An integral part of innate immunity is the complement system, a defence system, consisting of fluid-phase and cell surface-bound proteins. Its role to ensure adequate responses to danger factors and thus promoting host defence against pathogens has been well described already for decades. Recently, numerous further reaching functions of complement have been discovered, among these are tissue homeostasis and regeneration, also with respect to the skeletal system. The influence of complement activation on bone was recognised first in pathological conditions of inflamed bone tissue and surrounding areas, observed, for example, in rheumatoid arthritis and osteoarthritis. Greatly enhanced levels of complement proteins were detected in synovial fluids and sera of arthritic patients compared to healthy individuals. Additionally, complement-mediated signalling was shown to modulate periodontitis disease development and progression. Periodontitis is an infectious condition of the periodontium, which involves severe bone loss. Moreover, the complement system critically modulates bone regeneration and healing outcome after fracture. This is seen in uneventful fracture healing, but particularly under severe inflammatory conditions induced by an additional traumatic injury. Therefore, complement activation plays an important role in both sterile and non-sterile inflammatory conditions of the bone, which will be addressed here in respect of findings in bone fractures, arthritides, periodontitis and osteomyelitis. Importantly, complement proteins are thought to be critical not simply in the states of an activated immune system, but also for bone growth during physiological development and bone homeostasis, given for example their presence in long-bone growth-plate cartilage. Furthermore, bone-cell development from precursor cells and bone-cell metabolism and communication, for example, between bone-forming osteoblasts and bone-resorbing osteoclasts, are dependent on or even critically influenced by the presence of complement proteins and complement-mediated signalling. The present review summarises the current view on the role of the complement cascade on bone, both under homeostatic physiological conditions and under inflammatory and infectious conditions, which strongly affect the bone and skeletal health. Furthermore, this review addresses the potential and the feasibility of therapeutic interventions involving the complement cascade, derived from experimental and clinical data. Modulating the complement system could help in the future to reduce bone infections, ensure a balanced bone turnover and to generally improve skeletal health.

Chronic psychosocial stress/trauma represents an increasing burden in our modern society and a risk factor for the development of mental disorders, including posttraumatic stress disorder (PTSD). PTSD, in turn, is highly comorbid with a plethora of inflammatory disorders and has been associated with increased bone fracture risk. Since a balanced inflammatory response after fracture is crucial for successful bone healing, we hypothesize that stress/trauma alters the inflammatory response after fracture and, consequently, compromises fracture healing. Here we show, employing the chronic subordinate colony housing (CSC) paradigm as a clinically relevant mouse model for PTSD, that mice subjected to CSC displayed increased numbers of neutrophils in the early fracture hematoma, whereas T lymphocytes and markers for cartilage-to-bone transition and angiogenesis were reduced. At late stages of fracture healing, CSC mice were characterized by decreased bending stiffness and bony bridging of the fracture callus. Strikingly, a single systemic administration of the β-adrenoreceptor (AR) blocker propranolol before femur osteotomy prevented bone marrow mobilization of neutrophils and invasion of neutrophils into the fracture hematoma, both seen in the early phase after fracture, as well as a compromised fracture healing in CSC mice. We conclude that chronic psychosocial stress leads to an imbalanced immune response after fracture via β-AR signaling, accompanied by disturbed fracture healing. These findings offer possibilities for clinical translation in patients suffering from PTSD and fracture.

Various synthetic biomaterials are used to replace lost or damaged bone tissue that, more or less successfully, osseointegrate into the bone environment. Almost all biomaterials used in orthopedic medicine activate the host-immune system to a certain degree. The complement system, which is a crucial arm of innate immunity, is rapidly activated by an implanted foreign material into the human body, and it is intensely studied regarding blood-contacting medical devices. In contrast, much less is known regarding the role of the complement system in response to implanted bone biomaterials. However, given the increasing knowledge of the complement regulation of bone homeostasis, regeneration, and inflammation, complement involvement in the immune response following biomaterial implantation into bone appears very likely. Moreover, bone cells can produce complement factors and are target cells of activated complement. Therefore, new bone formation or bone resorption around the implant area might be greatly influenced by the complement system. This review aims to summarize the current knowledge on biomaterial-mediated complement activation, with a focus on materials primarily used in orthopedic medicine. In addition, methods to modify the interactions between the complement system and bone biomaterials are discussed, which might favor osseointegration and improve the functionality of the device.

No abstract

As an essential nutrient, the organic water-soluble compound choline is important for human health. Choline is required for numerous biological processes, including the synthesis of neurotransmitters, and it is an important prerequisite for structural integrity and the functioning of cells. A choline-rich diet provides crucial choline sources, yet additional choline dietary supplements might be needed to fully meet the body’s requirements. Dependent on the structure of choline in different sources, absorption and metabolism may differ and strongly impact the bioavailability of circulating choline. This study in healthy volunteers aimed to compare the pharmacokinetics of free choline and of selected choline metabolites between the single dose intake of phosphatidylcholine, present in SuperbaBoostTM krill oil, and choline bitartrate salt. Results demonstrate that albeit free choline levels in plasma were comparable between both choline sources, peak choline concentration was reached significantly later upon intake of SuperbaBoostTM. Moreover, the occurrence of choline metabolites differed between the study products. Levels of the biologically important metabolites betaine and dimethylglycine (DMG) were higher, while levels of trimethylamine N-oxide (TMAO) were substantially lower upon intake of SuperbaBoostTM compared to choline bitartrate.