Osteoinductive Effect of Cerebrospinal Fluid from Brain-Injured Patients

Abstract

Patients with traumatic brain injury (TBI) are predisposed to heterotopic ossification, which is believed to be due to osteoinductive factors released at the site of the brain injury. To date, little is known about the presence of such factors in human cerebrospinal fluid (CSF). This study investigated whether CSF of TBI patients is osteoinductive. In addition, known osteoinductive factors--such as bone morphogenetic protein (BMP)-2, BMP-4, and BMP-7, and S100B--were measured in CSF. Eighty-four consecutive patients were classified according to brain pathology: TBI (n = 11), non-traumatic brain pathology (NTBP) (n = 26), and no brain pathology (control group) (n = 47). The osteoinductive effect of CSF was measured repeatedly in proliferation assays using a fetal human osteoblast cell line. The mean proliferation rate (normalized to the internal negative control) of the TBI, NTBP, and control groups was 138.2% (SD 13.1), 110.0% (SD 22.1), and 118.8% (SD 16.9), respectively. The potentially confounding effect of age was investigated further by restricting the selection of patients for analysis to that of the oldest patient in the TBI group and use of multiple regression analysis. After implementation of both, it was shown that age is highly unlikely to account for the higher rates of proliferation observed among the TBI patients in this study. Of note, the TBI group had a significantly higher mean proliferation rate than the NTBP (p = 0.001) and the control group (p = 0.006). S100B and BMP-2, -4, or -7 concentrations were measured using enzyme-linked immunosorbent assay (ELISA). There was no correlation between proliferation rates and S100B (r = 0.023). Only three of 36 CSF samples had measurable levels of BMP-2 and -7, and none had detectable concentrations of BMP-4. Consequently, it is unlikely that S100B or BMP-2, -4, or -7 are the putative osteoinductive factors. The results indicate that CSF from TBI patients has an osteoinductive effect in vitro. However, the osteoinductive factor has still to be characterized.

Increased levels of calcitonin gene-related peptide in serum accelerate fracture healing following traumatic brain injury

“…Gautschi et al (11) revealed increased proliferation of osteoblastic cells and accelerated differentiation of osteoprogenitor cells using serum from TBI and fracture patients, which also strongly supports the use of a humoral mechanism in enhanced fracture-healing and the induction of heterotopic ossification following TBI. In a previous study, Gautschi et al revealed the osteoinductive potential of cerebrospinal fluid derived from TBI patients (12). In our results, CGRP staining was observed in the choroid plexus in the TBI-fracture group but not in the fracture-only and control groups.…”

BMP-9-induced muscle heterotopic ossification requires changes to the skeletal muscle microenvironment

“…Cerebrospinal fluid (CSF) has an important osteogenic effect in the hFOB cell line, (46) which suggests that a breach of the brain-blood barrier may release an osteogenic factor into the CSF that migrates to damaged muscle tissue. However, Gautschi and colleagues were unable to demonstrate by ELISA that BMP-2, -4, and -7 levels are higher in human CSF from patients suffering from traumatic brain injury and nontraumatic brain pathology than in CSF from healthy patients.…”

“…However, Gautschi and colleagues were unable to demonstrate by ELISA that BMP-2, -4, and -7 levels are higher in human CSF from patients suffering from traumatic brain injury and nontraumatic brain pathology than in CSF from healthy patients. (46) They concluded that BMPs are not present in high enough concentrations to be responsible for the osteogenic cell response that triggers HO.…”

Chiropractic Care of a Patient With Neurogenic Heterotopic Ossification of the Anterior Longitudinal Ligament After Traumatic Brain Injury: A Case Report

“…Heterotopic ossification also commonly occurs after spinal cord injuries and burns. 3,4 One study revealed that taking serum from polytraumatized patients and introducing it to osteoblasts and fibroblasts in vitro resulted in enhanced osteogenesis. 5 Heterotopic ossification may occur after trauma or surgery, but NHO is more prevalent in high-energy combat-related injuries of military service members.…”