Abstract
The heparan sulfate proteoglycan Syndecan-1, a mediator of signals between the extracellular matrix and cells involved is able to interact with OPG, one of the major regulators of osteoclastogenesis. The potential of osteoblasts to induce osteoclastogenesis is characterized by a switch of OPG (low osteoclastogenic potential) towards RANKL production (high osteoclastogenic potential). In the present study, we investigated the influence of endogenous Syndecan-1 on local bone-cell-communication via the RANKL/OPG-axis in murine osteoblasts and osteoclasts in wild type and Syndecan-1 lacking cells. Syndecan-1 expression and secretion was increased in osteoblasts with high osteoclastogenic potential. Syndecan-1 deficiency led to increased OPG release by osteoblasts that decreased the availability of RANKL. In co-cultures of Syndecan-1 deficient osteoblasts with osteoclast these increased OPG in supernatant caused decreased development of osteoclasts. Syndecan-1 and RANKL level were increased in serum of aged WT mice, whereas Syndecan-1 deficient mice showed high serum OPG concentration. However, bone structure of Syndecan-1 deficient mice was not different compared to wild type. In conclusion, Syndecan-1 could be regarded as a new modulator of bone-cell-communication via RANKL/OPG axis. This might be of high impact during bone regeneration or bone diseases like cancer where Syndecan-1 expression is known to be even more prevalent.
Highlights
Syndecans, a family of four heparan sulfate proteoglycans (HSPG), are known to be expressed in many different cell types at low levels, and in a differentiation dependent manner[1]
During differentiation of osteoclasts in presence of rmRANKL, the mRNA expression of Sdc[1] increased significantly over time and, at day 6, is higher compared to Syndecan-4 (p < 0.01), while the expression of other Syndecans remained mostly unchanged (Fig. 1C)
Using co-cultured wild type osteoblasts and osteoclasts, after 7 days of culture in DM + medium (Table 1), positive Syndecan-1 detection was shown in osteoblastic cells (OB), in mononucleated as well as in multinucleated osteoclastic cells (OC) (Fig. 1E)
Summary
A family of four heparan sulfate proteoglycans (HSPG), are known to be expressed in many different cell types at low levels, and in a differentiation dependent manner[1]. The immobilization of OPG at the cell surface via binding to membrane bound HSPG seemed to facilitate the interaction with membrane bound RANKL, and this inhibited o steoclastogenesis[13]. In a recent study using knock-in mice and MC3T3 osteoblastic cell line with an OPG mutant that was incapable of heparan sulfate binding, the interaction of OPG with HSPG on the surface of osteoblasts was indispensable for normal bone homeostasis[14]. The overall question of this study was if Syndecan-1 influences bone cell communication via the OPG/ RANKL axis leading to changes in bone structure in healthy organisms. This was investigated by using osteoblasts and osteoclasts isolated from unchallenged WT and Syndecan-1 deficient mice. The capacity of bone cell communication using co-culture in vitro was analysed as well as the impact of Syndecan-1 deficiency on bone structure and Syndecan-1 appearance during aging of mice
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