Upregulation of Inflammatory Genes and Downregulation of Sclerostin Gene Expression Are Key Elements in the Early Phase of Fragility Fracture Healing

Abstract

BackgroundFracture healing is orchestrated by a specific set of events that culminates in the repair of bone and reachievement of its biomechanical properties. The aim of our work was to study the sequence of gene expression events involved in inflammation and bone remodeling occurring in the early phases of callus formation in osteoporotic patients.Methodology/Principal FindingsFifty-six patients submitted to hip replacement surgery after a low-energy hip fracture were enrolled in this study. The patients were grouped according to the time interval between fracture and surgery: bone collected within 3 days after fracture (n = 13); between the 4th and 7th day (n = 33); and after one week from the fracture (n = 10). Inflammation- and bone metabolism-related genes were assessed at the fracture site. The expression of pro-inflammatory cytokines was increased in the first days after fracture. The genes responsible for bone formation and resorption were upregulated one week after fracture. The increase in RANKL expression occurred just before that, between the 4th–7th days after fracture. Sclerostin expression diminished during the first days after fracture.ConclusionsThe expression of inflammation-related genes, especially IL-6, is highest at the very first days after fracture but from day 4 onwards there is a shift towards bone remodeling genes, suggesting that the inflammatory phase triggers bone healing. We propose that an initial inflammatory stimulus and a decrease in sclerostin-related effects are the key components in fracture healing. In osteoporotic patients, cellular machinery seems to adequately react to the inflammatory stimulus, therefore local promotion of these events might constitute a promising medical intervention to accelerate fracture healing.

IL-6 Enhances Osteocyte-Mediated Osteoclastogenesis by Promoting JAK2 and RANKL Activity In Vitro

“…A previous study confirmed that IL-6, TNF-α (Tumour Necrosis Factor α), and IL-1β (Interleukin-1β) contribute to bone remodelling in the early stage during fracture healing, and activated bone remodelling also appears after fracture surgery [1]. Bone remodelling is maintained by osteoblasts, osteocytes, and osteoclasts, which are regulated by inflammatory factors and hormones [2].…”

Parathyroid hormone-related protein (107-111) improves the bone regeneration potential of gelatin–glutaraldehyde biopolymer-coated hydroxyapatite

“…Of note, the putative PTHrP (107-139) fragment has been reported to decrease the expression of both genes in bone after its systemic administration for 4 weeks to ovariectomized mice, and also in rat osteoblastic UMR-106 cells [21]. Moreover, Sost downregulation has been shown to be an important event in the early phase of fracture healing in humans [43]. Furthermore, a previous study demonstrates that systemic or local injection of a DKK1 adenovirus hampered cortical defect healing in the mouse tibial diaphysis [36].…”

Unraveling macrophage contributions to bone repair

“…In patients with hip fractures, high levels of macrophage-related cytokines including interleukin-1, interleukin-6 and tumor necrosis factor (TNF) have been detected within the first few days after injury. 32 In a mouse model of fracture, interleukin-1 and TNF were localized predominately to macrophages and inflammatory cells in the marrow and periosteum adjacent to fracture sites. 31 In mouse models of fracture in which recruitment of inflammatory macrophages 28 or inflammatory cytokine signaling [33][34][35] was compromised through germline genetic alterations, there were prolonged negative impacts on fracture healing.…”