About

Frederick S. Kaplan, M.D., is the Isaac and Rose Nassau Professor of Orthopaedic Molecular Medicine and Chief of the Division of Molecular Orthopaedic Medicine at the University of Pennsylvania School of Medicine. He is an alumnus of Johns Hopkins University School of Medicine, graduating in 1976, and completed his residency in Orthopaedic Surgery at The Hospital of The University of Pennsylvania and The Children’s Hospital of Philadelphia from 1980 to 1981. Kaplan was a Hartford Foundation Research Fellow in human genetics and molecular biology from 1989 to 1991, working in the laboratory of Dr. Michael Zasloff, which led to his exploration of mechanisms for heterotopic bone formation and skeletal metamorphosis in childhood diseases. Kaplan is renowned for his pioneering work on the molecular genetics of heterotopic ossification, especially in rare disorders such as fibrodysplasia ossificans progressiva (FOP). His work led to the discovery of the FOP gene, elucidation of the molecular pathophysiology of skeletal metamorphosis, and the identification of progressive osseous heteroplasia and its causative gene. Along with Dr. Eileen Shore, he co-directs the only center dedicated to this research and has organized the global scientific community around these conditions. Recognized as the world’s leading expert on genetic disorders of heterotopic ossification and skeletal metamorphosis, Kaplan has received numerous accolades, including the first endowed chair in orthopaedic molecular medicine in 1997. His contributions extend from clinical research to bench science, and he is highly regarded for his dedication to patient care and advancing understanding of these rare diseases.

Research topics

• Medicine
• Biology
• Pathology
• Surgery
• Internal medicine

Selected publications

• List of contributors

  Elsevier eBooks · 2026-01-01

  book-chapter
  PublisherDOI

• Fibrodysplasia ossificans progressiva

  Elsevier eBooks · 2026-01-01

  book-chapter
  PublisherDOI

• Characterization of flare-ups and impact of garetosmab in adults with fibrodysplasia ossificans progressiva: a plain language summary of a post hoc analysis of the LUMINA-1 trial

  Future Rare Diseases · 2026-03-20

  articleOpen access
  PublisherDOI

• Palovarotene in fibrodysplasia ossificans progressiva: review and perspective

  Expert Opinion on Pharmacotherapy · 2025-01-21 · 5 citations

  reviewOpen access

  INTRODUCTION: Palovarotene is a retinoic acid receptor gamma agonist that was studied in phase-2 and phase-3 clinical trials for the inhibition of new heterotopic ossification (HO) in fibrodysplasia ossificans progressiva (FOP). Despite numerous setbacks and regulatory delays, palovarotene is now the first approved FOP treatment in the U.S.A., Canada and Australia but remains unapproved in Europe where concerns surrounding the drug and its path to regional market authorization persist. AREAS COVERED: The developmental history of palovarotene and an overview of the clinical trials and the regulatory approval journey are discussed by global FOP experts. EXPERT OPINION: While post hoc analyses indicate that palovarotene may have modest benefits for the inhibition of new HO formation in FOP, a number of limitations and concerns remain about its generalized use. Although the long-term risks and benefits of treatment with palovarotene remain unknown, the regional approval of palovarotene marks a milestone for the FOP community at the very beginning of a new era of clinical trials.

  PublisherOA PDFDOI

• Ectopic pseudojoints in fibrodysplasia ossificans progressiva

  JBMR Plus · 2025-06-18

  articleOpen accessSenior author

  Pseudoarthroses (false joints) occur as a complication of fracture healing in the normotopic skeleton but have not been reported at ectopic sites. Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare genetic disorder characterized by progressive heterotopic ossification (HO) and congenital skeletal abnormalities including developmental arthropathy in the normotopic skeleton. Here, we report ectopic pseudojoint formation in 6 patients with FOP, all occurring after painful flare-ups and HO in soft connective tissues of the knee, hip, and forearm. To our knowledge, FOP is the only human condition in which ectopic pseudojoint formation occurs. These findings support that dysregulated BMP pathway signaling from mutant ACVR1 mediates not only HO, but also ectopic pseudojoint formation, and that ectopic pseudojoints can arise from de novo musculoskeletal elements.

