title: The y6 receptor suppresses bone resorption and stimulates bone formation in mice via a suprachiasmatic nucleus relay.
abstract: The neuropeptide Y system is known to play an important role in the regulation of bone homeostasis and while the functions of its major receptors, Y1R and Y2R, in this process have become clearer, the contributions of other Y-receptors, like the y6 receptor (y6R), are unknown. Y6R expression is restricted to the suprachiasmatic nucleus (SCN) of the hypothalamus, an area known to regulate circadian rhythms, and the testis. Here we show that lack of y6R signalling, results in significant reduction in bone mass, but no changes in bone length. Male and female y6R knockout (KO) mice display reduced cortical and cancellous bone volume in axial and appendicular bones. Mechanistically, the reduction in cancellous bone is the result of an uncoupling of bone remodelling, leading to an increase in osteoclast surface and number, and a reduction in osteoblast number, osteoid surface, mineralizing surface and bone formation rate. y6R KO mice displayed increased numbers of osteoclast precursors and produced greater numbers of osteoclasts in RANKL-treated cultures. They also produced fewer CFU-ALP osteoblast precursors in the marrow and showed reduced mineralization in primary osteoblastic cultures, as well as reduced expression for the osteoblast lineage marker, alkaline phosphatase, in bone isolates. The almost exclusive location of y6Rs in the hypothalamus suggests a critical role of central neuronal pathways controlling this uncoupling of bone remodelling which is in line with known actions or other Y-receptors in the brain. In conclusion, y6R signalling is required for maintenance of bone mass, with loss of y6R uncoupling bone remodelling and resulting in a negative bone balance. This study expands the scope of hypothalamic regulation of bone, highlighting the importance for neural/endocrine coordination and their marked effect upon skeletal homeostasis.
authors.affiliation: Osteoporosis and Bone Biology Division, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia.
authors.forename: Ee-Cheng
authors.initials: EC
authors.lastname: Khor
authors.affiliation: Neuroscience Division, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia.
authors.forename: Ernie
authors.initials: E
authors.lastname: Yulyaningsih
authors.affiliation: Osteoporosis and Bone Biology Division, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia.
authors.forename: Frank
authors.initials: F
authors.lastname: Driessler
authors.affiliation: Osteoporosis and Bone Biology Division, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia.
authors.forename: Natasha
authors.initials: N
authors.lastname: Kovaĉić
authors.affiliation: Osteoporosis and Bone Biology Division, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia.
authors.forename: Natalie K Y
authors.initials: NKY
authors.lastname: Wee
authors.affiliation: Osteoporosis and Bone Biology Division, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia.
authors.forename: Rishikesh N
authors.initials: RN
authors.lastname: Kulkarni
authors.affiliation: Neuroscience Division, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia; Faculty of Medicine, University of NSW, Kensington, Sydney, NSW 2052, Australia.
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Lee
authors.affiliation: Osteoporosis and Bone Biology Division, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia.
authors.forename: Ronaldo F
authors.initials: RF
authors.lastname: Enriquez
authors.affiliation: School of Pathology and Laboratory Medicine, The University of Western Australia, Crawley, WA 6009, Australia.
authors.forename: Jiake
authors.initials: J
authors.lastname: Xu
authors.affiliation: Neuroscience Division, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Neuroscience Division, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia; Faculty of Medicine, University of NSW, Kensington, Sydney, NSW 2052, Australia.
authors.forename: Herbert
authors.initials: H
authors.lastname: Herzog
authors.affiliation: Osteoporosis and Bone Biology Division, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia; Faculty of Medicine, University of NSW, Kensington, Sydney, NSW 2052, Australia. Electronic address: p.baldock@garvan.org.au.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Baldock
mesh_terms: D000375:Aging / Q000378:metabolism; D000818:Animals; D001853:Bone Marrow / Q000378:metabolism; D001862:Bone Resorption / Q000378:metabolism* / Q000473:pathology; D002113:Calcification, Physiologic; D002452:Cell Count; D002454:Cell Differentiation; D005260:Female; D005786:Gene Expression Regulation; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010006:Osteoblasts / Q000378:metabolism / Q000473:pathology; D010010:Osteoclasts / Q000473:pathology; D010011:Osteocytes / Q000378:metabolism / Q000473:pathology; D010012:Osteogenesis / Q000235:genetics; D017476:Receptors, Neuropeptide Y / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013493:Suprachiasmatic Nucleus / Q000378:metabolism* / Q000473:pathology
chemical_list: D017476:Receptors, Neuropeptide Y; C109492:neuropeptide Y6 receptor
keywords: Bone; Hypothalamus; Neuropeptide Y; Osteoblast; Osteoclast; y6 receptor