Bone and Mineral Metabolism

SUN-799 - Pde5A Inhibition Modulates Osteogenic Gene Expression and Bone Mass in Diabetes-Induced Skeletal Dysfunction.

Sunday, June 14, 2026

9:00 AM - 4:00 PM CT

Location: ENDOExpo; Poster Floor

Abstract Poster Presenter(s)

SP

Surabhi Parte, BS (she/her/hers)

Associate Researcher
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
Jersey City, NJ, United States

Co-Author(s)

FS

Farhath Sultana, PhD

Institute for Translational Medicine and Pharmacology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
NEW YORK, New York, United States
AG

Anisa Gumerova, M.D., Ph.D.

Icahn School of Medicine at Mount Sinai
New York City, United States
OM

Ofer Moldavski, PhD

Institute for Translational Medicine and Pharmacology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
New York, NY, New York, United States
ZT

Zehra Tumoglu, M.D.

Institute for Translational Medicine and Pharmacology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
New York, NY, New York, United States
OB

Orly Barak, PhD

Institute for Translational Medicine and Pharmacology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
NEW YORK, New York, United States
AS

Amanda Seepersaud, n/a

Icahn School of Medicine at Mount Sinai
New York City, United States
HP

Hayden Hajoon Pong, n/a

Icahn School of Medicine at Mount Sinai
New York City, United States

Senior Author/Primary Investigator(s)

TY

Tony Yuen, PhD

Institute for Translational Medicine and Pharmacology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
NEW YORK, New York, United States
MZ

Mone Zaidi, MD, PhD (he/him/his)

Institute for Translational Medicine and Pharmacology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
New York, NY, New York, United States
SK

Se-Min Kim, MD (he/him/his)

Associate Professor
Institute for Translational Medicine and Pharmacology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
New York, New York, United States

The nitric oxide (NO) - cyclic guanosine monophosphate (cGMP) - protein kinase G (PKG) signaling pathway plays a critical role in bone remodeling. Here, we investigated the role of PDE5a signaling in hyperglycemia-induced bone loss using complementary in vivo and in vitro approaches.

RNAscope technology for single-transcript detection in formalin-fixed paraffin-embedded mouse bones identified Pde5a mRNA expression in osteoblasts lining the bone surface and in bone marrow stromal precursors, confirming relevant cellular targets in bone.

To assess cell-specific effect of PDE5 inhibition, Dmp1-Cre+; Pde5afl/fl was generated and examined by dual-energy X-ray absorptiometry (DXA). Longitudinal DXA every 4 wks from 12 to 32 wks showed lower bone mass in Dmp1-Cre+; Pde5afl/fl compared with Cre- control early point, which evened out at a later age. Lumbar spine (L4–6) BMD was lower by 0.011 g/cm² * at 16 wks and by 0.006 g/cm² **at 18 wks. Left femoral BMD was also reduced by 0.006 g/cm² * at 16 wks with no differences in BMD were observed at later ages.

To assess functional effects of PDE5a inhibition under hyperglycemia, first, we performed RNA sequencing of osteoblasts isolated from streptozotocin-induced diabetic mice, which demonstrated significant downregulation of osteogenic genes (Bglap, Col1a1, Bmp2 and Wnt5a), along with marked suppression of Nos2 and Prkg2 (log2FC = -3.36* and -0.99**, respectively).
Subsequently, osteoblasts differentiated from female mouse primary fibroblasts were cultured in high glucose (50mM) with and without tadalafil (1nM and 10nM). High glucose suppressed multiple osteogenic markers, including Col1a1, Alp, and OCN, which was reversed with PDE5a inhibition (log2FC = 1.11, log2FC = 0.39, and log2FC = -0.3, respectively). Low-dose tadalafil partially restoring matrix and early differentiation markers, while late marker OCN showed limited recovery. In contrast, VEGF expression was robustly enhanced by PDE5a inhibition (log2FC = 1.02*), particularly at higher concentration, suggesting improved angiogenic–osteogenic signaling. Pde5a transcript levels were unchanged across treatment conditions.

Collectively, these data suggest that diabetes suppresses PKG2-dependent osteogenic signaling despite preserved PDE5a expression, and that PDE5a inhibition functionally modulates osteoblast gene expression and bone mass in a context- and dose-dependent manner. Ongoing studies using osteoblast-specific Pde5a knockout models (Col1a1-Cre+, Pde5afl^/fl^) will further define the cell-specific role of PDE5a in diabetic bone disease.

(* < 0.05, ** < 0.001)

*Unless otherwise noted, all abstracts presented at ENDO must not be released to the press or the public until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.*