Pignolo, Robert J.

AbstractGenetic variants are vital in informing clinical phenotypes, aiding physical diagnosis, guiding genetic counseling, understanding the molecular basis of disease, and potentially stimulating drug development. Here we describe two families with an ultrarare ACVR1 gain‐of‐function pathogenic variant (codon 375, Arginine > Proline; ACVR1R375P) responsible for a mild nonclassic fibrodysplasia ossificans progressiva (FOP) phenotype. Both families include people with the ultrarare ACVR1R375P variant who exhibit features of FOP while other individuals currently do not express any clinical signs of FOP. Thus, the mild ACVR1R375P variant greatly expands the scope and understanding of this rare disorder.

Retinoids are metabolic derivatives of vitamin A and regulate the function of many tissues and organs both prenatally and postnatally. Active retinoids, such as all trans-retinoic acid, are produced in the cytoplasm and then interact with nuclear retinoic acid receptors (RARs) to up-regulate the transcription of target genes. The RARs can also interact with target gene response elements in the absence of retinoids and exert a transcriptional repression function. Studies from several labs, including ours, showed that chondrogenic cell differentiation and cartilage maturation require (i) the absence of retinoid signaling and (ii) the repression function by unliganded RARs. These and related insights led to the proposition that synthetic retinoid agonists could thus represent pharmacological agents to inhibit heterotopic ossification (HO), a process that recapitulates developmental skeletogenesis and involves chondrogenesis, cartilage maturation, and endochondral ossification. One form of HO is acquired and is caused by injury, and another severe and often fatal form of it is genetic and occurs in patients with fibrodysplasia ossificans progressiva (FOP). Mouse models of FOP bearing mutant ACVR1R206H, characteristic of most FOP patients, were used to test the ability of the retinoid agonists selective for RARα and RARγ against spontaneous and injury-induced HO. The RARγ agonists were found to be most effective, and one such compound, palovarotene, was selected for testing in FOP patients. The safety and effectiveness data from recent and ongoing phase II and phase III clinical trials support the notion that palovarotene may represent a disease-modifying treatment for patients with FOP. The post hoc analyses showed substantial efficacy but also revealed side effects and complications, including premature growth plate closure in some patients. Skeletally immature patients will need to be carefully weighed in any future regulatory indications of palovarotene as an important therapeutic option in FOP.

Background Goals of care (GOC) conversations in the emergency department (ED) are often a brief discussion of code status rather than a patient-oriented dialogue. We aimed to develop a guide to facilitate conversations between ED clinicians and patients to elicit patient values and establish goals for end-of-life care, while maintaining ED efficiency. Paths of ED Care, a conversation guide, is the product of this work. Design A multidisciplinary/multispecialty group used recommended practices to adapt a GOC conversation guide for ED patients. ED clinicians used the guide and provided feedback on content, design, and usability. Patient-clinician interactions were recorded for discussion analysis, and both were surveyed to inform iterative refinement. A series of discussions with patient representatives, multidisciplinary clinicians, bioethicists, and health care designers yielded feedback. We used a process similar to the International Patient Decision Aid Standards and provide comparison to these. Results A conversation guide, eight pages with each page 6 by 6 inches in dimension, uses patient-oriented prompts and includes seven sections: 1) evaluation of patient/family understanding of disease, 2) explanation of possible trajectories, 3) introduction to different pathways of care, 4) explanation of pathways, 5) assessment of understanding and concerns, 6) code status, and 7) personalized summary. Limitations Recruitment of sufficient number of patients/providers to the project was the primary limitation. Methods are limited to qualitative analysis of guide creation and feasibility without quantitative analysis. Conclusions Paths of ED Care is a guide to facilitate patient-centered shared decision making for ED patients, families, and clinicians regarding GOC. This may ensure care concordant with patients’ values and preferences. Use of the guide was well-received and facilitated meaningful conversations between patients and providers.

