Muriel Babey

All Publications

• A maternal brain hormone that builds bone. Nature Babey, M. E., Krause, W. C., Chen, K., Herber, C. B., Torok, Z., Nikkanen, J., Rodriguez, R., Zhang, X., Castro-Navarro, F., Wang, Y., Wheeler, E. E., Villeda, S., Leach, J. K., Lane, N. E., Scheller, E. L., Chan, C. K., Ambrosi, T. H., Ingraham, H. A. 2024

  Abstract

  In lactating mothers, the high calcium (Ca2+) demand for milk production triggers significant bone loss1. Although oestrogen normally counteracts excessive bone resorption by promoting bone formation, this sex steroid drops precipitously during this postpartum period. Here we report that brain-derived cellular communication network factor 3 (CCN3) secreted from KISS1 neurons of the arcuate nucleus (ARCKISS1) fills this void and functions as a potent osteoanabolic factor to build bone in lactating females. We began by showing that our previously reported female-specific, dense bone phenotype2 originates from a humoral factor that promotes bone mass and acts on skeletal stem cells to increase their frequency and osteochondrogenic potential. This circulatory factor was then identified as CCN3, a brain-derived hormone from ARCKISS1 neurons that is able to stimulate mouse and human skeletal stem cell activity, increase bone remodelling and accelerate fracture repair in young and old mice of both sexes. The role of CCN3 in normal female physiology was revealed after detecting a burst of CCN3 expression in ARCKISS1 neurons coincident with lactation. After reducing CCN3 in ARCKISS1 neurons, lactating mothers lost bone and failed to sustain their progeny when challenged with a low-calcium diet. Our findings establish CCN3 as a potentially new therapeutic osteoanabolic hormone for both sexes and define a new maternal brain hormone for ensuring species survival in mammals.

  View details for DOI 10.1038/s41586-024-07634-3

  View details for PubMedID 38987585

  View details for PubMedCentralID 6329772

• No Evidence of Association Between Undercarboxylated Osteocalcin and Incident Type 2 Diabetes. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research Babey, M. E., Ewing, S. K., Strotmeyer, E. S., Napoli, N., Schafer, A. L., Vittinghoff, E., Gundberg, C. M., Schwartz, A. V. 2022; 37 (5): 876-884

  Abstract

  Mouse models suggest that undercarboxylated osteocalcin (ucOC), produced by the skeleton, protects against type 2 diabetes development, whereas human studies have been inconclusive. We aimed to determine if ucOC or total OC is associated with incident type 2 diabetes or changes in fasting glucose, insulin resistance (HOMA-IR), or beta-cell function (HOMA-Beta). A subcohort (n = 338; 50% women; 36% black) was identified from participants without diabetes at baseline in the Health, Aging, and Body Composition Study. Cases of incident type 2 diabetes (n = 137) were defined as self-report at an annual follow-up visit, use of diabetes medication, or elevated fasting glucose during 8 years of follow-up. ucOC and total OC were measured in baseline serum. Using a case-cohort design, the association between biomarkers and incident type 2 diabetes was assessed using robust weighted Cox regression. In the subcohort, linear regression models analyzed the associations between biomarkers and changes in fasting glucose, HOMA-IR, and HOMA-Beta over 9 years. Higher levels of ucOC were not statistically associated with increased risk of incident type 2 diabetes (adjusted hazard ratio = 1.06 [95% confidence interval, 0.84-1.34] per 1 standard deviation [SD] increase in ucOC). Results for %ucOC and total OC were similar. Adjusted associations of ucOC, %ucOC, and total OC with changes in fasting glucose, HOMA-IR, and HOMA-Beta were modest and not statistically significant. We did not find evidence of an association of baseline undercarboxylated or total osteocalcin with risk of incident type 2 diabetes or with changes in glucose metabolism in older adults. © 2022 American Society for Bone and Mineral Research (ASBMR).

