Perturbed bone composition and integrity with disorganized osteoblast function in zinc receptor/Gpr39‐deficient mice

Abstract

Changes in bone matrix composition are frequently found with bone diseases and may be associated with increased fracture risk. Bone is rich in the trace element zinc. Zinc was established to play a significant role in the growth, development, and maintenance of healthy bones; however, the mechanisms underlying zinc effects on the integrity of the skeleton are poorly understood. Here, we show that the zinc receptor (ZnR)/Gpr39 is required for normal bone matrix deposition by osteoblasts. Initial analysis showed that Gpr39-deficient ( Gpr39) mice had weaker bones as a result of altered bone composition. Fourier transform infrared spectroscopy analysis showed high mineral-to-matrix ratios in the bones of Gpr39 mice. Histologic analysis showed abnormally high numbers of active osteoblasts but normal osteoclast numbers on the surfaces of bones from Gpr39 mice. Furthermore, Gpr39 osteoblasts had disorganized matrix deposition in vitro with cultures exhibiting abnormally low collagen and high mineral contents, findings that demonstrate a cell-intrinsic role for ZnR/Gpr39 in these cells. We show that both collagen synthesis and deposition by Gpr39 osteoblasts are perturbed. Finally, the expression of the zinc transporter Zip13 and a disintegrin and metalloproteinase with thrombospondin motifs family of zinc-dependent metalloproteases that regulate collagen processing was downregulated in Gpr39 osteoblasts. Altogether, our results suggest that zinc sensing by ZnR/Gpr39 affects the expression levels of zinc-dependent enzymes in osteoblasts and regulates collagen processing and deposition.-Jovanovic, M., Schmidt, F. N., Guterman-Ram, G., Khayyeri, H., Hiram-Bab, S., Orenbuch, A., Katchkovsky, S., Aflalo, A., Isaksson, H., Busse, B., Jähn, K., Levaot, N. Perturbed bone composition and integrity with disorganized osteoblast function in zinc receptor/Gpr39-deficient mice.

GPR39 agonist TC-G 1008 promotes osteoblast differentiation and mineralization in MC3T3-E1 cells

“…A representative schematic of the molecular mechanism is shown in Figure 10. In agreement with our findings, a recent study showed that GPR39 knockout mice had weak bones as a result of abnormal bone composition, while cultured GPR39 null osteoblasts show low collagen matrix and abnormal matrix deposition [21]. Therefore, GPR39-mediated osteoblast differentiation appears to be vital both in vitro and in vivo, indicating its significant role in controlling bone formation.…”

The Zinc Sensing Receptor, ZnR/GPR39, in Health and Disease

“…The endogenous Zn 2+ , released during physiological activity, acts as a first messenger and triggers intracellular Ca 2+ signaling via the specific Gαq-coupled receptor ZnR/GPR39 [ 34 , 56 ]. Activity of ZnR/GPR39 in tissues relevant to Zn 2+ signaling has been identified in neurons, colon epithelial cells (colonocytes), skin epidermal cells (keratinocytes), pancreatic cells, prostate cancer cells, salivary gland cells, and in bones [ 57 , 58 , 59 , 60 , 61 ]. In neurons, stimulation of the mossy fibers triggers ZnR/GPR39-dependent Ca 2+ rises in postsynaptic CA3 (Cornu Ammonis 3) neurons [ 62 ] that are diminished in the presence of a non-permeable Zn 2+ chelator, or in the absence of the Zn 2+ transporter-3 (ZnT3), which is responsible for synaptic Zn 2+ accumulation.…”

“…While several zinc transporters of the ZIP family have been associated with skeletal function [ 137 ], a role for ZnR/GPR39 was not described. Using GPR39 knockout mice, a recent study indicates that this receptor is important for osteoblast differentiation [ 61 ]. Hence, mice lacking ZnR/GPR39 showed impaired bone composition with decreased collagen content, likely involving ADAMTS metalloproteinase, which regulates collagen processing [ 61 ].…”

“…Using GPR39 knockout mice, a recent study indicates that this receptor is important for osteoblast differentiation [ 61 ]. Hence, mice lacking ZnR/GPR39 showed impaired bone composition with decreased collagen content, likely involving ADAMTS metalloproteinase, which regulates collagen processing [ 61 ]. Most importantly, ZnR/GPR39 deficient osteoblasts showed lower ZIP13 expression, linking ZnR/GPR39 and Zn 2+ transporters for the first time.…”

“…A recent study suggested that GPR39 expression is modulated in gastric adenocarcinoma [ 179 ], yet this study applied a previously incorrectly suggested ligand of GPR39 and not Zn 2+ [ 180 ]. Interestingly, a link between the ZnR/GPR39 and mRNA levels of the Zn 2+ transporter ZIP13 was recently shown in bone [ 61 ], but whether ZnR/GPR39 regulates other members of the ZIP family of Zn 2+ transporters is unknown. Such a link between ZnR/GPR39 and ZIP transporters may further link the receptor to tumorigenesis.…”