  PublisherOA PDFDOI

• Medical guidelines for fibrodysplasia ossificans progressiva

  JBMR Plus · 2025-09-11 · 6 citations

  articleOpen access1st authorCorresponding

  Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare genetic condition characterized by congenital malformations of the great toes and progressive heterotopic ossification (HO) in specific anatomic patterns. Present management summarized here is focused on early diagnosis, assiduous avoidance of injury and iatrogenic harm, symptomatic amelioration of painful flare-ups, and optimization of residual function. Twenty-one members of the International Clinical Council on FOP (ICC) and seven consultants from 15 countries, chosen for their clinical expertise in FOP, developed this summary statement. Further advances in therapeutics will be based on rigorous clinical trials to assess novel and emerging treatment and prevention strategies. A detailed and updated exploration of the topics outlined in this brief perspective can be found in "The Medical Management of Fibrodysplasia Ossificans Progressiva: Current Treatment Considerations" which can be found on the International Clinical Council on FOP (ICC) website (www.iccfop.org).

  PublisherDOI

• Thoracic Deformity in Fibrodysplasia Ossificans Progressiva

  JBJS Reviews · 2025-05-01 · 4 citations

  review1st authorCorresponding

  » Fibrodysplasia ossificans progressiva (FOP), the most severe form of heterotopic ossification (HO) in humans, may lead to severe thoracic deformity (TD) and thoracic insufficiency syndrome (TIS), the most common cause of mortality in individuals with FOP.» In this study, we examine the multiple causes of TD in FOP and propose a dynamic model for the development and evolution of TD that can be used to guide clinical care. This model posits that multiple factors, all originating from the causative gain-of-function mutation in activin receptor A, type 1, lead to TD in FOP.» Factors that lead to TD in FOP include early developmental costovertebral and facet joint arthropathy and joint ankylosis, progressive episodic flare-ups (both trauma induced or spontaneous) and subsequent HO, dysregulated soft tissue sensitivity to mechanical stimuli, growth plate dysregulation, and congenital rib fusions. These factors contribute to TD in FOP through a combination of intra-articular and extra-articular mechanisms, all amplified by growth.» Although FOP is a rare condition, it is illustrative of how a mutation in a critical receptor in the bone morphogenetic protein signaling pathway can cause a litany of musculoskeletal dysfunction that can lead to life-threatening consequences. Clinicians caring for individuals who have FOP must be aware of the occurrence, evolution, and implications of progressive TD and resultant TIS so that appropriate preventive measures such as avoidance of pulmonary infections, incentive spirometry, and diaphragmatic strengthening can be instituted.

  PublisherDOI

• FOP: From Biomolecules to Hope

  Biomolecules · 2025-02-24

  editorialOpen access1st authorCorresponding

  In the introduction to his 1970 textbook BIOCHEMISTRY, Albert Lehninger wrote “Living things are composed of lifeless molecules [...]

  PublisherOA PDFDOI

• Characterization of flare-ups and impact of garetosmab in adults with fibrodysplasia ossificans progressiva: a post hoc analysis of the randomized, double-blind, placebo-controlled LUMINA-1 trial

