Browsing by Author "Malluche, Hartmut H."

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    Familial complete pachydermoperiostosis presenting with vertebral hypertrophy and myelopathy
    (Oxford University Press, 2025-05-08) Honaker, Eric; Birkhead, Andrew; Guillen, Kennedy; Knuckles, Melissa; Lima, Florence; Zarate, Yuri A.; Cassidy, Carter; Malluche, Hartmut H.; Rao, Madhumathi; Pathology and Laboratory Medicine, School of Medicine
    Pachydermoperiostosis (PDP) is a rare, male-predominant (9:1) primary hypertrophic osteoarthropathy of the skin and bone, commonly called the acromegaly mimic. Clinical diagnosis of PDP is based on a triad of digital clubbing, pachydermia with coarse facial features, and radiographic evidence of long bone periostosis. It can manifest in a complete or incomplete form, with skin involvement distinguishing the complete subtype. The etiology of PDP remains uncertain, though it has been associated with pathogenic variants in genes involved in prostaglandin E2 metabolism genes (HPGD) in autosomal recessive primary hypertrophic osteoarthropathy-1 and SLCO2A1 in autosomal dominant primary hypertrophic osteoarthropathy. We present a 31-yr-old male with complete PDP with atypical clinical features of vertebral involvement, severe myelopathy and radiculopathy, mild digital clubbing, and frontal pachydermia. IGF-1 and HGH levels were normal despite the acromegalic features. Genetic testing did not identify variants in HPGD or SLCO2A1. The patient exhibited elevated bone-specific alkaline phosphatase levels and increased BMD, supporting the diagnosis of PDP. Iliac crest bone biopsies were technically difficult and contained only dense cortical bone. Dermatologic manifestations were managed with glycopyrrolate, dupilumab, and topical treatments. His bone disease was treated with intravenous bisphosphonates, yielding a marked decrease in bone-specific alkaline phosphatase levels. This case reveals the necessity of considering PDP in differential diagnoses for patients with atypical acromegalic features and highlights the potential for vertebral involvement in PDP, expanding the understanding of its clinical presentation.
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    A Ligand Trap of the Activin Receptor Type IIA Inhibits Osteoclast Stimulation of Bone Remodeling in Diabetic Mice with Chronic Kidney Disease
    (Elsevier, 2017-01) Sugatini, Toshifumi; Agapova, Olga A.; Fang, Yifu; Berman, Alycia G.; Wallace, Joseph M.; Malluche, Hartmut H.; Faugere, Marie-Claude; Smith, William; Sung, Victoria; Hruska, Keith A.; Department of Biomedical Engineering, School of Engineering and Technology
    Dysregulation of skeletal remodeling is a component of renal osteodystrophy. Previously, we showed that activin receptor signaling is differentially affected in various tissues in chronic kidney disease (CKD). We tested whether a ligand trap for the activin receptor type 2A (RAP-011) is an effective treatment of the osteodystrophy of the CKD-mineral bone disorder. With a 70% reduction in the glomerular filtration rate, CKD was induced at 14 weeks of age in the ldlr-/- high fat–fed mouse model of atherosclerotic vascular calcification and diabetes. Twenty mice with CKD, hyperphosphatemia, hyperparathyroidism, and elevated activin A were treated with RAP-011, wherease 19 mice were given vehicle twice weekly from week 22 until the mice were killed at 28 weeks of age. The animals were then evaluated by skeletal histomorphometry, micro-computed tomography, mechanical strength testing, and ex vivo bone cell culture. Results in the CKD groups were compared with those of the 16 sham-operated ldlr-/- high fat–fed mice. Sham-operated mice had low-turnover osteodystrophy and skeletal frailty. CKD stimulated bone remodeling with significant increases in osteoclast and osteoblast numbers and bone resorption. Compared with mice with CKD and sham-operated mice, RAP-011 treatment eliminated the CKD-induced increase in these histomorphometric parameters and increased trabecular bone fraction. RAP-011 significantly increased cortical bone area and thickness. Activin A–enhanced osteoclastogenesis was mediated through p-Smad2 association with c-fos and activation of nuclear factor of activated T cells c1 (NFATc1). Thus, an ActRIIA ligand trap reversed CKD-stimulated bone remodeling, likely through inhibition of activin–A induced osteoclastogenesis.