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Biglycan (BGN) is a member of the class I family of small leucine rich proteoglycans (SLRPs). It encodes for a 42 kDa protein core containing leucine-rich repeats (LRRs), to which one or two glycosaminoglycan (GAG) side chains are covalently bound. Biglycan is expressed ubiquitous and is synthesized as a precursor from which an N-terminal pro-peptide is cleaved off by bone morphogenetic protein (BMP) 1 to yield the mature form. Secreted biglycan interacts with numerous components of the extracellular matrix (ECM), for example, type I, II, III, and VI collagen and elastin via its core protein or GAG chains.
Biglycan-mediated pro-inflammatory signaling
Studies over the past few years have provided strong evidence that diglycans act as a dangerous signal in their soluble proportions, bridging the innate and adaptive immune systems.
In its soluble form, biglycan is able to bind to both TLR2 and -4, which rapidly activated the mitogen-activated protein kinase p38, extracellular signal-regulated kinase (Erk), and nuclear factor kappa–light-chain enhancer of activated B cells (NF-κB) and consequently secretion of TNF-α. These signaling events were dependent on the MyD88 (myeloid differentiation primary response 88) gene Via TLR2/4- dependent signaling, biglycan triggers the synthesis of various chemoattractants for neutrophils and macrophages. Subsequently, the newly attracted macrophages, being stimulated by pro-inflammatory cytokines, will in turn start to synthesize biglycan de novo, thereby enhancing the inflammatory response. The role of biglycan in inflammation was also emphasized in vivo in biglycan-deficient mice, which showed longer survival correlated with a lower plasma level of TNF-α in lipopolysaccharide (LPS)-induced sepsis compared with wild-type animals.
Besides identifying biglycan as an ECM-derived DAMP, these studies have led to new concepts. First, biglycan has to be present in its soluble form, because when bound to the ECM, biglycan cannot act as a DAMP. Second, the magnitude of the biglycan signal can be ramped up rapidly by proteolytic liberation from ECM stores without the need for de novo synthesis. Third, both infiltrating macrophages, stimulated by pro-inflammatory cytokines and, at later time points, resident cells start to de novo synthesize biglycan at sites of injury or damage, in order to drive and shape the inflammatory response reaction over time. Fourth, by activating both the receptor for the Gram-negative (TLR4) and the Gram-positive (TLR2) bacterial response, biglycan, as a signal of tissue damage, acts as an amplifier for TLR-induced inflammation. These initial findings were confirmed by several reports describing the coincidence of biglycan overexpression with enhanced inflammation and severe tissue injury in a TLR-dependent manner.
Fig. 1. Biglycan-mediated proinflammatory signaling involves multireceptor crosstalk in macrophages. (Nastase et al. Journal of Histochemistry & Cytochemistry.2012).
Further studies have shown that the pro-inflammatory action of biglycan is not only mediated through its interaction with TLR2/4, but also through signaling in the NLR family, pyrin domain–containing 3 (NLRP3) inflammasome. NLRP3-inflammatory body is a cytoplasmic protein complex containing nod-like receptors (NLR), procaspase-1, and the adaptor molecule ASC (apoptosis-associated speck-like protein containing carboxy-terminal CARD). Activation of the inflammasome results in the maturation of caspase-1 with subsequent processing of pro–interleukin-1β (IL-1β) into mature IL-1β. Tschopp and Biglycan induces secretion of mature IL-1β, a pro-inflammatory cytokine important both in acute and chronic inflammation, without any need for other costimulatory factors. NLRP3-dependent secretion of mature IL-1β typically requires two signals. The first signal provided by the ligand of TLR or NOD2 activates NF-κB to synthesize pre-IL-1β and NLRP3. The second signal activates NLRP3/ASC and caspase-1 and results in cleavage of pre-IL-1β. Surprisingly, a single biglycan can automatically trigger two signals, induces the synthesis of pro-IL-1β and NLRP3 by binding to and activating TLR2/4 signaling.
Recent studies have shown that d biglycan signaling is an important link between the innate immune system and the adaptive immune system. In macrophages and dendritic cells, biglycan induces expression of CXCL13 by TLR2/4 signaling. It is conceivable that biglycan, by attracting B cells to non-lymphoid organs, it can promote the development of tertiary lymphoid tissues and the deterioration of diseases. Soluble biglycans specifically promote the recruitment of B1 lymphocytes, which are involved in the early, T-cell independent immune response. Thus, these findings underline biglycan act as a potent inducer of inflammation, which can rapidly trigger autoantibody production without T-cell involvement.
Biglycan signaling in bone formation
In the past few years, it has been particularly interesting to identify potential molecular mechanisms for developing phenotype in biglycan-deficient mice. The results indicate that biglycan-deficient mice lacking a small number of bone marrow-derived stromal cells (BMSC-osteogenic precursors) with increasing age. In addition, the response of BMSCs to TGF-β is also impaired, suggesting a possible role of BMP signaling in the development of this phenotype. Indeed, biglycan was shown to modulate bone morphogenetic protein 4 (BMP4)-mediated osteoblast differentiation in murine calvarial cells by controlling Smad1 phosphorylation and Cbfa1 (core binding factor α1) expression. Another study also confirmed the role of biglycan in osteoblast differentiation and subsequent matrix mineralization through the BMP4 signaling pathway. The opposite effect of biglycan in BMP4 signaling is shown in the context of embryonic development. At the molecular level, biglycans bind to BMP4 and the notochord, increasing the binding efficiency and blocking BMP4 activity. In addition to BMP4, in vitro binding analysis revealed the interaction of biglycan and other BMPs, such as BMP2 and 6. Biglycan can directly bind BMP2 and its receptor ALK6 (also known as BMP-RIB), to stimulate BMP2-dependent osteoblast differentiation.
Biglycan also activate the canonical Wnt/β-catenin signaling. Activation of the Wnt/β-catenin pathway involving Wnt ligand binding to the Frizzled receptor (FZ) and its co-receptors, LRP6, increasing the stability of β-catenin in the cytoplasm and promotes its translocation to the nucleus. Consequently, β-catenin activates LEF1/TCF (lymphoid enhancer-binding factor/T-cell-specific factor)-related gene transcription. Biglycan bind directly to Wnt signaling ligands and LRP6 via their protein cores. The lack of biglycan led to impaired Wnt-induced LRP6 phosphorylation and LEF1/TCF-mediated transcriptional activity in calvarial cells. The same study showed that in vivo, biglycan regulates WISP1 expression during bone formation in a fracture-healing model.
Fig. 2. Network of biglycan signaling in osteoblast differentiation and stabilizing role of biglycan in skeletal muscle. (Nastase et al. Journal of Histochemistry & Cytochemistry.2012).