Vitamin D3 metabolite enables bone fracture repair

Upwards of 10% of all bone fractures fail to heal properly, with dysfunctional repair even more common in individuals with metabolic defects. Vitamin D has been implicated in fracture healing, which involves formation of a soft callus at the fracture site that is later mineralized and ossified. In this episode, René St-Arnaud and colleagues determined that that ossification is impaired in Cyp24a1-deficient mice, which are unable to synthesize the vitamin D metabolite 24R,25-dihydroxyvitamin D3, following traumatic bone injury. FAM57B2 was upregulated in the fracture callus of Cyp24a1-deficient mice and an interaction between FAM57B2 and 24R,25-dihydroxyvitamin D3 in chondrocytes produced lactosylceramide, which supports callus mineralization. Importantly, lactosylceramide supplementation improved mineralization in both Cyp24a1- and Fam57b2-deficient calluses, suggesting that this 24R,25-dihydroxyvitamin D3–dependent pathway has potential to be targeted to optimize bone repair after fracture.

CaMK4 drives podocyte injury

Podocyte dysfunction is a hallmark of kidney injury and occurs in both autoimmune and nonautoimmune renal diseases. Calcium signaling underlies podocyte injury; however, the factors that promote calcium signaling in podocytes in response to injury are not fully understood. In this episode, George Tsokos and colleagues demonstrate that Ca²⁺/calmodulin–dependent kinase 4 (CaMK4) is increased in podocytes from patients with lupus nephritis and focal segmental glomerulosclerosis and in mouse models of lupus and kidney injury. Moreover, administration of a CaMK4 inhibitor prevented nephritis in lupus-prone mice and ameliorated podocyte damage in mice with kidney injury. Togeither, this study identifies CaMK4 activation as a driver of podocyte dysfunction and suggests CaMK4 inhibition be further explored for treating podocytopathies.

JCI’s Conversations with Giants in Medicine: Cornelia Bargmann

How are behavioral decisions modified by context and experience? Cornelia Bargmann of Rockefeller University has made this her life’s work, exploring the intersection between genes, the environment, and the nervous system in the roundworm, C. elegans. Bargmann is also seeking to help cure, manage, and prevent all disease by the year 2100 by serving as Head of Science for the Chan Zuckerberg Initiative.

Altered abiraterone metabolism in individuals with HSD3B1 variant

Prostate cancer is driven by stimulation of the androgen receptor (AR) with testosterone and the potent metabolite 5α-dihydrotestosterone; therefore, androgen deprivation, via medical or surgical castration, is the standard treatment for disease. Unfortunately, extragonadal androgen production often increases in response to castration. In particular, patients with a 1245A>C variant of HSD3B1, which encodes 3β-hydroxysteroid dehydrogenase-1(3βHSD1), exhibit rapid development of castration resistance. In this episode, Nima Sharifi and colleagues evaluated the effect of the HSD3B1(1245C) variant on metabolism of abiraterone, a drug used to block extragonadal androgens. Compared to those with HSD3B1(1245A), those with the mutation had increased levels of the metabolite 3-keto-5α-abiraterone, which has androgenic activity. These results support further investigation into the clinical consequences of increased 3-keto-5α-abiraterone in patients harboring HSD3B1(1245C).

JAK inhibitor treatment shows benefit for patients with interferonopathies

Patients with IFN-mediated autoinflammatory diseases, such as CANDLE and SAVI, present with a variety of severe manifestations, including fever and inflammatory organ damage, and have a high mortality rate. Many of these patients fail to respond to IL-1-blocking agents or other approved therapies for autoinflammatory disease.  In this episode, Gina A. Montealegre Sanchez, Raphaela Goldbach-Mansky, and colleagues present the results of compassionate use, dose-escalation study of the JAK1/2 inhibitor baricitinib in small cohort of patients with interferonopathies. Baricitinib treatment reduced clinical manifestations and inflammatory biomarkers in most patients with few adverse effects, supporting the use of JAK inhibitors for this subtype of autoinflammatory disease.