As a traditional defense line of innate immunity, complement has a broad range of physiologic functions, including the protection against invasive pathogens, the maintenance of tissue homeostasis, cellular integrity in tissue regeneration, removal of apoptotic cells and elimination of immune complexes. Involved in more than 40 zymogens, receptors, and regulators, the complex system can be activated via 3 distinct pathways: the classical, lectin, or alternative pathway and every step of the enzymatic cascade is under strict regulation to avoid excessive or insufficient activation.
The indispensable role of complement system reveals that any deficiency or mutation in complement proteins may cause increased susceptibility to a variety of diseases, such as osteology related disorders. Periodontal ehlers-danlos syndrome (pEDS) is the typical pathema, which is an autosomal-dominant disorder characterized by early-onset periodontitis leading to premature loss of teeth, joint hypermobility, skin hyperextensibility, and tissue fragility. Combined with severe periodontal inflammation, EDS in childhood is characterized by extensive gingivitis in response to mild plaque accumulation.
Periodontal Ehlers-Danlos Syndrome (pEDS)
Genomic analysis identified monoallelic missense or in-frame insertion/deletion mutations in C1R and C1S genes are closely associated with pEDS. Gene C1R and C1S can encode subunits C1r and C1s respectively, which is the first component of the classical complement pathway. These two proteins form a heterotetramer that then combines with six C1q subunits to form the C1 complex to initiate the activation of the classical pathway. The pathogenic variants of C1R and C1S may affect intracellular retention and mild endoplasmic reticulum enlargement, along with the alterations of interfaces and inter-domain hinges of C1r and C1s. Furthermore, the pathogenesis mechanism of these mutations differs from homozygous loss of function and from loss of the C1 esterase inhibitor.
Fig.1 The structure of C1r and C1s. (Kapferer-Seebacher, et al. 2016)
As a key correlation factor in the pathomechanism of osteology related disorders, complement has been studied as an important diadynamic criteria and is beneficial to predict the severity of the disease. So the complement components have become an attractive therapeutic target for disease treatment.
Creative Biolabs provides a series of therapeutic antibodies, inhibitors, soluble complement regulators, as well as customized services for the complement-associated osteology related disorders. Our comprehensive complement platform offers a great number of complement-related products in a rapid and cost-effective manner. If you are interested, please feel free to contact us for more details.
Reference
1. Kapferer-Seebacher, I.; et al. (2016). Periodontal Ehlers-Danlos syndrome is caused by mutations in C1R and C1S, which encode subcomponents C1r and C1s of complement. The American Journal of Human Genetics. 99(5), 1005-1014.
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Questions & Answer
A: The complement system plays a critical role in bone homeostasis by participating in the regulation of bone remodeling. Complement proteins, particularly C3a and C5a, can stimulate osteoclast activity and bone resorption, while other complement proteins, such as C3b, can promote the differentiation of osteoblasts and bone formation.
A: Challenges include the need for targeted delivery of complement inhibitors to bone tissue, potential off-target effects, and understanding the precise roles of different complement components in bone remodeling. Designing therapies that maintain the delicate balance between bone formation and resorption is also a challenge.
A: Complement therapeutics could potentially be used to modulate the immune response to bone grafts and engineered tissues, promoting integration and reducing rejection. However, further research is needed to explore these applications fully.
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