Mice with sclerostin gene deletion are resistant to the severe sublesional bone loss induced by spinal cord injury
- 338 Downloads
Bone loss after spinal cord injury (SCI) is rapid, severe, and refractory to interventions studied to date. Mice with sclerostin gene deletion are resistant to the severe sublesional bone loss induced by SCI, further indicating pharmacological inhibition of sclerostin may represent a promising novel approach to this challenging medical problem.
The bone loss secondary to spinal cord injury (SCI) is associated with several unique pathological features, including the permanent immobilization, neurological dysfunction, and systemic hormonal alternations. It remains unclear how these complex pathophysiological changes are linked to molecular alterations that influence bone metabolism in SCI. Sclerostin is a key negative regulator of bone formation and bone mass. We hypothesized that sclerostin could function as a major mediator of bone loss following SCI.
To test this hypothesis, 10-week-old female sclerostin knockout (SOST KO) and wild type (WT) mice underwent complete spinal cord transection or laminectomy (Sham).
At 8 weeks after SCI, substantial loss of bone mineral density was observed at the distal femur and proximal tibia in WT mice but not in SOST KO mice. By μCT, trabecular bone volume of the distal femur was markedly decreased by 64 % in WT mice after SCI. In striking contrast, there was no significant reduction of bone volume in SOST KO/SCI mice compared with SOST KO/sham. Histomorphometric analysis of trabecular bone revealed that the significant reduction in bone formation rate following SCI was observed in WT mice but not in SOST KO mice. Moreover, SCI did not alter osteoblastogenesis of marrow stromal cells in SOST KO mice.
Our findings demonstrate that SOST KO mice were protected from the major sublesional bone loss that invariably follows SCI. The evidence indicates that sclerostin is an important mediator of the marked sublesional bone loss after SCI, and that pharmacological inhibition of sclerostin may represent a promising novel approach to this challenging clinical problem.
KeywordsBone formation Bone mineral density Mechanical unloading Sclerostin Spinal cord injury Trabecular bone volume
Bone formation rate
Bone mineral density
Dual-energy x-ray absorptiometer
Mineral apposition rate
Mineralizing surface/bone surface
Mesenchymal stem cells
Spinal cord injury
This work was supported by the Veterans Health Administration, Rehabilitation Research, and Development Service (grants 5I01RX001313 and 5I01RX000687 to WQ; B9212-C and B2020-C to WAB). Ministry of Science and Technology PRC grant 2014DFA32120 and the Natural Science Foundation of China (NSFC) grant 81471000 to YW. Amgen Inc. provided SOST KO mice. Authors’ roles: CPC, HK, XL, WAB, and WQ were responsible for study design and data analysis. YP, LH, WZ, JL, YQ, YW, LR, and WQ conducted the bone biology study. Jay Cao performed microCT analysis. The manuscript was written by WZ and WQ and was revised and approved by all authors. WQ takes responsibility for the integrity of the data analysis.
Compliance with ethical standards
Yuanzhen Peng, Wei Zhao, Xiaodong Li, Lauren M Harlow, Jiliang Li, Yiwen Qin, Jianping Pan, Yingjie Wu, Liyuan Ran, Hua Zhu Ke, William A. Bauman, Christopher Cardozo, and Weiping Qin declare that they have no conflict of interest.
YP, WZ, LH, JL, YQ, JP, YW, LR, CPC, WAB, and WQ have nothing to disclose. XL is current employee and shareholder of Amgen Inc., and HZK is current employee and shareholder of UCB Pharma.
