Abstract
Osteoporosis is a growing health concern, characterised by deterioration of bone and increased fracture incidence. Anabolic treatments for reversing bone loss are presently limited. A bone anabolic response was recently reported following deletion of hypothalamic neuropeptide Y2 receptors in mice. In contrast, no discernable bone phenotype was observed in Y4 receptor knockout (Y4-/-) mice, revealing specificity
between the Y receptors in their control of bone formation.
Studies in this thesis revealed a second anabolic response in the absence of another Y
receptor subtype; the Y1 receptor. The potential interaction between the Y1 and Y2-
anabolic pathways with each other and with Y4 was investigated through the generation of
mouse models lacking multiple Y receptor subtypes. Interestingly, no synergistic elevation
in bone volume was observed in Y1-/-Y2-/- double knockout mice, indicative of shared
mechanisms of action. In contrast, the synergistic elevation in bone volume of male Y2-/-
Y4-/- mice was likely due to additive effects of leptin signalling. Consequentially, potential
interaction between Y receptors and leptin was investigated by crossing the Y receptor
knockouts onto the leptin deficient ob/ob background, revealing differential responses of
the Y receptor pathways to leptin deficiency, with the anabolic response of the Y2-/- model
retained in Y2-/-/ob mice but abolished in Y1-/-/ob mice compared to Y1-/-. Differential
responses of these two pathways were also revealed following gonadectomy of Y1-/- and
Y2-/- mice. Importantly, these studies also demonstrated the ability of the central Y2-
anabolic pathway to halt gonadectomy-induced bone loss.
Interestingly, cultured stromal cells from germline Y2-/- mice exhibited an enhanced ability
to undergo mineralisation and adipocyte differentiation, associated with a greater number of
mesenchymal progenitor cells present within the bone of Y2-/- mice, suggesting a potential
mechanism for the greater mineralisation of the Y2-/- model in vitro and in vivo. Y1
receptor expression was also detected in stromal cells from wild type mice, but was nearly
abolished in Y2-/- mice. Together these findings demonstrate an important therapeutic
potential for these pathways in the treatment of osteoporosis and indicate that modulation
of Y receptor signalling within the bone microenvironment may alter proportions of
mesenchymal progenitor populations with effects on bone formation.