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BACKGROUND: Traumatic brain injury is associated with an increased rate of heterotopic ossification within skeletal muscle, possibly as a result of humoral factors. In this study, we investigated whether cells from skeletal muscle adopt an osteoblastic phenotype in response to serum from patients with traumatic brain injury. METHODS: Serum was collected from thirteen patients with severe traumatic brain injury, fourteen patients with a long-bone fracture, and ten control subjects. Primary cultures of skeletal muscle cells isolated from patients undergoing orthopaedic surgery were performed and characterized with use of immunofluorescence microscopy, reverse transcription-polymerase chain reaction, and Western blot analysis. Proliferation and osteoblastic differentiation were assessed with use of commercial cell assays, Western blot analysis (for Osterix protein), and the Villanueva bone stain. RESULTS: All serum-treated cell populations expressed the osteoblast marker Osterix after one week in culture. Cells treated with serum from all study groups in mineralization medium had increased alkaline phosphatase activity and mineralized nodules within the mesenchymal cell subpopulation after three weeks in culture. Serum from patients with traumatic brain injury induced a significant increase (p = 0.02) in the rate of proliferation of primary skeletal muscle cells (1.87 [95% confidence interval, 1.66 to 2.09]) compared with the rate induced by serum from patients with a fracture (1.42 [95% confidence interval, 1.21 to 1.58]) or by serum from controls (1.35 [95% confidence interval, 1.15 to 1.54]). CONCLUSIONS: Human serum supports the osteoblastic differentiation of cells derived from human skeletal muscle, and serum from patients with severe traumatic brain injury accelerates proliferation of these cells. These findings suggest the early presence of humoral factors following traumatic brain injury that stimulate the expansion of mesenchymal cells and osteoprogenitors within skeletal muscle. CLINICAL RELEVANCE: A better understanding of the pathophysiological mechanisms that lead to the formation of heterotopic ossification in patients with a traumatic brain injury may be helpful in the prevention and treatment of this complication.