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Modulation of Canonical Wnt Signaling by the Extracellular Matrix Component Biglycan

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Modulation of Canonical Wnt Signaling by the Extracellular Matrix Component Biglycan Modulation of canonical Wnt signaling by the extracellular matrix component biglycan Agnes D. Berendsena, Larry W. Fishera, Tina M. Kiltsa, Rick T. Owensb, Pamela G. Robeya, J. Silvio Gutkindc, and Marian F. Younga,1 aCraniofacial and Skeletal Diseases Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892; bLifeCell Corporation, Branchburg, NJ 08876; and cOral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892 Edited by Darwin J. Prockop, Texas A&M Health Science Center, Temple, TX, and approved September 9, 2011 (received for review July 1, 2011) Although extracellular control of canonical Wnt signaling is crucial is stabilized within the cytosol and then translocated to the nu- for tissue homeostasis, the role of the extracellular microenviron- cleus, where it accumulates and activates lymphoid enhancer- ment in modulating this signaling pathway is largely unknown. In binding factor/T cell-specific factor (TCF)-mediated gene tran- the present study, we show that a member of the small leucine- scription. The extracellular microenvironment that regulates rich proteoglycan family, biglycan, enhances canonical Wnt sig- this pathway by modulating the activity of Wnt proteins and/or naling by mediating Wnt function via its core protein. Immuno- their antagonists remains largely unknown. In this regard, precipitation analysis revealed that biglycan interacts with both several different proteoglycans and/or their glycosaminoglycan the canonical Wnt ligand Wnt3a and the Wnt coreceptor low- chain components that are abundantly present at the cell sur- density lipoprotein receptor-related protein 6 (LRP6), possibly face have been reported to stimulate the Wnt/β-catenin path- via the formation of a trimeric complex. Biglycan-deficient cells way. These include free heparan sulfate (4), heparin chains (5–7), treated with exogenous Wnt3a had less Wnt3a retained in cell and heparan sulfate proteoglycans, such as glypican-3 (8) and layers compared with WT cells. Furthermore, the Wnt-induced syndecan-1 (9). levels of LRP6 phosphorylation and expression of several Wnt The canonical Wnt signaling pathway appears to be particu- target genes were blunted in biglycan-deficient cells. Both larly important for bone biology. Mutations in either LRP5 or recombinant biglycan proteoglycan and biglycan core protein LRP6 or their downstream signaling targets have been associated increased Wnt-induced β-catenin/T cell-specific factor–mediated with several bone-related diseases (10). Wnt signaling has been transcriptional activity, and this activity was completely inhibited proposed to control bone mass through diverse mechanisms, by Dickkopf 1. Interestingly, recombinant biglycan was able to including renewal of stem cells (11), stimulation of preosteoblast rescue impaired Wnt signaling caused by a previously described replication (12), and enhancement of osteoblast activity (13). missense mutation in the extracellular domain of human LRP6 Wnt signaling in mature osteoblasts has been shown to control (R611C). Furthermore, biglycan’s modulation of canonical Wnt sig- bone resorption by regulating the expression and secretion of naling affected the functional activities of osteoprogenitor cells, the osteoclastogenesis inhibitor osteoprotegerin (14). Despite including the RUNX2-mediated transcriptional activity and cal- the significant progress made over the past decade, our under- cium deposition. Use of a transplant system and a fracture heal- standing of the role of the extracellular microenvironment in ing model revealed that expression of Wnt-induced secreted modulating Wnt/β-catenin signaling in bone remains limited. In protein 1 was decreased in bone formed by biglycan-deficient this regard, we are particularly interested in one of the members cells, further suggesting reduced Wnt signaling in vivo. We pro- of the small leucine-rich proteoglycan family, biglycan (15), be- pose that biglycan may serve as a reservoir for Wnt in the peri- cause of its pronounced expression in bone, where it is concen- cellular space and modulate Wnt availability for activation of the trated in the pericellular space (16). Previous studies in our canonical Wnt pathway. laboratory have shown that mice deficient in biglycan develop age-related osteopenia resulting from a bone formation defect mineralization | regeneration | skeleton involving a reduced number of osteoblasts at the bone surface (17). In addition, expression of BGN (located on the X chro- anonical Wnt signaling regulates diverse biological processes mosome) may be related to stature in humans, given that