Stimulation of fracture mineralization by salt-inducible kinase inhibitors.

Introduction: Over 6.8 million fractures occur annually in the US, with 10% experiencing delayed- or non-union. Anabolic therapeutics like PTH analogs stimulate fracture repair, and small molecule salt inducible kinase (SIK) inhibitors mimic PTH action.

DNAJB1-PRKACA fusion drives fibrolamellar liver cancer through impaired SIK signaling and CRTC2/p300-mediated transcriptional reprogramming.

Fibrolamellar carcinoma (FLC) is a liver cancer of adolescents and young adults characterized by fusions of the genes encoding the protein kinase A catalytic subunit, PRKACA, and heat shock protein, DNAJB1. The chimeric DNAJB1-PRKACA protein has increased kinase activity and is essential for FLC xenograft growth. Here, we explore the critical oncogenic pathways controlled by DNAJB1-PRKACA using patient-derived FLC models, engineered systems, and patient samples.

Control of alveolar bone development, homeostasis, and socket healing by salt inducible kinases.

Unlabelled: Alveolar bone supports and anchors teeth. The parathyroid hormone-related protein (PTHrP) pathway plays a key role in alveolar bone biology. Salt inducible kinases (SIKs) are important downstream regulators of PTH/PTHrP signaling in the appendicular skeleton where SIK inhibition increases bone formation and trabecular bone mass.

Regulation of intracellular cAMP levels in osteocytes by mechano-sensitive focal adhesion kinase via PDE8A.

Osteocytes are the primary mechano-sensitive cell type in bone. Mechanical loading is sensed across the dendritic projections of osteocytes leading to transient reductions in focal adhesion kinase (FAK) activity. Knowledge regarding the signaling pathways downstream of FAK in osteocytes is incomplete.

A homozygous mutation causes osteogenesis and dentinogenesis imperfecta with craniofacial anomalies.

Osteogenesis imperfecta (OI) is a heterogeneous spectrum of hereditary genetic disorders that cause bone fragility, through various quantitative and qualitative defects of type 1 collagen, a triple helix composed of two α1 and one α2 chains encoded by and , respectively. The main extra-skeletal manifestations of OI include blue sclerae, opalescent teeth, and hearing impairment. Moreover, multiple genes involved in osteoblast maturation and type 1 collagen biosynthesis are now known to cause recessive forms of OI.

The performance of artificial intelligence chatbot large language models to address skeletal biology and bone health queries.

Artificial intelligence (AI) chatbots utilizing large language models (LLMs) have recently garnered significant interest due to their ability to generate humanlike responses to user inquiries in an interactive dialog format. While these models are being increasingly utilized to obtain medical information by patients, scientific and medical providers, and trainees to address biomedical questions, their performance may vary from field to field. The opportunities and risks these chatbots pose to the widespread understanding of skeletal health and science are unknown.

Blood and bones: Mechanical cues and Hippo signaling drive vascular invasion during limb formation.

Although mechanical cues are known to influence the postnatal skeleton, the impact of bone cell mechano-transduction on early skeletal development remains less clear. In this issue of Developmental Cell, Collins et al. (2023) report that YAP/TAZ deletion in osteoblast precursors reduces Cxcl12 expression, leading to defects in bone vascularization.

Supporting Our Physician Parents (SOPPort): A pilot program for parental wellness at the Massachusetts General Hospital.

Physician parents encounter unique challenges in balancing new parenthood with work responsibilities, especially upon their return from parental leave. We designed a pilot program that incorporated 1:1 parental coaching to expectant and new physician parents and provided stipends for lactation support and help at home. Additional initiatives included launching a virtual new parent group during the COVID-19 pandemic and starting an emergency backup pump supplies program.

Selective reduction of visceral adipose tissue with injectable ice slurry.

Reduction in visceral adipose tissue (VAT) mass reduces body weight and metabolic disease risk in obese patients. However surgical removal of VAT is highly invasive and thus not clinically feasible. We developed an injectable ice slurry for selective reduction of adipose tissue through cryolipolysis.

A parathyroid hormone/salt-inducible kinase signaling axis controls renal vitamin D activation and organismal calcium homeostasis.

The renal actions of parathyroid hormone (PTH) promote 1,25-vitamin D generation; however, the signaling mechanisms that control PTH-dependent vitamin D activation remain unknown. Here, we demonstrated that salt-inducible kinases (SIKs) orchestrated renal 1,25-vitamin D production downstream of PTH signaling. PTH inhibited SIK cellular activity by cAMP-dependent PKA phosphorylation.

Kidney glycolysis serves as a mammalian phosphate sensor that maintains phosphate homeostasis.

How phosphate levels are detected in mammals is unknown. The bone-derived hormone fibroblast growth factor 23 (FGF23) lowers blood phosphate levels by reducing kidney phosphate reabsorption and 1,25(OH)2D production, but phosphate does not directly stimulate bone FGF23 expression. Using PET scanning and LC-MS, we found that phosphate increases kidney-specific glycolysis and synthesis of glycerol-3-phosphate (G-3-P), which then circulates to bone to trigger FGF23 production.

Structure-based design of selective, orally available salt-inducible kinase inhibitors that stimulate bone formation in mice.