  View details for DOI 10.1002/jbmr.4519

  View details for PubMedID 35118705

  View details for PubMedCentralID PMC10441038

• An Unusual Case of Colonic Intussusception Masquerading as a Transverse Colon Mass. The American journal of gastroenterology Ramesh, R., Juhn, A., Babey, M., Patel, K., Liu, B. 2016; 111 (7): 921

  View details for DOI 10.1038/ajg.2016.263

  View details for PubMedID 27356812

• Osteoblast-Specific Loss of IGF1R Signaling Results in Impaired Endochondral Bone Formation During Fracture Healing. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research Wang, T., Wang, Y., Menendez, A., Fong, C., Babey, M., Tahimic, C. G., Cheng, Z., Li, A., Chang, W., Bikle, D. D. 2015; 30 (9): 1572-84

  Abstract

  Insulin-like growth factors (IGFs) are important local regulators during fracture healing. Although IGF1 deficiency is known to increase the risk of delayed union or non-union fractures in the elderly population, the underlying mechanisms that contribute to this defect remains unclear. In this study, IGF1 signaling during fracture healing was investigated in an osteoblast-specific IGF1 receptor (IGF1R) conditional knockout (KO) mouse model. A closed tibial fracture was induced in IGF1R(flox/flox) /2.3-kb α1(1)-collagen-Cre (KO) and IGF1R(flox/flox) (control) mice aged 12 weeks. Fracture callus samples and nonfractured tibial diaphysis were collected and analyzed by μCT, histology, immunohistochemistry, histomorphometry, and gene expression analysis at 10, 15, 21, and 28 days after fracture. A smaller size callus, lower bone volume accompanied by a defect in mineralization, bone microarchitectural abnormalities, and a higher cartilage volume were observed in the callus of these KO mice. The levels of osteoblast differentiation markers (osteocalcin, alkaline phosphatase, collagen 1α1) were significantly reduced, but the early osteoblast transcription factor runx2, as well as chondrocyte differentiation markers (collagen 2α1 and collagen 10α1) were significantly increased in the KO callus. Moreover, increased numbers of osteoclasts and impaired angiogenesis were observed during the first 15 days of fracture repair, but decreased numbers of osteoclasts were found in the later stages of fracture repair in the KO mice. Although baseline nonfractured tibias of KO mice had decreased trabecular and cortical bone compared to control mice, subsequent studies with mice expressing the 2.3-kb α1(1)-collagen-Cre ERT2 construct and given tamoxifen at the time of fracture and so starting with comparable bone levels showed similar impairment in fracture repair at least initially. Our data indicate that not only is the IGF1R in osteoblasts involved in osteoblast differentiation during fracture repair, but it plays an important role in coordinating chondrocyte, osteoclast, and endothelial responses that all contribute to the endochondral bone formation required for normal fracture repair.

  View details for DOI 10.1002/jbmr.2510

  View details for PubMedID 25801198

  View details for PubMedCentralID PMC5690481

• Gender-Specific Differences in the Skeletal Response to Continuous PTH in Mice Lacking the IGF1 Receptor in Mature Osteoblasts. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research Babey, M., Wang, Y., Kubota, T., Fong, C., Menendez, A., ElAlieh, H. Z., Bikle, D. D. 2015; 30 (6): 1064-76

  Abstract

  The primary goal of this study was to determine whether the IGF1R in mature osteoblasts and osteocytes was required for the catabolic actions of continuous parathyroid hormone (cPTH). Igf1r was deleted from male and female FVN/B mice by breeding with mice expressing cre recombinase under control of the osteocalcin promoter ((0CN) Igfr1(-/-) ). Littermates lacking the cre recombinase served as controls. PTH, 60 μg/kg/d, was administered continuously by Alzet minipumps for 4 weeks. Blood was obtained for indices of calcium metabolism. The femurs were examined by micro-computed tomography for structure, immunohistochemistry for IGF1R expression, histomorphometry for bone formation rates (BFR), mRNA levels by qPCR, and bone marrow stromal cell cultures (BMSC) for alkaline phosphatase activity (ALP(+) ), mineralization, and osteoblast-induced osteoclastogenesis. Whereas cPTH led to a reduction in trabecular bone volume/tissue volume (BV/TV) and cortical thickness in the control females, no change was found in the control males. Although trabecular BV/TV and cortical thickness were reduced in the (0CN) Igfr1(-/-) mice of both sexes, no further reduction after cPTH was found in the females, unlike the reduction in males. BFR was stimulated by cPTH in the controls but blocked by Igf1r deletion in the females. The (0CN) Igfr1(-/-) male mice showed a partial response. ALP(+) and mineralized colony formation were higher in BMSC from control males than from control females. These markers were increased by cPTH in both sexes, but BMSC from male (0CN) Igfr1(-/-) also were increased by cPTH, unlike those from female (0CN) Igfr1(-/-) . cPTH stimulated receptor activator of NF-κB ligand (RANKL) and decreased osteoprotegerin and alkaline phosphatase expression more in control female bone than in control male bone. Deletion of Igf1r blocked these effects of cPTH in the female but not in the male. However, PTH stimulation of osteoblast-driven osteoclastogenesis was blocked by deleting Igfr1 in both sexes. We conclude that cPTH is catabolic in female but not male mice. Moreover, IGF1 signaling plays a greater role in the skeletal actions of cPTH in the female mouse than in the male mouse, which may underlie the sex differences in the response to cPTH.

