Skeletal Disorders and Mineral Homeostasis Section

National Institute Of Dental & Craniofacial Research

Investigators

Linked publications & trials

Abstract

Fibrous Dysplasia/McCune-Albright Syndrome: Clinical work this year included an expansion of our understanding of the spectrum of craniofacial FD by defining the prevalence, risk factors, and implications of the finding of optic disc edema (PMID: 32979536), the clinical presentation and management of vascular anomalies in craniofacial FD ( PMID: 32556405), and the importance, utility and implications the measurement of retinal nerve fiber layer thickness of the optic nerve by optical coherence tomography (PMID: 32644197). Our recent determination that the R201H mutation that causes FD/MAS is almost two times as prevalent as the other pathogenic mutation, R201C, will help guide efforts currently under way to develop small molecule drugs that target Gs (PMID: 33512531). An important finding in FD has been the identification of the central role of Gs/cAMP-mediated receptor activator of nuclear factor kappa- ligand (RANKL)-dependent osteoclastogenesis in the pathophysiology of the disease (PMID: 30496606). This translational work supported the preliminarily very successful ongoing clinical trial of the anti-RANKL mAb drug denosumab in FD that Dr. Alison Boyce is currently conducting (NCT03571191). Future work is planned in this area. Hypoparathyroidism: Modulation of the function of the CASR by small molecule allosteric modulators of the CASR has represented a major breakthrough in the field of mineral homeostasis ( PMID: 9543122). Early phase studies of negative allosteric modulators of the CASR (calcilytics) ( PMID: 31063613) made us confident that a drug in this class could represent an effective treatment of our cohort of our patients with ADH1, the most profoundly affected and difficult to treat group of patients with hypoparathyroidism. Based on our earlier successful proof of principle study ( PMID: 31063613), we partnered with BridgeBio Pharma as part of a public-private partnership to develop a calcilytic to treat ADH1. The ensuing partnership and preliminary results of our ongoing phase 2 study conducted by the Principal Investigator, Rachel Gafni, and recently presented at ENDO 2021 make clear that our hypothesis was correct. Additional early results 100% response rate, and correction of all abnormal parameters of mineral homeostasis will be presented by Rachel Gafni in an oral presentation at the upcoming meeting of the Amer Soc Bone and Miner Res 2021, ASBMR. This work suggests that this drug will be a generationally life-altering therapy for patients and families with this debilitating autosomal dominant disorder. The study of monogenic disorders of altered mineral homeostasis, such as ADH1, and its treatment with novel clinical tools such as encaleret, allow for the utilization of experiments in nature and the study human mineral physiology in ways not previously possible. This study, and future work will inform our understanding of the role of CASR signaling in Ca/Pi/PTH/FGF23 physiology never before possible. Tumor-induced osteomalacia (TIO): Our contribution to the identification of fibronectin-FGFR1 translocations as potential drivers of the development of the PMTs that cause TIO immediately raised the question if FGFR1 signaling was a driver of TIO ( PMID: 27443518). This led us to conduct a compassionate use study led by our Clinical Fellow, Iris Hartley, of the FGFR inhibitor infigratinib in a patient with metastatic PMT through ( PMID: 32905668). This strikingly successful study not only added five years of life to this man with incapacitating metastatic TIO, it also proved the etiologic role of FGFR1 signaling by the FN1-FGFR1 chimeric protein in the pathomechamism of PMTs and TIO. Based on the early success of this study, we conducted on open label, phase 2 study of infigratinib in patients with benign TIO. Again, the drug proved effective in decreasing FGF23 and normalizing blood phosphate, however, in the first four patients treated the primary endpoint, normalization of blood phosphate after discontinuation, was not met. At the end of the treatment period, FGF23 levels returned to baseline values in all patients. This, combined with the fact treatment was associated with dose-limiting ocular adverse events in all subjects ( PMID: 32888946), led to early closure of the study. Cutaneous Skeletal Hypophosphatemia Syndrome: One of the prevailing clinical questions in the disorder we previously described, CSHS ( PMID: 24006476), was the source of elevated, pathogenic FGF23. For years it had been postulated the associated skin lesions might be the source. This often led to painful, disfiguring, and always unsuccessful resection of the large areas of affected skin in CSHS. Based on our previous seminal finding that bone is the physiological source of FGF23 ( PMID: 12952917), we hypothesized that dysplastic bone is the source in CSHS. To test this hypothesis, our former postdoctoral fellow, Diana Ovejero, created a mouse model of CSHS. After Dianas return to Spain, Luis Fernandez de Castro refined the model, compared it to models we obtained from a collaborator in the NCI, Stuart Yupsa, in which the same Ras variants are dermally expressed, and has been able to convincingly demonstrate that dysplastic bone, not skin, is the source of FGF23. This work will be present as a plenary poster at the upcoming ASBMR meeting. Familial Hyperphosphatemic Tumoral Calcinosis: While our determination of the physiology, clinical, biochemical, and genetic spectrum of our cohort of patients with HFTC over the past decade, including our recent characterization of the pathognomonic dental phenotype (PMID: 33977199), has led the field in defining HFTC, efforts to treat these patients had been very frustrating. This has now become the focus of our ongoing and future efforts. Part of this work is being done with collaborators Babak Saboury in the NIH Clinical Center Department of Imaging Services and Dale Kiesewetter the NIBIB and entails the development of 18F NaF PET/CT scanning as clinical tool to measure disease burden in HFTC. This work will be critical as a validated, clinically meaningful endpoint when therapies make it to the clinic. Fueled by the finding of altered posttranslational modification of FGF23 by loss-of-function variants in polypeptide N-Acetylgalactosaminyltransferase 3 (GALNT3) in HFTC, we set out to study if and how the posttranslational modification step may be regulated. An evolving hypothesis in the field, based almost exclusively on mouse models, is that the HIF/Fe/EPO (erythropoietin) pathway plays a role in FGF23 regulation. To test this hypothesis, we took advantage of an extremely rare cohort of patients studied at the NIH Clinical Center, patients with somatic gain-of-function variants of HIF2A (EPAS1), who have markedly elevated levels of EPO. We were able to clearly demonstrate that these patients have markedly elevated levels of processed, C-terminal FGF23 that are highly correlated with EPO levels, but completely normal intact FGF23 and blood phosphate (PMID: 33049075). This work is the first human study to convincingly demonstrate the role of the HIF/Fe/EPO pathway in FGF23 regulation.