{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,14]],"date-time":"2026-01-14T01:09:52Z","timestamp":1768352992606,"version":"3.49.0"},"reference-count":35,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2024,3,6]],"date-time":"2024-03-06T00:00:00Z","timestamp":1709683200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["DK101536"],"award-info":[{"award-number":["DK101536"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,4,30]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Cavernous nerve (CN) injury, caused by prostatectomy and diabetes, initiates a remodeling process (smooth muscle apoptosis and increased collagen) in the corpora cavernosa of the penis of patients and animal models that is an underlying cause of erectile dysfunction (ED), and the Sonic hedgehog (SHH) pathway plays an essential role in the response of the penis to denervation, as collagen increases with SHH inhibition and decreases with SHH treatment.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Aim<\/jats:title>\n                  <jats:p>We examined if part of the mechanism of how SHH prevents penile remodeling and increased collagen with CN injury involves bone morphogenetic protein 4 (BMP4) and gremlin1 (GREM1) and examined the relationship between SHH, BMP4, GREM1, and collagen in penis of ED patients and rat models of CN injury, SHH inhibition, and SHH, BMP4, and GREM1 treatment.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Corpora cavernosa of Peyronie\u2019s disease (control), prostatectomy, and diabetic ED patients were obtained (N\u00a0=\u200930). Adult Sprague Dawley rats (n\u2009=\u200990) underwent (1) CN crush (1-7\u00a0days) or sham surgery; (2) CN injury and BMP4, GREM1, or mouse serum albumin (control) treatment via Affi-Gel beads or peptide amphiphile (PA) for 14\u00a0days; (3) 5E1 SHH inhibitor, IgG, or phosphate-buffered saline (control) treatment for 2 to 4\u00a0days; or (4) CN crush with mouse serum albumin or SHH for 9\u00a0days.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Outcomes<\/jats:title>\n                  <jats:p>Immunohistochemical and Western analysis for BMP4 and GREM1, and collagen analysis by hydroxyproline and trichrome stain were performed.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>BMP4 and GREM1 proteins were identified in corpora cavernosa smooth muscle of prostatectomy, diabetic, and Peyronie\u2019s patients, and in rat smooth muscle, sympathetic nerve fibers, perineurium, blood vessels, and urethra. Collagen decreased 25.4% in rats with CN injury and BMP4 treatment (P\u2009=\u2009.02) and increased 61.3% with CN injury and GREM1 treatment (P\u2009=\u2009.005). Trichrome stain showed increased collagen in rats treated with GREM1. Western analysis identified increased BMP4 and GREM1 in corpora cavernosa of prostatectomy and diabetic patients, and after CN injury (1-2\u00a0days) in our rat model. Localization of BMP4 and GREM1 changed with SHH inhibition. SHH treatment increased the monomer form of BMP4 and GREM1, altering their range of signaling.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Clinical implications<\/jats:title>\n                  <jats:p>A better understanding of penile remodeling and how fibrosis occurs with loss of innervation is essential for development of novel ED therapies.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Strengths and limitations<\/jats:title>\n                  <jats:p>The relationship between SHH, BMP4, GREM1, and collagen is complex in the penis.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>BMP4 and GREM1 are downstream targets of SHH that impact collagen and may be useful in collaboration with SHH to prevent penile remodeling and ED.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/jsxmed\/qdae015","type":"journal-article","created":{"date-parts":[[2024,3,7]],"date-time":"2024-03-07T17:52:11Z","timestamp":1709833931000},"page":"367-378","source":"Crossref","is-referenced-by-count":4,"title":["BMP4 and GREM1 are targets of SHH signaling and downstream regulators of collagen in the penis"],"prefix":"10.1093","volume":"21","author":[{"given":"Jiangping","family":"Deng","sequence":"first","affiliation":[{"name":"Department of Urology, University of Illinois at Chicago , Chicago, IL 60612 , United States"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Timothy","family":"Searl","sequence":"additional","affiliation":[{"name":"Department of Urology, University of Illinois at Chicago , Chicago, IL 60612 , United States"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samuel","family":"Ohlander","sequence":"additional","affiliation":[{"name":"Department of Urology, University of Illinois at Chicago , Chicago, IL 60612 , United States"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Danuta","family":"Dynda","sequence":"additional","affiliation":[{"name":"Division of Urology, Southern Illinois University School of Medicine , Springfield, IL 62794 United States"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel A","family":"Harrington","sequence":"additional","affiliation":[{"name":"Department of Diagnostic and Biomedical Sciences, University of Texas Health Science Center at Houston , Houston, TX 77054 , United States"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kevin T","family":"McVary","sequence":"additional","affiliation":[{"name":"Department of Urology, Loyola University Stritch School of Medicine , Maywood, IL 60153 , United States"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carol A","family":"Podlasek","sequence":"additional","affiliation":[{"name":"Department of Urology, University of Illinois at Chicago , Chicago, IL 60612 , United States"},{"name":"Department of Physiology, University of Illinois at Chicago , Chicago, IL 60612 , United States"},{"name":"Department of Bioengineering, University of Illinois at Chicago , Chicago, IL 60612 , United States"},{"name":"Department of Biochemistry, University of Illinois at Chicago , Chicago, IL 60612 , United States"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2024,3,6]]},"reference":[{"issue":"1","key":"2024050206202521500_ref1","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1016\/S0022-5347(17)34871-1","article-title":"Impotence and its medical and psychosocial correlates: results of the Massachusetts male aging study","volume":"151","author":"Feldman","year":"1994","journal-title":"J Urol"},{"issue":"3","key":"2024050206202521500_ref2","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1111\/j.1743-6109.04041.x","article-title":"Prevalence of erectile dysfunction among young adults: results of a largescale survey","volume":"1","author":"Heruti","year":"2004","journal-title":"J Sex Med"},{"issue":"4","key":"2024050206202521500_ref3","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1016\/j.sxmr.2017.05.004","article-title":"Erectile dysfunction in young men\u2014a review of the prevalence and risk factors","volume":"5","author":"Nguyen","year":"2017","journal-title":"Sex Med Rev"},{"issue":"2","key":"2024050206202521500_ref4","doi-asserted-by":"crossref","first-page":"87","DOI":"10.3816\/CGC.2004.n.017","article-title":"Current concepts in the management of erectile dysfunction in men with prostate cancer","volume":"3","author":"Kendirci","year":"2004","journal-title":"Clin Prostate Cancer"},{"issue":"9","key":"2024050206202521500_ref5","doi-asserted-by":"crossref","first-page":"891","DOI":"10.1016\/S1470-2045(11)70162-0","article-title":"SPCG-4 investigators. 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