Osteoporosis is a major public health problem. Currently, there are no orally available therapies that increase bone formation. Intermittent parathyroid hormone (PTH) stimulates bone formation through a signal transduction pathway that involves inhibition of salt-inducible kinase isoforms 2 and 3 (SIK2 and SIK3).

Rapid genomic changes by mineralotropic hormones and kinase SIK inhibition drive coordinated renal Cyp27b1 and Cyp24a1 expression via CREB modules.

Vitamin D metabolism centers on kidney regulation of Cyp27b1 by mineralotropic hormones, including induction by parathyroid hormone (PTH), suppression by fibroblast growth factor 23 (FGF23) and 1,25-dihydroxyvitamin D (1,25(OH)D), and reciprocal regulations for Cyp24a1. This coordinated genomic regulation results in production of endocrine 1,25(OH)D, which, together with PTH and FGF23, controls mineral homeostasis. However, how these events are coordinated is unclear.

Partial prevention of glucocorticoid-induced osteocyte deterioration in young male mice with osteocrin gene therapy.

Glucocorticoid excess suppresses osteocyte remodeling of surrounding bone minerals, causes apoptosis of osteoblasts and osteocytes, and disrupts bone remodeling, eventually, leading to glucocorticoid-induced osteoporosis and bone fragility. Preventing apoptosis and preserving osteocyte morphology could be an effective means of preventing bone loss during glucocorticoid treatment. We hypothesized that osteocrin, which preserves osteocyte viability and morphology in Sp7-deficient mice, could prevent osteocyte death and dysfunction in a glucocorticoid excess model.

Salt inducible kinases and PTH1R action.

Parathyroid hormone is a central regulator of calcium homeostasis. PTH protects the organism from hypocalcemia through its actions in bone and kidney. Recent physiologic studies have revealed key target genes for PTH receptor (PTH1R) signaling in these target organs.

Actions of Parathyroid Hormone Ligand Analogues in Humanized PTH1R Knockin Mice.

Rodent models are commonly used to evaluate parathyroid hormone (PTH) and PTH-related protein (PTHrP) ligands and analogues for their pharmacologic activities and potential therapeutic utility toward diseases of bone and mineral ion metabolism. Divergence, however, in the amino acid sequences of rodent and human PTH receptors (rat and mouse PTH1Rs are 91% identical to the human PTH1R) can lead to differences in receptor-binding and signaling potencies for such ligands when assessed on rodent vs human PTH1Rs, as shown by cell-based assays in vitro. This introduces an element of uncertainty in the accuracy of rodent models for performing such preclinical evaluations.

Control of osteocyte dendrite formation by Sp7 and its target gene osteocrin.

Some osteoblasts embed within bone matrix, change shape, and become dendrite-bearing osteocytes. The circuitry that drives dendrite formation during "osteocytogenesis" is poorly understood. Here we show that deletion of Sp7 in osteoblasts and osteocytes causes defects in osteocyte dendrites.

Dnmt3a-mutated clonal hematopoiesis promotes osteoporosis.

Osteoporosis is caused by an imbalance of osteoclasts and osteoblasts, occurring in close proximity to hematopoietic cells in the bone marrow. Recurrent somatic mutations that lead to an expanded population of mutant blood cells is termed clonal hematopoiesis of indeterminate potential (CHIP). Analyzing exome sequencing data from the UK Biobank, we found CHIP to be associated with increased incident osteoporosis diagnoses and decreased bone mineral density.

Dual targeting of salt inducible kinases and CSF1R uncouples bone formation and bone resorption.

Bone formation and resorption are typically coupled, such that the efficacy of anabolic osteoporosis treatments may be limited by bone destruction. The multi-kinase inhibitor YKL-05-099 potently inhibits salt inducible kinases (SIKs) and may represent a promising new class of bone anabolic agents. Here, we report that YKL-05-099 increases bone formation in hypogonadal female mice without increasing bone resorption.

Comparable Initial Engagement of Intracellular Signaling Pathways by Parathyroid Hormone Receptor Ligands Teriparatide, Abaloparatide, and Long-Acting PTH.

Multiple analogs of parathyroid hormone, all of which bind to the PTH/PTHrP receptor PTH1R, are used for patients with osteoporosis and hypoparathyroidism. Although ligands such as abaloparatide, teriparatide (hPTH 1-34 [TPTD]), and long-acting PTH (LA-PTH) show distinct biologic effects with respect to skeletal and mineral metabolism endpoints, the mechanistic basis for these clinically-important differences remains incompletely understood. Previous work has revealed that differential signaling kinetics and receptor conformation engagement between different PTH1R peptide ligands.

Sclerostin and Osteocalcin: Candidate Bone-Produced Hormones.

In addition to its structural role, the skeleton serves as an endocrine organ that controls mineral metabolism and energy homeostasis. Three major cell types in bone - osteoblasts, osteoclasts, and osteocytes - dynamically form and maintain bone and secrete factors with systemic activity. Osteocalcin, an osteoblast-derived factor initially described as a matrix protein that regulates bone mineralization, has been suggested to be an osteoblast-derived endocrine hormone that regulates multiple target organs including pancreas, liver, muscle, adipose, testes, and the central and peripheral nervous system.