Osteoblast specific Y1 receptor deletion enhances bone mass

Abstract

Neuropeptide Y, Y1 receptors are found in neuronal as well as bone tissue and Y1 signalling has been implicated in the regulation of bone mass. However, the contribution of Y1 receptors located in these different tissues, particularly that of the bone-specific Y1 receptors, to the regulation of bone homeostasis is unclear. Here we demonstrate that osteoblastspecific Y1 receptor deletion resulted in a marked increase in femoral cancellous bone volume, trabecular thickness and trabecular number. This is the result of elevated osteoblast activity as shown by increased mineral apposition rate and bone formation rate, and is associated with an upregulation in the mRNA expression levels of alkaline phosphatase, osteocalcin and dentin matrix protein-1. Furthermore, osteoblastic Y1 receptor deletion also led to increased mineral apposition rate on both the endocortical and the periosteal surfaces resulting in increased femoral diameter. Together these data demonstrate a direct role for the Y1 receptor on osteoblasts in the regulation of osteoblast activity and bone formation in vivo and suggest that targeting Y1 receptor signalling directly in the bone may have potential therapeutic implications for stimulating bone accrual in diseases such as osteoporosis.

Neuropeptide Y Y1 receptor antagonism increases bone mass in mice

“…2H) were significantly elevated (pb 0.05) in the treated mice compared to vehicle-administered controls. Together, these data recapitulate the bone phenotype previously observed for germline and osteoblast-specific Y1 receptor deficient mice [14,15], confirming the importance of Y1 receptor signalling for controlling bone mass and revealing the potential of Y1 targeting as a novel therapeutic intervention for modulating bone mass.…”

“…This improvement in bone mass occurred in association with an increase in the rate of mineralized tissue production (mineral apposition rate). These data extend our previous observations of effects of germline or osteoblast-specific Y1 receptor ablation [14] and [15] by demonstrating the clinically relevant finding that Y1 receptor ablation can be manipulated pharmacologically to stimulate bone growth.…”

“…Both germline and osteoblast-specific Y1 receptor deletion contribute to a marked anabolic effect on cortical bone [14,15]. Consistent with these genetic models, 5 μmol BIBO3304 stimulated a significant increase in osteoblast activity on the external (periosteal) surface (Fig.…”

“…More recently, NPY has been shown to regulate bone homeostasis via actions in peripheral tissues. Insights from Y1 receptor knockout (KO) models have revealed that the absence of peripheral Y1 receptors led to pronounced anabolic effects on bone [14], [15] and [16]. As a result of these anabolic effects, germline Y1 receptor KO mice displayed an increase in bone mass, with consistent changes in femoral, tibial, and vertebral bones.…”

The endogenous opioid dynorphin is required for normal bone homeostasis in mice

“…Briefly, ALP activity in cells was detected using p-nitrophenylphosphate (pNPP) (Sigma-Aldrich, St. Louis, MO, USA) as the substrate. Mineralization of calcium deposits was assessed by von Kossa staining (2% silver nitrate staining under UV light for 30 min at room temperature), followed by multiple washes with distilled water to remove background staining (Lee et al, 2011). The extent of ALP staining or mineralisation was quantified using the Leica QWin imaging system (Leica Microsystems, Heerbrugg, Switzerland).…”