  View details for DOI 10.1002/jbmr.2433

  View details for PubMedID 25502173

  View details for PubMedCentralID PMC9045460

• Insulin-like growth factor-1 receptor in mature osteoblasts is required for periosteal bone formation induced by reloading. Acta astronautica Kubota, T., Elalieh, H. Z., Saless, N., Fong, C., Wang, Y., Babey, M., Cheng, Z., Bikle, D. D. 2013; 92 (1): 73-78

  Abstract

  Skeletal loading and unloading has a pronounced impact on bone remodeling, a process also regulated by insulin-like growth factor 1 (IGF-1) signaling. Skeletal unloading leads to resistance to the anabolic effect of IGF-1, while reloading after unloading restores responsiveness to IGF-1. However, a direct study of the importance of IGF-1 signaling in the skeletal response to mechanical loading remains to be tested. In this study, we assessed the skeletal response of osteoblast-specific Igf-1 receptor deficient (Igf-1r-/- ) mice to unloading and reloading. The mice were hindlimb unloaded for 14 days and then reloaded for 16 days. Igf-1r-/- mice displayed smaller cortical bone and diminished periosteal and endosteal bone formation at baseline. Periosteal and endosteal bone formation decreased with unloading in Igf-1r+/+ mice. However, the recovery of periosteal bone formation with reloading was completely inhibited in Igf-1r-/- mice, although reloading-induced endosteal bone formation was not hampered. These changes in bone formation resulted in the abolishment of the expected increase in total cross-sectional area with reloading in Igf-1r-/- mice compared to the control mice. These results suggest that the Igf-1r in mature osteoblasts has a critical role in periosteal bone formation in the skeletal response to mechanical loading.

  View details for DOI 10.1016/j.actaastro.2012.08.007

  View details for PubMedID 23976802

  View details for PubMedCentralID PMC3747570

• Pituitary surgery for small prolactinomas as an alternative to treatment with dopamine agonists. Pituitary Babey, M., Sahli, R., Vajtai, I., Andres, R. H., Seiler, R. W. 2011; 14 (3): 222-30

  Abstract

  Despite the fact that consensus guidelines recommend long-term dopamine agonist (DA) therapy as a first-line approach to the treatment of small prolactinoma, some patients continue to prefer a primary surgical approach. Concerns over potential adverse effects of long-term medical therapy and/or the desire to become pregnant and avoid long-term medication are often mentioned as reasons to pursue surgical removal. In this retrospective study, 34 consecutive patients (30 female, 4 male) preferably underwent primary pituitary surgery without prior DA treatment for small prolactinomas (microprolactinoma 1-10 mm, macroprolactinoma 11-20 mm) at the Department of Neurosurgery, University of Bern, Switzerland. At the time of diagnosis, 31 of 34 patients (91%) presented with symptoms. Patients with microprolactinomas had significantly lower preoperative prolactin (PRL) levels compared to patients with macroprolactinomas (median 143 μg/l vs. 340 μg/l). Ninety percent of symptomatic patients experienced significant improvement of their signs and symptoms upon surgery. The postoperative PRL levels (median 3.45 μg/l) returned to normal in 94% of patients with small prolactinomas. There was no mortality and no major morbidities. One patient suffered from hypogonadotropic hypogonadism after surgery despite postoperative normal PRL levels. Long-term remission was achieved in 22 of 24 patients (91%) with microprolactinomas, and in 8 of 10 patients (80%) with macroprolactinomas after a median follow-up period of 33.5 months. Patients with small prolactinomas can safely consider pituitary surgery in a specialized centre with good chance of long-term remission as an alternative to long-term DA therapy.