Cduring development and tissue homeostasis (1). Further- patients with Turner syndrome (XO) have short stature and low more, defective Wnt signaling plays major roles in diseases such levels of BGN, whereas patients with supernumerary sex chro- as cancer (2) and osteoporosis (3). The extracellular control of mosomes have increased limb length and high levels of BGN Wnt signaling is dependent on both the extracellular storage of (18). In vitro studies revealed that biglycan’s modulation of Wnt proteins and the secretion of Wnt antagonists, such as se- growth factor activities, including both TGF-β (19) and bone creted frizzled-related proteins, Wnt inhibitory factor 1, sclero- morphogenetic protein 2/4 (20) signaling in osteoprogenitor stin, and Dickkopf (Dkk) family members (1). In addition to cells, likely contributes to the mechanism through which biglycan binding signaling molecules, matrix components also can be ac- affects bone formation. Although biglycan and canonical Wnt tively involved in modulating the activation of Wnt/β-catenin signaling are both associated with skeletal tissues, whether this signaling. Activation of the canonical pathway starts by binding proteoglycan plays a direct role in modulating this signaling of Wnt to the frizzled receptor and its coreceptor low-density lipoprotein receptor-related protein 6 (LRP6) or its close rela- tive LRP5. This binding results in LRP6 phosphorylation and Author contributions: A.D.B., L.W.F., J.S.G., and M.F.Y. designed research; A.D.B. and T.M.K. performed research; L.W.F., R.T.O., P.G.R., and J.S.G. contributed new reagents/ activation and recruitment of the Axin complex, which is com- analytic tools; A.D.B., L.W.F., P.G.R., J.S.G., and M.F.Y. analyzed data; and A.D.B. and posed of the scaffolding protein Axin, the tumor-suppressor M.F.Y. wrote the paper. protein adenomatous polyposis coli, casein kinase 1, and glyco- The authors declare no conflict of interest. gen synthase kinase 3, to the receptors. This complex is re- This article is a PNAS Direct Submission. sponsible for the constitutive proteasome-mediated degradation 1To whom correspondence should be addressed. E-mail: [email protected]. β of cytoplasmic -catenin protein in the absence of a Wnt signal. This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. However, on activation of the Wnt/β-catenin pathway, β-catenin 1073/pnas.1110629108/-/DCSupplemental. 17022–17027 | PNAS | October 11, 2011 | vol. 108 | no. 41 www.pnas.org/cgi/doi/10.1073/pnas.1110629108 Downloaded by guest on September 26, 2021 pathway is not known. In the present study, we used bone as the interaction between biglycan and Wnt3a. To confirm a direct a model system to identify a novel player, biglycan, in the ex- interaction between biglycan core proteins and Wnt3a, we tracellular microenvironment that modulates canonical Wnt immunoprecipitated mixtures of recombinant human biglycan signaling. (nonglycanated) with recombinant human Wnt3a using anti- bodies specific to biglycan, followed by immunoblotting with Results biglycan- and Wnt3a-specific antibodies. We found that biglycan Biglycan Interacts with Wnt3a and LRP6 via Its Core Protein. Given core proteins directly interacted with Wnt3a (Fig. 1B). that biglycan was previously reported to bind growth factors, Because Wnt3a was previously reported to bind and activate such as TGF-β,wefirst assessed whether biglycan could directly canonical Wnt signaling through the LRP6 receptor (22), we interact with Wnt3a, a prototypical, well-characterized activator hypothesized that biglycan also could interact with this receptor of the β-catenin-dependent canonical pathway (21). Immuno- to locally enhance Wnt function. Immunoprecipitation of cell precipitation of mixtures of recombinant human biglycan (with lysates of HEK-293T cells overexpressing V5-tagged human and without glycanation) with recombinant human Wnt3a using biglycan and V5-tagged human LRP6 using antibodies specific antibodies specific to the C terminus of Wnt3a pulled down for biglycan or LRP6, followed by immunoblotting of pull-down Wnt3a only in the absence of biglycan (Fig. 1A, Left). This result lysates with V5-specific antibodies, revealed that biglycan indeed suggests that biglycan blocks the ability of the antibodies against was bound to LRP6 (Fig. 1 C and D). Furthermore, we found Wnt3a to pull down Wnt3a, thus indirectly suggesting that that immunoprecipitation of cell lysates using antibodies specific biglycan interacts with Wnt3a at the C terminus. This suggestion for LRP6 resulted in the pull-down of LRP6, biglycan, and Wnt3 fi is further supported by the nding that antibodies to the N-ter- when cells overexpressed HA-tagged human/mouse Wnt3 in minal region of Wnt3a pulled down Wnt3a from the mixture addition to V5-tagged human biglycan
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