Biglycan in the Skeleton

Abstract

Small leucine rich proteoglycans (SLRPs), including Biglycan, have key roles in many organ and tissue systems. The goal of this article is to review the function of Biglycan and other related SLRPs in mineralizing tissues of the skeleton. The review is divided into sections that include Biglycan's role in structural biology, signaling, craniofacial and long bone homeostasis, remodeled skeletal tissues, and in human genetics. While many cell types in the skeleton are now known to be affected by Biglycan, there are still unanswered questions about its mechanism of action(s).

Keywords: extracellular matrix; glycosaminoglycan; proteoglycan.

Figure 1.

SLRPs, such as Biglycan, bind collagen fibrils, either through the core protein or the GAG chains thereby regulating the diameter of the individual fibrils as well as their spatial assembly into thicker bundles. (A) Depicts a collagen fiber, and cross section, when Biglycan is present in its glycosylated form. (B) Post translational modifications to the glycanation state of SLRPs, e.g. total loss of GAG chains, results in structural abnormalities of the collagen fiber. (C) Lack of even a single type of SLRP, impairs collagen fibrillogenesis as well as arrangement of collagen molecules into highly organized fibers. Abbreviations: GAG, glycosaminoglycan; SLRPs, small leucine rich proteoglycans.

Figure 2.

Bone marrow stromal cells express and secrete Biglycan, which directly binds many growth factors, morphogens, cell surface receptors and other ECM structural and adhesive molecules. When Bgn (or any other SLRP) is missing, these cytokines are not being sequestered in the cellular microenvironment, thus modifying the closely regulated signal transduction of both osteoblasts and osteoclasts. Here, we focus on the effect of TNFα overactivation. TNFα binds to its receptor on the membrane of both BMSCs (A) or hematopoietic/preosteoclastic cells (B). A. In pre-osteoblasts, TNFα activates Smurf1/2, inhibiting SMAD1/5/8 phosphorylation, which leads to the inhibition of osteogenic gene expression regulated by the osteoblastogenesis transcription factor, RUNX2. TNF-α also induces the expression of Dickkopf-1 (DKK-1), an inhibitor of Wnt signaling, leading to a decrease in bone formation. Furthermore, Canonical wnt signaling promotes OPG expression, thus the inhibition of this pathway leads to decreased OPG levels. TNF-α activation directly increases the expression M-CSF and RANKL by BMSCs. B. in pre-osteoclasts, TNF-α signaling leads to phosphorylation of the IKK complex with subsequent phosphorylation and proteolytic breakdown of IκB, an inhibitor of the NFκB. The activated NFκB, together with C-fos, c-jun, increase the experssion and activity of NFATc1, the master transcription factor in osteoclast differentiation, which then translocates into the nucleus, increasing the expression of osteoclast target genes such as TRAP, calcitonin receptor, cathepsin K and OSCAR. TNF-α signaling also enhances preosteoclast expression of RANK and c-fms, the M-CSF receptor. The combined effect is a decrease in bone formation signals with an increase in osteoclast differentiation, activity and survival, resulting in a low bone mass phenotype. Abbreviations: BGN, Biglycan; BMSC, bone marrow stromal cells; BSP, bone sialoprotein; ECM, extracellular matrix; OPN, osteopontin; SLRP, small leucine rich proteoglycan; TRAP, tartrate-resistant acid phosphatase.

Figure 3.

Published mutations in the BGN gene. (A) The location of Biglycan gene at the end of the long (q) arm of the human X chromosome. (B) Location of the current known deletions of the gene that cause Meester-Loeys syndrome. (C) High magnification of the exons of BGN illustrating the specific pathogenic variants found in human patients suffering from Meester-Loeys syndrome (in red) and X-linked spondyloepimetaphyseal dysplasia (in green). Abbreviations: BGN, Biglycan; LRR, leucine-rich repeat; MRLS, Meester-Loeys syndrome; SEMDX, spondyloepimetaphyseal dysplasia.