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However, it is assumed that the CXCL12\/CXCR4 axis likely contributes to OA progression through subchondral bone-cartilage crosstalk. This study compares the efficacy of the CXCR4 inhibitors AMD31000 and novel endogenous peptide inhibitors in human cartilage and isolated chondrocytes (hAC).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Human cartilage and hAC were obtained from OA patients undergoing arthroplasty. Expression of both CXCL12 receptors CXCR4 and ACKR3, were assessed by immunohistology and qRT-PRC. The effects of CXCR4 inhibitors, including AMD3100, EPI-X4, and its derivative EPI-X4 JM#21, were evaluated regarding cell viability, migration, chondrogenic and osteogenic differentiation, and proliferation of chondrocytes in presence of 200\u00a0ng\/mL CXCL12.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>The current data demonstrate that CXCR4 is significantly upregulated in OA cartilage and senescent chondrocytes, while ACKR3 expression remains largely unchanged. CXCR4 inhibition had no detrimental effects on chondrocyte viability, proliferation, or chondrogenic differentiation potential but effectively reduced CXCL12-induced cell migration. EPI-X4 JM#21 emerged as a potent CXCR4 antagonist and ACKR3 agonist, outperforming AMD3100 in suppressing chondrocyte migration. Although CXCR4 was significantly upregulated during osteogenic differentiation of hAC, the inhibition of the receptor had no effect on calcium deposition.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These findings suggest that EPI-X4 JM#21 may represent potential alternative to AMD3100 for targeting the CXCL12\/CXCR4 pathway in OA, warranting further in vivo validation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13075-025-03691-9","type":"journal-article","created":{"date-parts":[[2025,12,2]],"date-time":"2025-12-02T08:16:25Z","timestamp":1764663385000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Targeting the CXCL12\/CXCR4 pathway by an optimized derivative or EPI-X4 preserves chondrocyte function and offers a novel therapeutic approach in rheumatic diseases"],"prefix":"10.1186","volume":"27","author":[{"given":"Leonie","family":"Ruths","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah","family":"de Hesselle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felix","family":"Hau\u00dfner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sofya","family":"Albers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mirja","family":"Harms","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tobias","family":"Freitag","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"M\u00fcnch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jana","family":"Riegger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,12,2]]},"reference":[{"issue":"11","key":"3691_CR1","doi-asserted-by":"publisher","first-page":"1853","DOI":"10.1002\/jor.22145","volume":"30","author":"CA Toupadakis","year":"2012","unstructured":"Toupadakis CA, Wong A, Genetos DC, Chung DJ, Murugesh D, Anderson MJ, et al. 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