ABSTRACT Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disease caused by mutations in activin A receptor type I/activin-like kinase 2 (ACVR1/ALK2), a bone morphogenetic protein (BMP) type I receptor, resulting in the formation of extraskeletal or heterotopic ossification (HO) and other features consistent with premature aging. During the first decade of life, episodic bouts of inflammatory swellings (flare-ups) occur, which are typically triggered by soft tissue trauma. Through an endochondral process, these exacerbations ultimately result in skeletal muscles, tendons, ligaments, fascia, and aponeuroses transforming into ectopic bone, rendering movement impossible. We have previously shown that soft tissue injury causes early FOP lesions characterized by cellular hypoxia, cellular damage, and local inflammation. Here we show that muscle injury in FOP also results in senescent cell accumulation, and that senescence promotes tissue reprogramming toward a chondrogenic fate in FOP muscle but not wild-type (WT) muscle. Using a combination of senolytic drugs we show that senescent cell clearance and reduction in the senescence associated secretory phenotype (SASP) ameliorate HO in mouse models of FOP. We conclude that injury-induced senescent cell burden and the SASP contribute to FOP lesion formation and that tissue reprogramming in FOP is mediated by cellular senescence, altering myogenic cell fate toward a chondrogenic cell fate. Furthermore, pharmacological removal of senescent cells abrogates tissue reprogramming and HO formation. Here we provide proof-of-principle evidence for senolytic drugs as a future therapeutic strategy in FOP. © 2021 American Society for Bone and Mineral Research (ASBMR).

This editorial comments on the article by Valente et al .

ABSTRACT With an increasingly older population, the proportion of patients 85 years or older seeking interventions to protect their musculoskeletal health is growing. Osteoporosis in the geriatric population presents unique diagnostic and therapeutic challenges. Multimorbidity, frailty, falls, polypharmacy, and other neurobehavioral factors influence our approach to fracture prevention in this population. The vast majority of the evidence from clinical trials establish pharmacologic fracture efficacy in postmenopausal women. The evidence is scarce for the oldest old men and women, a population also at risk for adverse events and mortality. Most studies show continued efficacy of pharmacologic interventions in this age group, although they are largely limited by small sample sizes. We herein review the available evidence of pharmacologic interventions for fracture risk reduction in this population and explore the emerging senotherapeutic interventions in the pipeline. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Abstract The burden of senescent cells (SnCs), which do not divide but are metabolically active and resistant to death by apoptosis, is increased in older adults and those with chronic diseases. These individuals are also at the greatest risk for morbidity and mortality from SARS‐CoV‐2 infection. SARS‐CoV‐2 complications include cytokine storm and multiorgan failure mediated by the same factors as often produced by SnCs through their senescence‐associated secretory phenotype (SASP). The SASP can be amplified by infection‐related pathogen‐associated molecular profile factors. Senolytic agents, such as Fisetin, selectively eliminate SnCs and delay, prevent, or alleviate multiple disorders in aged experimental animals and animal models of human chronic diseases, including obesity, diabetes, and respiratory diseases. Senolytics are now in clinical trials for multiple conditions linked to SnCs, including frailty; obesity/diabetes; osteoporosis; and cardiovascular, kidney, and lung diseases, which are also risk factors for SARS‐CoV‐2 morbidity and mortality. A clinical trial is underway to test if senolytics decrease SARS‐CoV‐2 progression and morbidity in hospitalized older adults. We describe here a National Institutes of Health‐funded, multicenter, placebo‐controlled clinical trial of Fisetin for older adult skilled nursing facility (SNF) residents who have been, or become, SARS‐CoV‐2 rtPCR‐positive, including the rationale for targeting fundamental aging mechanisms in such patients. We consider logistic challenges of conducting trials in long‐term care settings in the SARS‐CoV‐2 era, including restricted access, consent procedures, methods for obtaining biospecimens and clinical data, staffing, investigational product administration issues, and potential solutions for these challenges. We propose developing a national network of SNFs engaged in interventional clinical trials.

