signaling through the TIR-domain-containing adapter-inducing interferon-ß (TRIF/TICAM1) adaptor rather than the myeloid differentiation primary response-88 (MYD88) adaptor. We find that T11 to T13 SCI did not significantly alter intestinal integrity nor cause intestinal bacteria translocation or endotoxemia, suggesting that NHO development is not driven by endotoxins from the gut in this model of SCI-induced NHO. Relevant to the human pathology, LPS increased expression of osteoblast markers in cultures of human fibro-adipogenic progenitors isolated from muscles surrounding NHO biopsies. In a case-control retrospective study in patients with traumatic brain injuries, infections with gram-negative Pseudomonas species were significantly associated with NHO development. Together these data suggest a functional association between gram-negative bacterial infections and NHO development and highlights infection management as a key consideration to avoid NHO development in patients. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Local and Systemic Factors Drive Ectopic Osteogenesis in Regenerating Muscles of Spinal-Cord-Injured Mice in a Lesion-Level-Dependent Manner.

Neuroimmune dysfunction is thought to promote the development of several acute and chronic complications in spinal cord injury (SCI) patients. Putative roles for adrenal stress hormones and catecholamines are increasingly being recognized, yet how these adversely affect peripheral tissue homeostasis and repair under SCI conditions remains elusive. Here, we investigated their influence in a mouse model of SCI with acquired neurogenic heterotopic ossification. We show that spinal cord lesions differentially influence muscular regeneration in a level-dependent manner and through a complex multi-step process that creates an osteopermissive environment within the first hours of injury. This cascade of events is shown to critically involve adrenergic signals and drive the acute release of the neuropeptide, substance P. Our findings generate new insights into the kinetics and processes that govern SCI-induced deregulations in skeletal muscle homeostasis and regeneration, thereby aiding the development of sequential therapeutic strategies that can prevent or attenuate neuromusculoskeletal complications in SCI patients.

Peripheral denervation participates in heterotopic ossification in a spinal cord injury model.

We previously reported the development of a new acquired neurogenic HO (NHO) mouse model, combining spinal cord transection (SCI) and chemical muscle injury. Pathological mechanisms responsible for ectopic osteogenesis after central neurological damage are still to be elucidated. In this study, we first hypothesized that peripheral nervous system (PNS) might convey pathological signals from injured spinal cord to muscles in NHO mouse model. Secondly, we sought to determine whether SCI could lead to intramuscular modifications of BMP2 signaling pathways. Twenty one C57Bl6 mice were included in this protocol. Bilateral cardiotoxin (CTX) injection in hamstring muscles was associated with a two-stage surgical procedure, combining thoracic SCI with unilateral peripheral denervation. Volumes of HO (Bone Volume, BV) were measured 28 days after surgery using micro-computed tomography imaging techniques and histological analyses were made to confirm intramuscular osteogenesis. Volume comparisons were conducted between right and left hind limb of each animal, using a Wilcoxon signed rank test. Quantitative polymerase chain reaction (qPCR) was performed to explore intra muscular expression of BMP2, Alk3 and Id1. Nineteen mice survive the complete SCI and peripheral denervation procedure. When CTX injections were done right after surgery (n = 7), bilateral HO were detected in all animals after 28 days. Micro-CT measurements showed significantly increased BV in denervated paws (1.47 mm3 +/- 0.5) compared to contralateral sides (0.56 mm3 +/-0.4), p = 0.03. When peripheral denervation and CTX injections were performed after sham SCI surgery (n = 6), bilateral HO were present in three mice at day 28. Quantitative PCR analyses showed no changes in intra muscular BMP2 expression after SCI as compared to control mice (shamSCI). Peripheral denervation can be reliably added to spinal cord transection in NHO mouse model. This new experimental design confirms that neuro inflammatory mechanisms induced by central or peripheral nervous system injury plays a key role in triggering ectopic osteogenesis.

Macrophage-derived oncostatin M contributes to human and mouse neurogenic heterotopic ossifications.

Neurogenic heterotopic ossification (NHO) is the formation of ectopic bone generally in muscles surrounding joints following spinal cord or brain injury. We investigated the mechanisms of NHO formation in 64 patients and a mouse model of spinal cord injury-induced NHO. We show that marrow from human NHOs contains hematopoietic stem cell (HSC) niches, in which mesenchymal stromal cells (MSCs) and endothelial cells provide an environment supporting HSC maintenance, proliferation, and differentiation. The transcriptomic signature of MSCs from NHOs shows a neuronal imprinting associated with a molecular network required for HSC support. We demonstrate that oncostatin M (OSM) produced by activated macrophages promotes osteoblastic differentiation and mineralization of human muscle-derived stromal cells surrounding NHOs. The key role of OSM was confirmed using an experimental model of NHO in mice defective for the OSM receptor (OSMR). Our results provide strong evidence that macrophages contribute to NHO formation through the osteogenic action of OSM on muscle cells within an inflammatory context and suggest that OSM/OSMR could be a suitable therapeutic target. Altogether, the evidence of HSCs in ectopic bones growing at the expense of soft tissue in spinal cord/brain-injured patients indicates that inflammation and muscle contribute to HSC regulation by the brain-bone-blood triad.

Recurrence of heterotopic ossification after removal in patients with traumatic brain injury: A systematic review.

OBJECTIVE: A systematic review of the literature to determine whether in patients with neurological heterotopic ossification (NHO) after traumatic brain injury, the extent of the neurological sequelae, the timing of surgery and the extent of the initial NHO affect the risk of NHO recurrence. DATA SOURCES: We searched MEDLINE via PubMed and Cochrane library for articles published up to June 2015. Results were compared with epidemiological studies using data from the BANKHO database of 357 patients with central nervous system (CNS) lesions who underwent 539 interventions for troublesome HO. RESULTS: A large number of studies were published in the 1980s and 1990s, most showing poor quality despite being performed by experienced surgical teams. Accordingly, results were contradictory and practices heterogeneous. Results with the BANKHO data showed troublesome NHO recurrence not associated with aetiology, sex, age at time of CNS lesion, multisite HO, or "early" surgery (before 6months). Equally, recurrence was not associated with neurological sequelae or disease extent around the joint. CONCLUSIONS: The recurrence of NHO is not affected by delayed surgery, neurological sequelae or disease extent around the joint. Surgical excision of NHO should be performed as soon as comorbid factors are under control and the NHO is sufficiently constituted for excision.