The Neuropeptide VIP Limits Human Osteoclastogenesis: Clinical Associations with Bone Metabolism Markers in Patients with Early Arthritis

Abstract

We aimed to evaluate the direct action of VIP on crucial molecules involved in human osteoclast differentiation and function. We also investigated the relationship between VIP serum levels and bone remodeling mediators in early arthritis patients. The expression of VIP receptors and osteoclast gene markers in monocytes and in vitro differentiated osteoclasts was studied by real-time PCR. NFATc1 activity was measured using a TransAM® kit. Osteoclastogenesis was confirmed by quantification of tartrate-resistant acid phosphatase positive multinucleated cells. OsteoAssay® Surface Multiple Well Plate was used to evaluate bone-resorbing activity. The ring-shaped actin cytoskeleton and the VPAC1 and VPAC2 expression were analyzed by immunofluorescence. We described the presence of VIP receptors in monocytes and mature osteoclasts. Osteoclasts that formed in the presence of VIP showed a decreased expression of osteoclast differentiation gene markers and proteolytic enzymes involved in bone resorption. VIP reduced the resorption activity and decreased both β3 integrin expression and actin ring formation. Elevated serum VIP levels in early arthritis patients were associated with lower BMD loss and higher serum OPG concentration. These results demonstrate that VIP exerts an anti-osteoclastogenic action impairing both differentiation and resorption activity mainly through the negative regulation of NFATc1, evidencing its bone-protective effects in humans.

Do Not Lose Your Nerve, Be Callus: Insights Into Neural Regulation of Fracture Healing

“…Factors listed have been shown to promote bone formation and/or improve fracture healing. Most factors promote osteogenic expression, although VIP has shown thus far to only inhibit OCs Molecular factor Primary receptor(s) Function in bone CGRP CLR and RAMP1 [ 38 ] ↑ osteogenic gene expression [ 38 ] SP NK-1R [ 39 ] ↑ osteocalcin and collagen expression [ 39 , 40 ] VIP VPAC1 and VPAC2 [ 41 , 42 ] ↓ OC differentiation [ 41 , 42 ] NPY Y1 [ 43 ] ↑ RUNX2 expression in MSCs [ 43 ] BDNF* TrkB [ 44 ] ↑ OPG expression [ 44 ] NGF* TrkA [ 20 , 45 ] ↑ BMP and VEGF expression [ 46 , 47 ] *Not made endogenously by peripheral nerves …”

“…Although the neuropeptide VIP is typically thought of in the context of the intestinal tract as a promoter of digestion, VIP receptor types 1 (VPAC1) and 2 (VPAC2) are expressed on OCs, prevent OC differentiation, and have been examined as a potential therapeutic in inflammatory bone disease [ 41 , 42 ]. Furthermore, it has recently been the focus of examination in the context of fracture healing.…”