Efficacy of targeting bone-specific GIP receptor in ovariectomy-induced bone loss

Abstract

Glucose-dependent insulinotropic polypeptide (GIP) has been recognized in the last decade as an important contributor of bone remodeling and is necessary for optimal bone quality. However, GIP receptors are expressed in several tissues in the body and little is known about the direct versus indirect effects of GIP on bone remodeling and quality. The aims of the present study were to validate two new GIP analogues, called [D-Ala2]-GIP-Tag and [D-Ala2]-GIP1-30, that specifically target either bone or whole body GIP receptors, respectively; and to ascertain the beneficial effects of GIP therapy on bone in a mouse model of ovariectomy-induced bone loss. Both GIP analogues exhibited similar binding capacities at the GIP receptor and intracellular responses as full-length GIP1-42. Furthermore, only [D-Ala2]-GIP-Tag, but not [D-Ala2]-GIP1-30, was undoubtedly found exclusively in the bone matrix and released at acidic pH. In ovariectomized animals, [D-Ala2]-GIP1-30 but not [D-Ala2]-GIP-Tag ameliorated bone stiffness at the same magnitude than alendronate treatment. Only [D-Ala2]-GIP1-30 treatment led to significant ameliorations in cortical microarchitecture. Although alendronate treatment increased the hardness of the bone matrix and the type B carbonate substitution in the hydroxyapatite crystals, none of the GIP analogues modified bone matrix composition. Interestingly, in ovariectomy-induced bone loss, [D-Ala²]-GIP-Tag failed to alter bone strength, microarchitecture and bone matrix composition. Overall, this study shows that the use of a GIP analogue that target whole body GIP receptors might be useful to improve bone strength in ovariectomized animals.

Enhanced agonist residence time, internalization rate and signalling of the GIP receptor variant [E354Q] facilitate receptor desensitization and long‐term impairment of the GIP system

“…GIP also displays a bone‐protective role as it both decreases bone resorption and increases bone formation . In addition, the use of a GIP analogue has been shown to improve bone strength in ovariectomized mice . The GIP receptor (GIPR) is a G protein‐coupled receptor (GPCR) belonging to subclass B1 of the GPCR family .…”

GIP analogues augment bone strength by modulating bone composition in diet-induced obesity in mice

“…In the present manuscript we have evaluated the effects of GIP analogue therapies on bone strength in a rodent model of diet-induced obesity. We compared two GIP analogues: the native peptide with a D-alanine in position 2, as well as this stable GIP analogue with an additional C-terminal modification of 6 aspartic acid residues, conferring a bone tropism and called GIP-Tag [24]. As evident from the present results, both peptides were capable of increasing bone matrix mineralization and maturity in vitro, but also reduced osteoclast activation in the presence of high glucose concentration (equivalent to 25 mmol/L), suggesting that these peptides might present with interesting properties to prevent fragility fracture in diabetes.…”

“…This analogue, called GIP-Tag, has N-terminal enzymatic protection by substitution of L-Ala 2 with D-Ala 2 , together with six aspartic acids at its C-terminal extremity that confers affinity for bone mineral. We have previously shown that GIP-Tag exhibits comparable binding activity at the GIPr and activates similar intracellular pathways in bone cells as the parent GIP peptide [24].…”

“…Initially, as expected, we confirmed that both (D-Ala²)-GIP and (D-Ala²)-GIP-Tag were resistant to DPP-4 mediated degradation (data not shown) as both peptides were still intact after a 8-h incubation with DPP-4. We previously observed that (D-Ala²)-GIP and (D-Ala²)-GIP-Tag exhibited similar bone related responses in the presence of 1 g/L glucose [24]. However, little was known about the response in the presence of elevated glucose concentration.…”

“…GIPr are found in extra-skeletal tissues, and it is therefore unclear whether the beneficial effects on bone are due to direct activation of bone cells or by indirect action on extra-skeletal organs that are responsible for better bone strength. To overcome this problem, we developed a novel GIP analogue that exhibits specific bone tropism [24]. This analogue, called GIP-Tag, has N-terminal enzymatic protection by substitution of L-Ala 2 with D-Ala 2 , together with six aspartic acids at its C-terminal extremity that confers affinity for bone mineral.…”