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Abstract
Neural regulation of bone via the neuropeptide Y (NPY) dependent pathway has marked inhibitory effect on osteoblast activity. The anti-anabolic actions of NPY on bone involve hypothalamic Y2 receptors in the brain and osteoblastic Y1 receptors in the periphery. This thesis examines whether peripheral signals, in particular, peptide YY (PYY) and leptin, also modulate bone homeostasis via the NPY system.
The contrasting effect of knockout and transgenic mouse models indicates that PYY regulates bone mass through suppression of osteoblast activity in cancellous and cortical bone, similar to the recently described skeletal actions of NPY. Mineral apposition rate (MAR) was greater in PYY knockout (PYY-/-) and reduced in PYY transgenic (PYYtg). Conversely, osteoclast activity was elevated in PYYtg. These alterations in bone cell activities resulted in changes in cancellous bone volume: greater in PYY-/- of both genders, and lower in female PYYtg. Interestingly, attenuating both PYY and NPY signalling abolishes the beneficial skeletal effect in cancellous bone volume observed in PYY-/- and NPY-/-, highlighting the complexity of the skeletal regulation by the NPY system. Nonetheless, the anti-anabolic actions of PYY on bone are consistent with clinical observations in anorexia nervosa and exercising amenorrhea, suggesting that the increased PYY levels may contribute to the reduced BMD observed in these disorders, providing a possible therapeutic target for the treatment of low bone mass.
In addition, we show that the diminished cortical bone of leptin-deficient (ob/ob) mice is mediated by increased NPY signalling, as demonstrated by the improved cortical bone of ob/ob mice towards wildtype levels following NPY deletion. NPY-deficient ob/ob exhibited thicker and denser cortical bone, associated with greater endocortical and periosteal MAR, compared to ob/ob. These effects of NPY deficiency in the cortical compartment are consistent with the role of NPY in co-ordinating bone homeostasis with energy homeostasis and are likely to be neural-mediated.
Together these findings clearly demonstrate that signals arises from the periphery, namely PYY and leptin, can modulate bone formation via the NPY signalling pathway, reinforcing the NPY system as a powerful modulator of bone homeostasis and as a potential therapeutic target for the development of skeletal anabolic agents.