SummarySkeletal defects in ringelschwanz mutant mice reveal that Lrp6 is required for proper somitogenesis and osteogenesis Research articleDevelopment and disease 5470 of somitogenesis (Aulehla et al., 2003; Hamblet et al., 2002) and of bone mass in adults in humans and mice (Boyden et al., 2002; Gong et al., 2001;Kato et al., 2002;Little et al., 2002). In the context of somite development, Wnt signaling mediated by Wnt3a has been implicated in the specification and propagation of progenitor cells of the paraxial mesoderm in the primitive streak or in the tail bud (Takada et al., 1994;Yoshikawa et al., 1997), and this Wnt signaling is transduced through the canonical β-catenin signaling pathway (Galceran et al., 1999; Galceran et al., 2001). As late functions, Wnt signaling is also known to play essential roles in the dorsoventral patterning of formed somites, which is required for proper development of the dermomyotome and the myotome (Capdevila et al., 1998; Fan et al., 1997;Münsterberg et al., 1995;Wagner et al., 2000). However, whether Wnt signaling plays any significant role in the periodic morphogenetic movement of somitogenesis that takes place in the presomitic mesoderm (PSM) had not been clear until recently. Mouse dishevelled 2 (Dvl2), together with its paralog dishevelled 1 (Dvl1), has recently been shown to be required for somite segmentation, through the analysis of Dvl2-single and Dvl1;Dvl2-double knockout mice (Hamblet et al., 2002). Furthermore, it has recently been demonstrated that a paralog of Axin, Axin2 (also called conductin) exhibits a dynamic and cyclic expression profile in the PSM. This finding, together with the detailed analysis of the notch-delta signaling activity in Wnt3a mutants, has provided clear evidence for the involvement of Wnt signaling in the process of somitogenesis in the PSM, functioning upstream of notch-delta signaling (Aulehla et al., 2003). On the other hand, recent studies have also elucidated another, unexpected functional aspect of Wnt signaling in the postnatal life, with the identification of Lrp5 as one of the key genetic factors that control bone mass. Positional cloning of the gene responsible for osteoporosispseudoglioma syndrome (OPPG), an autosomal recessive disorder in humans, revealed that loss-of-function mutations in LRP5 lead to a low bone mass phenotype (osteoporosis) (Gong et al., 2001). Despite the availability of Lrp6-null mouse mutants (Pinson et al., 2000), whether Lrp6 plays any roles in somitogenesis during development and in the control of bone mass during adult life has not been known, because of strong pleiotropic effects of Lrp6 deficiency that leads to neonatal lethality (Pinson et al., 2000). In the present study, we demonstrate that Lrp6 is required for somitogenesis and osteogenesis, through the analysis of a novel spontaneous mouse mutation ringelschwanz (rs), identified in this study as a viable hypomorphic allele of Lrp6. Materials and methods MiceThe rs mutant strain is maintained on the BALB/c background. For a backcross m...

In adults with X‐linked hypophosphatemia (XLH), excess FGF23 impairs renal phosphate reabsorption and suppresses production of 1,25‐dihydroxyvitamin D, resulting in chronic hypophosphatemia and persistent osteomalacia. Osteomalacia is associated with poor bone quality causing atraumatic fractures, pseudofractures, delayed fracture healing, and bone pain. Burosumab is a fully human monoclonal antibody against FGF23. UX023‐CL304 is an ongoing, open‐label, single‐arm, phase 3 study investigating the efficacy of subcutaneous burosumab, 1.0 mg/kg administered every 4 weeks, in improving osteomalacia in adults with XLH who have not been treated for at least 2 years before enrollment. The primary endpoint was improvement in osteoid volume/bone volume assessed by transiliac bone biopsies obtained at baseline and week 48. Additional assessments included serum phosphorus, markers of bone turnover, fracture/pseudofracture healing, and safety. Fourteen subjects enrolled, 13 completed 48 weeks, and 11 completed paired biopsies. All osteomalacia‐related histomorphometric measures improved significantly at week 48 (mean percent change: osteoid volume/bone volume, –54%, osteoid thickness, –32%, osteoid surface/bone surface, –26%, [median] mineralization lag time, –83%). Mean serum phosphorus concentration averaged across the mid‐point of the dose cycle between weeks 0 and 24 was 3.3 mg/dL, a 50% increase from 2.2 mg/dL at baseline. Markers of bone formation and resorption increased at week 48 (least squares [LS] mean increase: P1NP, +77%; CTx, +36%; both p < 0.0001). All subjects had one or more treatment‐emergent adverse event (AE). Most AEs were mild to moderate in severity. Two subjects experienced serious AEs (migraine; paresthesia) that were unrelated to treatment and resolved. Eleven subjects had 18 biopsy procedure‐related AEs: 14 for pain, two for itch, and one each for headache and bandage irritation. No deaths or incidents of hyperphosphatemia occurred. In conclusion, by normalizing phosphate homeostasis, burosumab significantly improved osteomalacia in adults with XLH, which likely explains the improved fracture healing and amelioration of skeletal complications. © 2019 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.

Burosumab, a fully human monoclonal antibody to FGF23, is the only approved treatment for X-linked hypophosphatemia (XLH), a rare genetic disorder characterized by renal phosphate wasting and substantial cumulative musculoskeletal morbidity. During an initial 24-week randomized, controlled trial, 134 adults with XLH received burosumab 1 mg/kg (n = 68) or placebo (n = 66) every 4 weeks. After 24 weeks, all subjects received open-label burosumab until week 48. This report describes the efficacy and safety of burosumab during the open-label treatment period. From weeks 24-48, serum phosphorus concentrations remained normal in 83.8% of participants who received burosumab throughout and were normalized in 89.4% who received burosumab after placebo. By week 48, 63.1% of baseline fractures/pseudofractures healed fully with burosumab, compared with 35.2% with burosumab after placebo. In both groups, burosumab was associated with clinically significant and sustained improvement from baseline to week 48 in scores for patient-reported outcomes of stiffness, pain, physical function, and total distance walked in 6 min. Rates of adverse events were similar for burosumab and placebo. There were no fatal adverse events or treatment-related serious adverse events. Nephrocalcinosis scores did not change from baseline by more than one grade at either week 24 or 48. These data demonstrate that in participants with XLH, continued treatment with burosumab is well tolerated and leads to sustained correction of serum phosphorus levels, continued healing of fractures and pseudofractures, and sustained improvement in key musculoskeletal impairments.

A variety of in vivo models have increased understanding of the role of Wnt signaling in bone since mutations in the LRP5 gene were found in human bone disorders. Canonical Wnt signaling encourages mesenchymal progenitor cells to differentiate into osteoblasts. In osteoblasts, Wnt pathway also promotes proliferation and mineralization, while blocks apoptosis and osteoclastogenesis by increasing the OPG/RANKL ratio. Lrp6-mediated signaling in osteoblasts may regulate osteoclastogenesis. However, the role of canonical Wnt signaling in osteoclasts remains unknown, and our understanding of the role of non-canonical Wnt signaling in bone biology is also not sufficient. As to pharmacological intervention, many levels may be considered to target in Wnt signaling pathway, although tumorigenicity and toxicity to other tissues are important. Mesd might be one of target molecules to increase the quantity of LRP5/6 in the plasma membrane. Since sclerostin is almost exclusively expressed in osteocytes, abrogating sclerostin is the most promising design.