  View details for DOI 10.1007/s11102-010-0283-y

  View details for PubMedID 21170594

  View details for PubMedCentralID PMC3146980

• Familial forms of diabetes insipidus: clinical and molecular characteristics. Nature reviews. Endocrinology Babey, M., Kopp, P., Robertson, G. L. 2011; 7 (12): 701-14

  Abstract

  Over the past two decades, the genetic and molecular basis of familial forms of diabetes insipidus has been elucidated. Diabetes insipidus is a clinical syndrome characterized by the excretion of abnormally large volumes of diluted urine (polyuria) and increased fluid intake (polydipsia). The most common type of diabetes insipidus is caused by lack of the antidiuretic hormone arginine vasopressin (vasopressin), which is produced in the hypothalamus and secreted by the neurohypophysis. This type of diabetes insipidus is referred to here as neurohypophyseal diabetes insipidus. The syndrome can also result from resistance to the antidiuretic effects of vasopressin on the kidney, either at the level of the vasopressin 2 receptor or the aquaporin 2 water channel (which mediates the re-absorption of water from urine), and is referred to as renal or nephrogenic diabetes insipidus. Differentiation between these two types of diabetes insipidus and primary polydipsia can be difficult owing to the existence of partial as well as complete forms of vasopressin deficiency or resistance. Seven different familial forms of diabetes insipidus are known to exist. The clinical presentation, genetic basis and cellular mechanisms responsible for them vary considerably. This information has led to improved methods of differential diagnosis and could provide the basis of new forms of therapy.

  View details for DOI 10.1038/nrendo.2011.100

  View details for PubMedID 21727914

• Acute onset of polyarthralgia and high anti-cyclic citrullinated peptide antibodies in a case of idiopathic granulomatous hypophysitis. The Journal of rheumatology Babey, M., Aeberli, D., Vajtai, I., Sahli, R. 2009; 36 (1): 204-7

  View details for DOI 10.3899/jrheum.080408

  View details for PubMedID 19208539

• Morbidity in 201 patients with small sized meningioma treated by microsurgery. Acta neurochirurgica Reinert, M., Babey, M., Curschmann, J., Vajtai, I., Seiler, R. W., Mariani, L. 2006; 148 (12): 1257-65; discussion 1266

  Abstract

  The management of patients with small, often asymptomatic meningiomas is controversial and includes observation, microsurgery (MS) and stereotactic radiosurgery (SRS). The purpose of this retrospective study was to analyze the morbidity and the extent of removal after MS for small (< or =3 cm) intracranial meningiomas and compare these results to those of SRS reported in the literature.All patients with an intracranial meningioma with a maximum diameter up to 3 cm operated on in our institution over a 10 year period (1992-2002) were included in the study and retrospectively analyzed. Patients were grouped into asymptomatic and symptomatic and according to tumor location as: group I (cranial vault, parasagittal, lateral sphenoid), group II (falx, frontobasal, medial sphenoid, parasellar and tentorial), group III (cavernous sinus, petroclival, petrosal, CPA and foramen magnum).There were a total of 201 patients, of whom 102 were asymptomatic and 99 were symptomatic. The overall risk of permanent neurological morbidity was 4.9% in asymptomatic and 23.2% in symptomatic patients. The combined risk in asymptomatic and symptomatic patients was 5.4% in group I, 11.5% in group II, and 39.9% in group III lesions. Radical removal was achieved in all patients in group I, in 93.7% of group II, and 80% of group III lesions. There was no disease related mortality.MS provides excellent efficacy and morbidity results in groups I and II meningiomas, especially in asymptomatic patients and might therefore be considered the first choice of treatment for these patients. The results of MS in group III were worse than those of SRS reported in the literature.

  View details for DOI 10.1007/s00701-006-0909-z

  View details for PubMedID 17086473