- 10.Balemans W, Ebeling M, Patel N, Van Hul E, Olson P, Dioszegi M, Lacza C, Wuyts W, Van Den Ende J, Willems P, Paes-Alves AF, Hill S, Bueno M, Ramos FJ, Tacconi P, Dikkers FG, Stratakis C, Lindpaintner K, Vickery B, Foernzler D, Van Hul W (2001) Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST). Hum Mol Genet 10:537–543CrossRefPubMedGoogle Scholar
- 11.Morvan F, Boulukos K, Clement-Lacroix P, Roman Roman S, Suc-Royer I, Vayssiere B, Ammann P, Martin P, Pinho S, Pognonec P, Mollat P, Niehrs C, Baron R, Rawadi G (2006) Deletion of a single allele of the Dkk1 gene leads to an increase in bone formation and bone mass. J Bone Miner Res 21:934–945CrossRefPubMedGoogle Scholar
- 14.Li X, Ominsky MS, Niu QT, Sun N, Daugherty B, D’Agostin D, Kurahara C, Gao Y, Cao J, Gong J, Asuncion F, Barrero M, Warmington K, Dwyer D, Stolina M, Morony S, Sarosi I, Kostenuik PJ, Lacey DL, Simonet WS, Ke HZ, Paszty C (2008) Targeted deletion of the sclerostin gene in mice results in increased bone formation and bone strength. J Bone Miner Res 23:860–869CrossRefPubMedGoogle Scholar
- 15.Li X, Ominsky MS, Warmington KS, Morony S, Gong J, Cao J, Gao Y, Shalhoub V, Tipton B, Haldankar R, Chen Q, Winters A, Boone T, Geng Z, Niu QT, Ke HZ, Kostenuik PJ, Simonet WS, Lacey DL, Paszty C (2009) Sclerostin antibody treatment increases bone formation, bone mass, and bone strength in a rat model of postmenopausal osteoporosis. J Bone Miner Res 24:578–588CrossRefPubMedGoogle Scholar
- 16.Li X, Warmington KS, Niu QT, Asuncion FJ, Barrero M, Grisanti M, Dwyer D, Stouch B, Thway TM, Stolina M, Ominsky MS, Kostenuik PJ, Simonet WS, Paszty C, Ke HZ (2010) Inhibition of sclerostin by monoclonal antibody increases bone formation, bone mass, and bone strength in aged male rats. J Bone Miner Res 25:2647–2656CrossRefPubMedGoogle Scholar
- 22.Qin W, Li X, Peng Y, Harlow LM, Ren Y, Wu Y, Li J, Qin Y, Sun J, Zheng S, Brown T, Feng JQ, Ke HZ, Bauman WA, Cardozo CC (2015) Sclerostin antibody preserves the morphology and structure of osteocytes and blocks the severe skeletal deterioration after motor-complete spinal cord injury in rats. J Bone Miner Res 30:1994–2004CrossRefPubMedGoogle Scholar
- 23.Arima H, Hanada M, Hayasaka T, Masaki N, Omura T, Xu D, Hasegawa T, Togawa D, Yamato Y, Kobayashi S, Yasuda T, Matsuyama Y, Setou M (2014) Blockade of IL-6 signaling by MR16-1 inhibits reduction of docosahexaenoic acid-containing phosphatidylcholine levels in a mouse model of spinal cord injury. Neuroscience 269:1–10CrossRefPubMedGoogle Scholar
- 27.Qin W, Sun L, Cao J, Peng Y, Collier L, Wu Y, Creasey G, Li J, Qin Y, Jarvis J, Bauman WA, Zaidi M, Cardozo C (2013) The central nervous system (CNS)-independent anti-bone-resorptive activity of muscle contraction and the underlying molecular and cellular signatures. J Biol Chem 288:13511–13521CrossRefPubMedPubMedCentralGoogle Scholar
- 37.Minematsu ANY, Imagita H, Sakata S (2014) Time course changes in trabecular bone microstructure in rats with spinal cord injury. J Life Sci 8:522–528Google Scholar
- 39.Voor MJ, Brown EH, Xu Q, Waddell SW, Burden RL, Burke DA, Magnuson DS (2012) Bone Loss Following Spinal Cord Injury in a Rat Model. J Neurotrauma 29(8):1676–168Google Scholar
- 40.Albright F BC, Cope O (1941) Acute atrophy of bone (osteoporosis) stimulating hypreparathyroidism. J Clin Endocrinol Metab 1:711–716Google Scholar
- 41.Bauman WA, Cardozo CP (2015) Osteoporosis in individuals with spinal cord injury. PM R 7(2):188–201Google Scholar
- 46.Berarducci A (2009) Stopping the silent progression of osteoporosis. Am Nurse Today 3:18Google Scholar
- 50.Chang KV, Hung CY, Chen WS, Lai MS, Chien KL, Han DS (2013) Effectiveness of bisphosphonate analogues and functional electrical stimulation on attenuating post-injury osteoporosis in spinal cord injury patients- a systematic review and meta-analysis. PLoS One 8:e81124CrossRefPubMedPubMedCentralGoogle Scholar