The brains of the bones: how osteocytes use WNT1 to control bone formation Frank Rauch J Clin Invest. 2017;127(7):2539-2540. https://doi.org/10.1172/JCI95386. Commentary WNT proteins drive the development and maintenance of many tissues, including bone. It is less clear which of the many WNT proteins act on bone or where these WNTs act in the skeleton; however, loss-of-function mutations in WNT1 cause bone fragility in children and adults. In this issue of the JCI, Joeng and colleagues demonstrate that bone formation is under the control of WNT1 produced by osteocytes, the cells that reside deep in the bone matrix and form dendritic networks. The implication of WNT1 in the control of bone formation identifies a potential new target for the treatment of low bone mass disorders, such as osteoporosis. Find the latest version: https://jci.me/95386/pdf The Journal of Clinical Investigation COMMENTARY The brains of the bones: how osteocytes use WNT1 to control bone formation Frank Rauch Shriners Hospital for Children and McGill University, Montreal, Quebec, Canada. in the biological adaptation of bones to mechanical stimuli (7). More generally, the WNT proteins drive the development and maintenance of many tissues, osteocyte system is ideally positioned for including bone. It is less clear which of the many WNT proteins act on integrating input from local and system- bone or where these WNTs act in the skeleton; however, loss-of-function ic factors and for orchestrating teams of mutations in WNT1 cause bone fragility in children and adults. In this issue effector cells (osteoblasts and osteoclasts) of the JCI, Joeng and colleagues demonstrate that bone formation is under that are recruited to carry out the resulting the control of WNT1 produced by osteocytes, the cells that reside deep in the action plan. bone matrix and form dendritic networks. The implication of WNT1 in the control of bone formation identifies a potential new target for the treatment WNT1 in osteocytes of low bone mass disorders, such as osteoporosis. In this issue, Joeng et al. set out to explore the mechanism whereby WNT1 deter- mines bone mass (9). Previous observa- tions from this group established that glob- Which WNT, where? WNT1 mutations have been reported to al loss of WNT1 causes low bone mass and A role for WNT signaling in bone devel- date. Bone and brain phenotypes similar fractures, but left open the question as to opment and maintenance was first dis- to those seen in these children are also whether this phenotype was explained by covered through the study of osteoporosis present in the swaying mouse, which has the absence of functional WNT1 specifical- pseudoglioma syndrome, an ultra-rare dis- a naturally occurring Wnt1 mutation (6). ly in osteocytes. As WNT1 is expressed in ease that is characterized by blindness, low Heterozygous WNT1 mutations give rise to many cell types and tissues, such as B lym- bone mass, and frequent fractures in chil- less severe bone fragility and manifest as phocytes and brain, it was still possible that dren (1). This disorder is caused by homo- early-onset osteoporosis in adolescents or the observed effects on the skeleton were zygous loss-of-function mutations in the young adults (2, 4). a secondary consequence of hematolog- gene encoding LDL receptor–related pro- Mouse studies have indicated that the ic or neurologic abnormalities. Joeng and tein 5 (LRP5), which acts as a coreceptor WNT1-expressing bone cells are osteo- colleagues have now shown that targeted for WNT ligands on the surface of osteo- cytes, rather than bone-forming osteo- inactivation of Wnt1 in osteocytes repli- blasts, the cells responsible for bone for- blasts or bone-resorbing osteoclasts (2). cates the skeletal phenotype of animals mation. When WNT ligands bind to LRP5, Osteocytes are former osteoblasts that with global WNT1 deficiency, including bone formation is stimulated; therefore, have become embedded in mineralized impaired bone formation, extremely low mutations that inactivate LRP5 lead to bone matrix (7), where they maintain bone mass, and spontaneous fractures. In slow bone formation and low bone mass. contact with each other, and with cells on contrast, WNT1 overexpression in osteo- This basic machinery was discov- the bone surface, via canalicular canals cytes markedly increased bone formation ered more than 15 years ago, but it is still through which they project their dendrites. and resulted in more trabecular and corti- unclear which of the many WNT proteins This canalicular system also allows for a cal bone. Neither WNT1 inactivation nor play an important role in human bone. remarkably close contact between osteo- overexpression seemed to have a major Studies in children with another rare bone cytes and bone matrix: the combined effect on bone resorption. Together, these fragility disorder provided an answer. Spe- length of canaliculi in a cubic centimeter experiments indicated that WNT1 produc- cifically, homozygous inactivating