  Journal of Bone and Mineral Research · 2024-08-31 · 8 citations

  articleOpen access

  Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare disorder, characterized by progressive heterotopic ossification (HO) and painful soft-tissue inflammatory flare-ups. This was a post hoc analysis from a phase 2 (NCT03188666) trial in which adults with FOP received intravenous anti-activin A antibody garetosmab 10 mg/kg or placebo every 4 wk over 28 wk (Period 1), followed by a 28-wk open-label treatment and extension (Periods 2 and 3). Here we describe flare-ups, their relationship to new HO lesions, and the impact of garetosmab on flare-ups. Volume of new HO lesions was measured by CT. Patient-reported flare-ups were defined by any 2 of the following: new onset of pain, swelling, joint stiffness, decrease in movement, or perceived presence of HO. Flare-ups were experienced by 71% (17/24) of placebo-treated patients, 59% (10/17) of whom developed a new HO lesion irrespective of flare-up location; 24% of flare-ups location-matched new HO lesions. Twenty-nine new HO lesions occurred in the placebo cohort by week 28, of which 12 (41%) occurred in the same location as new or ongoing flare-ups. A higher volume of newly formed heterotopic bone (week 28) occurred in placebo-treated patients who had experienced a prior flare-up vs those without (median [Q1:Q3] of 16.6 [12.0:31.1] vs 3.2 cm3). Garetosmab was previously shown to decrease patient-reported flare-up frequency in Period 1; here, garetosmab reduced the median (Q1:Q3) duration of patient-reported flares (15.0 [6.0:82.0] vs 48.0 [15.0:1.00] d) and the severity of flare-ups vs placebo. Frequency of corticosteroid use was numerically reduced in those treated with garetosmab (40.0%) vs placebo (58.3%). In this analysis, 71% of placebo-treated adults with FOP experienced flare-ups over 28 wk, which were associated with an increased volume of newly formed heterotopic bone. Garetosmab reduced the severity and duration of flare-ups, with effects sustained during the entire trial.

  PublisherOA PDFDOI

• Matrix metalloproteinase-9 deficiency confers resilience in fibrodysplasia ossificans progressiva in a man and mice

  Journal of Bone and Mineral Research · 2024-02-16 · 15 citations

  articleOpen accessSenior authorCorresponding

  Single case studies of extraordinary disease resilience may provide therapeutic insight into conditions for which no definitive treatments exist. An otherwise healthy 35-year-old man (patient-R) with the canonical pathogenic ACVR1R206H variant and the classic congenital great toe malformation of fibrodysplasia ossificans progressiva (FOP) had extreme paucity of post-natal heterotopic ossification (HO) and nearly normal mobility. We hypothesized that patient-R lacked a sufficient post-natal inflammatory trigger for HO. A plasma biomarker survey revealed a reduction in total matrix metalloproteinase-9 (MMP-9) compared to healthy controls and individuals with quiescent FOP. Whole exome sequencing identified compound heterozygous variants in MMP-9 (c.59C > T, p.A20V and c.493G > A, p.D165N). Structural analysis of the D165N variant predicted both decreased MMP-9 secretion and activity that were confirmed by enzyme-linked immunosorbent assay and gelatin zymography. Further, human proinflammatory M1-like macrophages expressing either MMP-9 variant produced significantly less Activin A, an obligate ligand for HO in FOP, compared to wildtype controls. Importantly, MMP-9 inhibition by genetic, biologic, or pharmacologic means in multiple FOP mouse models abrogated trauma-induced HO, sequestered Activin A in the extracellular matrix (ECM), and induced regeneration of injured skeletal muscle. Our data suggest that MMP-9 is a druggable node linking inflammation to HO, orchestrates an existential role in the pathogenesis of FOP, and illustrates that a single patient's clinical phenotype can reveal critical molecular mechanisms of disease that unveil novel treatment strategies.

  PublisherOA PDFDOI

Recent grants

• NIH Grant R01AR041916

  NIH · $5.3M · 2016

Frequent coauthors

• Eileen M. Shore

  University of Pennsylvania

  351 shared

• Michael Zasloff

  MedStar Heart & Vascular Institute

  235 shared

• Robert J. Pignolo

  Mayo Clinic

  126 shared

• Francis H. Gannon

  Baylor College of Medicine

  120 shared

• Maximilian Muenke

  National Human Genome Research Institute

  67 shared

• Edward C. Hsiao

  Royal North Shore Hospital

  64 shared

• Richard Keen

  Royal National Orthopaedic Hospital

  62 shared

• Randolph B. Cohen

  50 shared

Labs

• Molecular Orthopaedics, PennPI

Education

• M.D., Orthopaedics

  The University of Pennsylvania

• Short course in Medical & Experimental Mammalian Genetics

  The Jackson Laboratory

  1988

• M.D.

  Johns Hopkins University

  1976

• B.A

  Johns Hopkins University

  1972

Awards & honors

• First endowed chair in the nation for orthopaedic molecular…
• Recognized as one of the 15 people who make America great by…
• Hartford Foundation Research Fellow in human genetics and mo…
• Winner of Hollywood Independent Filmmaker Award for Tin Sold…