Abstract Background: Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare, autosomal dominant disorder driven by mutations in ACVR1 that render it responsive to Activin A. FOP is characterized by progressive heterotopic ossification (HO) and distressing inflammatory events called “flare-ups.” Flare-ups can precede new HO; however, limited prospective data exists on this phenomenon. Garetosmab (GAR), an investigational human monoclonal antibody against Activin A, blocks formation of new HO in FOP. Methods: This is a post-hoc analysis of LUMINA-1 (NCT03188666) a phase 2, randomized, double-blind, placebo-controlled study, which evaluated the safety and efficacy of GAR (10 mg/kg/week IV) versus placebo (PBO) in adult patients with FOP over 28 weeks. Patient-reported flare-ups were collected via a patient diary and severity level was reported as mild, moderate or severe. Clinician-reported flare-ups were collected as adverse events in the trial. HO lesions were imaged by 18F-NaF positron emission tomography (PET) and whole-body low-dose X-ray computed tomography (CT). Results: There was a two-fold higher proportion of patients who reported one or more flare-ups on PBO 17/24 (71%) compared with GAR 7/20 (35%). Clinicians reported a four-fold higher proportion of patients experiencing one or more flare-ups on PBO 10/24 (42%) compared with GAR 2/20 (10%). Overall rates of flare-up events were two-fold higher on PBO vs. GAR (1.4 vs. 0.65 events/patient/28 weeks) for patient-reported events and eight-fold higher on PBO vs. GAR by clinician report (0.83 vs. 0.10 events/patient/28 weeks). Most flare-ups occurred on the extremities and back; pain was the most commonly reported symptom. Patient-reported flare-ups on PBO were more frequently reported as severe (29.4%) compared with GAR (7.7%). Among subjects with at least 12 weeks of follow-up from start of patient-reported flare-up, development of new HO near the site was 5/27 (18.5%) on PBO and (0%) on GAR. Of all new HO lesions, 41% on PBO and 0% on GAR occurred with spatial and temporal relation to flare-up. Conclusions: Approximately two-thirds of patients on PBO reported flare-ups over 28 weeks. GAR was associated with reductions in frequency and severity of flare-ups. Fewer than 20% of patient-reported flare-ups were associated with new HO, indicating frequent discordance of these phenomena, and compatible with previous reports. GAR’s ability to reduce patient- and clinician-reported flare-ups, as well as new HO lesions may provide an important therapeutic option.

ABSTRACT Changes in aging bone that lead to osteoporosis are mediated at multiple levels, including hormonal alterations, skeletal unloading, and accumulation of senescent cells. This pathological interplay is superimposed upon medical conditions, potentially bone‐wasting medications, modifiable and unmodifiable personal risk factors, and genetic predisposition that accelerate bone loss with aging. In this study, the focus is on bone hemostasis and its dysregulation with aging. The major physiological changes with aging in bone and the role of cellular senescence in contributing to age‐related osteoporosis are summarized. The aspects of bone aging are reviewed including remodeling deficits, uncoupling phenomena, inducers of cellular senescence related to bone aging, roles of the senescence‐associated secretory phenotype, radiation‐induced bone loss as a model for bone aging, and the accumulation of senescent cells in the bone microenvironment as a predominant mechanism for age‐related osteoporosis. The study also addresses the rationale and potential for therapeutic interventions based on the clearance of senescent cells or suppression of the senescence‐associated secretory phenotype. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

ABSTRACT Circulating osteogenic progenitor (COP) cells are a population of cells in the peripheral blood with the capacity for bone formation, as well as broader differentiation into mesoderm-like cells in vitro. Although some of their biological characteristics are documented in vitro, their role in diseases of the musculoskeletal system remains yet to be fully evaluated. In this review, we provide an overview of the role of COP cells in a number of physiological and pathological conditions, as well as identify areas for future research. In addition, we suggest possible areas for clinical utilization in the management of musculoskeletal diseases. © 2020 American Society for Bone and Mineral Research (ASBMR).