Modulation of the Inflammatory Response and Bone Healing

Abstract

The optimal treatment for complex fractures and large bone defects is an important unsolved issue in orthopedics and related specialties. Approximately 5-10% of fractures fail to heal and develop non-unions. Bone healing can be characterized by three partially overlapping phases: the inflammatory phase, the repair phase, and the remodeling phase. Eventual healing is highly dependent on the initial inflammatory phase, which is affected by both the local and systemic responses to the injurious stimulus. Furthermore, immune cells and mesenchymal stromal cells (MSCs) participate in critical inter-cellular communication or crosstalk to modulate bone healing. Deficiencies in this inter-cellular exchange, inhibition of the natural processes of acute inflammation, and its resolution, or chronic inflammation due to a persistent adverse stimulus can lead to impaired fracture healing. Thus, an initial and optimal transient stage of acute inflammation is one of the key factors for successful, robust bone healing. Recent studies demonstrated the therapeutic potential of immunomodulation for bone healing by the preconditioning of MSCs to empower their immunosuppressive properties. Preconditioned MSCs (also known as "primed/ licensed/ activated" MSCs) are cultured first with pro-inflammatory cytokines (e.g., TNFα and IL17A) or exposed to hypoxic conditions to mimic the inflammatory environment prior to their intended application. Another approach of immunomodulation for bone healing is the resolution of inflammation with anti-inflammatory cytokines such as IL4, IL10, and IL13. In this review, we summarize the principles of inflammation and bone healing and provide an update on cellular interactions and immunomodulation for optimal bone healing.

Influence of the TGF-β Superfamily on Osteoclasts/Osteoblasts Balance in Physiological and Pathological Bone Conditions

“…The recruited neutrophils and M1 macrophages (until day 3) remove the damaged cells and tissue [ 108 ]. During the resolution of acute inflammation, macrophages evolve to M2 phenotype, and the MSCs are recruited by a gradient of cytokines and chemoattractants, such as CXCL12 and MCP-1 (also called CCL2) [ 8 , 105 , 108 ]. The bone repair phase is initiated by the formation of the fibrocartilaginous callus.…”

“…Each phase of bone fracture repair and remodeling requires different hormones (PTH, 1,25-(OH)2D3), cytokines, growth factors, such as insulin like growth factor (IGF), FGF, and members of the TGF-β superfamily synthesized by bone cells [ 8 , 9 , 10 , 11 ]. Before describing the regulation of bone fracture healing phases by the TGF-β superfamily, this review first introduces the members of this superfamily, their signaling pathways, as well as crosstalk with Wnt and Notch signaling.…”

“…Many cytokines, growth factors, hormones (PTH), and vitamins are involved in the phases of bone repair and remodeling [ 8 , 9 , 10 , 11 ]. The growth factors belonging to the TGF-β (transforming growth factor β) superfamily (particularly bone morphogenetic proteins (BMP) and TGF-β1) are known to act locally on bone formation, by stimulating the proliferation and chondrogenic/osteogenic differentiation of mesenchymal stem cells (MSCs) [ 12 ].…”

<p>Inflammation, Bone Healing and Osteonecrosis: From Bedside to Bench</p>

“…Such trauma leads to activation of the innate immune system, and subsequent release of cytokines, chemokines, reactive oxygen species, and other proinflammatory stimuli, and triggering of the complement and coagulation systems. 1,2 These events are initiated by the recognition of specific chemical motifs called pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) by pattern recognition receptors (PRRs) on/within the cells at the site of injury. 3 PAMPs are derivatives of infectious organisms.…”

“…Chronic inflammation is a persistent injurious state in which acute inflammation and fibrosis continue, despite ongoing unsuccessful attempts at definitive resolution and repair. 1,9,10 In simple terms, innate immune processes (and if applicable the more restricted antigen-specific adaptive immune system) cannot overcome the offending adverse stimulus to reconstitute normal anatomy and physiology. 11,12 Thus, homeostasis is never achieved despite the continued mobilization of all biological resources.…”