muta- of mineralized bone amounts to 74 km, tion by osteocytes is essential for the con- tions in WNT1 lead to a severe form of with 80% of the bone matrix located with- trol of bone formation and bone mass. recessive osteogenesis imperfecta that is in 3 μm of the nearest canaliculus (8). It is Further mechanistic studies implicated characterized by frequent fractures in ear- thought that osteocytes monitor the defor- an mTOR pathway in the control of osteo- ly childhood and, in some patients, struc- mation of bone matrix that results from blasts through WNT1 (9). Overexpression tural brain abnormalities (2–5). Approxi- the exposure of the skeleton to mechan- of WNT1 in a stromal cell line accelerated mately 20 individuals with homozygous ical forces and thus play an essential role osteoblast differentiation and increased mineralization in vitro, and this effect was Related Article: p. 2678 diminished by rapamycin, which inhibits mTOR complex 1 (mTORC1) signaling. Conflict of interest: The author has declared that no conflict of interest exists. Accordingly, rapamycin treatment of mice Reference information: J Clin Invest. 2017;127(7):2539–2540. https://doi.org/10.1172/JCI95386. overexpressing WNT1 in osteocytes allevi- jci.org Volume 127 Number 7 July 2017 2539 COMMENTARY The Journal of Clinical Investigation ated the high-bone-mass phenotype. Con- treatment with teriparatide (parathyroid treal, Quebec, Canada) for helpful feed- versely, genetic stimulation of mTORC1 hormone 1-34), which decreases sclerostin back on this Commentary. signaling in osteocytes of the swaying expression in osteocytes (7). Interesting- mouse increased bone mass and prevented ly, recent pilot studies showed encourag- Address correspondence to: Frank Rauch, spontaneous fractures. Thus, mTORC1 sig- ing results with teriparatide treatment of Shriners Hospital for Children, 1003 Deca- naling at least in part mediates the effect of adults who had osteoporosis caused by rie, Montreal, Quebec, Canada H4A 0A9. WNT1 signaling on osteoblasts. heterozygous WNT1 mutations (13). Phone: 514.842.5964; Email: frauch@ Finally, Joeng et al. showed that shriners.mcgill.ca. anti-sclerostin antibody treatment of the Future directions 1. Gong Y, et al. LDL receptor-related protein 5 swaying mouse increased bone mass, In their series of elegant experiments, (LRP5) affects bone accrual and eye develop- improved mechanical bone properties, Joeng et al. have established that WNT1 ment. Cell. 2001;107(4):513–523. and decreased the fracture rate (9). These production in osteocytes plays a key role 2. Laine CM, et al. WNT1 mutations in early-onset observed improvements in the swaying in the control of bone formation and bone osteoporosis and osteogenesis imperfecta. mouse following anti-sclerostin adminis- mass. This leads to the question of what N Engl J Med. 2013;368(19):1809–1816. 3. Fahiminiya S, Majewski J, Mort J, Moffatt P, tration are significant on both mechanistic drives WNT1 production in osteocytes Glorieux FH, Rauch F. Mutations in WNT1 are a and translational levels. Sclerostin is an under physiological conditions. Is WNT1 cause of osteogenesis imperfecta. J Med Genet. osteocyte-secreted protein that decreases part of the mechanostat machinery, the 2013;50(5):345–348. WNT signaling and thereby inhibits bone putative system whereby osteocytes adapt 4. Keupp K, et al. Mutations in WNT1 cause dif- formation. It does so by interacting with bone strength to local mechanical require- ferent forms of bone fragility. Am J Hum Genet. 2013;92(4):565–574. LRP5 on the surface of osteoblasts, which ments, or is osteocytic WNT1 under the 5. Pyott SM, et al. WNT1 mutations in families prevents the binding of WNT ligands to control of systemic hormones? affected by moderately severe and progressive LRP5. Anti-sclerostin antibody treatment The results by Joeng et al. also make recessive osteogenesis imperfecta. Am J Hum therefore has bone anabolic properties. The WNT1 a potential player in bone disorders Genet. 2013;92(4):590–597. fact that the anabolic effect of anti-scleros- characterized by dysfunctional osteocytes 6. Joeng KS, et al. The swaying mouse as a model of osteogenesis imperfecta caused by WNT1 muta- tin therapy is still seen in the absence of and abnormal bone mass. For example, tions. Hum Mol Genet. 2014;23(15):4035–4042. WNT1 indicates that other WNT ligands in X-linked hypophosphatemic rickets, 7. Plotkin LI, Bellido T. Osteocytic signalling path- are available in the bone environment which is caused by phosphate-regulating ways as therapeutic targets for bone fragility. to signal through LRP5. Potential candi- endopeptidase homolog, X-linked (PHEX) Nat Rev Endocrinol. 2016;12(10):593–605. dates for such a compensatory mecha- mutations, the bone matrix surrounding 8. Repp F, et al. Spatial heterogeneity in the canalic- ular density of the osteocyte network in human nism include WNT7b and WNT10b, which osteocytes is hypomineralized, but over- osteons. Bone Rep.