Biglycan: a multivalent proteoglycan providing structure and signals

Abstract

Research over the past few years has provided fascinating results indicating that biglycan, besides being a ubiquitous structural component of the extracellular matrix (ECM), may act as a signaling molecule. Proteolytically released from the ECM, biglycan acts as a danger signal signifying tissue stress or injury. As a ligand of innate immunity receptors and activator of the inflammasome, biglycan stimulates multifunctional proinflammatory signaling linking the innate to the adaptive immune response. By clustering several types of receptors on the cell surface and orchestrating their downstream signaling events, biglycan is capable to autonomously trigger sterile inflammation and to potentiate the inflammatory response to microbial invasion. Besides operating in a broad biological context, biglycan also displays tissue-specific affinities to certain receptors and structural components, thereby playing a crucial role in bone formation, muscle integrity, and synapse stability at the neuromuscular junction. This review attempts to provide a concise summary of recent data regarding the involvement of biglycan in the regulation of inflammation and the musculoskeletal system, pointing out both a signaling and a structural role for this proteoglycan. The potential of biglycan as a novel therapeutic target or agent for the treatment of inflammatory diseases and skeletal muscular dystrophies is also addressed.

Figure 1.

Biglycan-mediated proinflammatory signaling involves multireceptor crosstalk in macrophages. In macrophages (Φ), soluble biglycan interacts with TLR2 and TLR4 and triggers (via MyD88, NF-κB, Erk, and p38) the synthesis of proinflammatory cytokines, such as TNF-α and pro–IL-1β as well as various chemoattractants for macrophages and T and B lymphocytes, such as MIP-2, MIP-1α, MCP-1, CXCL13, and RANTES. By clustering TLR2/4 with the P2X7 purinergic receptor, biglycan induces the NLRP3/ASC inflammasome and caspase-1 activation with subsequent cleavage of pro–IL-1β and release of mature IL-1β. Abbreviations used in the figure: ASC, apoptosis-associated speck-like protein containing carboxy-terminal CARD; CXCL, C-X-C motif chemokine; Erk, extracellular signal-regulated kinase; IL, interleukin; MCP, monocyte chemoattractant protein; MIP, macrophage inflammatory protein; MyD88, myeloid differentiation primary response 88; NF-κB, nuclear factor kappa–light-chain enhancer of activated B cells; NLRP3, NLR family, pyrin domain containing; p38, mitogen-activated protein kinase p38; RANTES, regulated upon activation, normal T cell expressed and secreted; TNF, tumor necrosis factor; TLR, Toll-like receptor.

Figure 2.

Network of biglycan signaling in osteoblast differentiation and stabilizing role of biglycan in skeletal muscle. In bone, biglycan stimulates the BMP/TGFβ pathways, leading to the transcription of osteoblast-related genes and osteoblast differentiation. By binding to the Wnt3a ligand and its receptor LRP6, biglycan potentiates the Wnt/β-catenin signaling pathway, thereby further contributing to osteoblast differentiation. In skeletal muscle, biglycan associates with the dystrophin-glycoprotein complex and contributes to its stability and to muscular integrity. For further details, refer to the text. Abbreviations used in the figure: BMP, bone morphogenic protein; BMP-R, bone morphogenic protein receptor; Cbfa1, core binding factor α1; FZ, Frizzled receptor; LRP, low-density lipoprotein receptor–related protein; nNOS, neuronal nitric oxide synthase; TCF, lymphoid enhancer binding factor/T-cell–specific factor; TGFβ, transforming growth factor β; TGFβ-R, transforming growth factor β receptor; Wnt, Wingless and Int.