Disrupting the Hypoxia–Fibrosis Loop in Keloid Myofibroblasts
Location
LSU Health NO Center for Advanced Learning and Simulation (CALS)
Document Type
Event
Start Date
20-6-2026 10:20 AM
End Date
20-6-2026 11:20 AM
Publication Date
June 2026
Description
Introduction: Keloids pose a significant challenge in orthopaedics, with prevalence rates of 2.1% in total knee arthroplasty and 2.2% in spine surgery. High-tension incisions and internal fixation hardware create a high-risk environment for debilitating contractures and nerve compression, and recurrence rates after surgical excision remain alarmingly high. These lesions develop under low O2 tension and involve a complex metabolic environment in which canonical TGFβ triggers an IL11 autocrine loop that drives a persistent fibrotic phenotype, further intensified by the NKA-Src (Tyr419) signaling hub and the PI3K-mTORC-HIF1α pathway, thereby sustaining Erk/MAPK activation and promoting scarring myofibroblast differentiation. A key element of this process is the HIF1α→HOXC6 axis, which is specifically upregulated in keloid myofibroblasts (KMFs) under hypoxia, amplifying abnormal proliferation and aberrant extracellular matrix deposition by converging with other effectors on Erk/MAPK myofibroblast activation. We have shown that NM1157 (Novomedix), a first-in-class small-molecule inhibitor of IL11, reduces the scarring phenotype in synoviocytes from patients with arthrofibrosis and in commercial KMFs under normoxia by blocking the IL11 autocrine loop. We predict that NM1157 will reduce excessive collagen type I (COL1) production by KMFs under hypoxia, thereby alleviating pathological cellular stress and impairing the HIF1α→HOXC6 signaling axis, which otherwise amplifies the fibrotic phenotype.
Methods: To simulate the high-stress, low-O2 conditions of keloiding orthopedic scars, human KMFs (ATCC) and healthy dermal fibroblasts (DFs; Cell Applications) were subjected to a 48-hour hypoxic challenge (1% O2) or normoxia (21% O2). Hypoxia was confirmed using the Image-iT Green fluorogenic probe. At the two oxygen tensions, experimental cell replicates were treated with 10 μM NM1157 or vehicle. At the endpoint, protein was extracted and quantified using a bicinchoninic acid assay. The Jess Simple Western (JSW) platform provided automated, total-protein-normalized quantification of the key mechanistic proteins HIF1α (~120 kDa) and HOXC6 (~27 kDa). Functional COL1 output was measured by sandwich ELISA (Abcam). Statistical significance was assessed using two-way ANOVA with Tukey’s post hoc tests at α = 0.05.
Results: The hypoxia probe confirmed the end-point status of KMFs under low O2. JSW analysis demonstrated that while hypoxia stabilized HIF1α in both cell types (p < 0.0001), significant induction of the oncogenic driver HOXC6 occurred exclusively in hypoxic KMFs (p = 0.0004), identifying a keloid-specific molecular vulnerability. NM1157 treatment significantly reduced the levels of both hypoxia-stabilized proteins. Furthermore, KMFs exhibited significantly higher basal COL1 levels than DFs (p = 0.0471), and these levels were further augmented by environmental hypoxia. NM1157 successfully mitigated COL1 output in all groups.
Discussion: This study identifies the HIF1α→HOXC6 axis as a keloid-specific "pathogenic switch" activated by the low-O2 environment of orthopedic wounds. While HIF1α stabilization is a universal response to hypoxia, its induction of HOXC6 —and resulting enhancement of Erk/MAPK signaling— is specific to KMFs. NM1157 has been shown to disrupt the decoupling of the NKA-Src hub, which can help lower hypoxia-stabilized protein levels and reduce excessive COL1 production. By potentially re-engaging the AMPK metabolic "brake," NM1157 shuts down the hyperactive mTORC pathway, restoring metabolic health, as evidenced by an 110% increase in metabolic activity in NM1157+ fibrotic synoviocytes. The new findings presented here, along with those previously reported by others in our lab, demonstrate that NM1157 successfully reverses hyperactive KMFs to a state resembling DFs.
Significance/Clinical relevance: NM1157 has the potential to be a transformative, first-in-class topical pharmacotherapy that disrupts the keloid-specific HIF1α→HOXC6 "pathogenic switch" and the IL11 autocrine loop, thereby reversing the hyperactive fibrotic phenotype of KMFs and helping mitigate the high recurrence rates of hypertrophic and keloiding scars that can impair functional recovery and success of high-tension site surgery.
Recommended Citation
Denny, Camille, "Disrupting the Hypoxia–Fibrosis Loop in Keloid Myofibroblasts" (2026). Dept. of Orthopaedics: Robert D. D’Ambrosia Lectureship & Research Day. 1.
https://digitalscholar.lsuhsc.edu/ortho_rd/2026/student/1
Disrupting the Hypoxia–Fibrosis Loop in Keloid Myofibroblasts
LSU Health NO Center for Advanced Learning and Simulation (CALS)
Introduction: Keloids pose a significant challenge in orthopaedics, with prevalence rates of 2.1% in total knee arthroplasty and 2.2% in spine surgery. High-tension incisions and internal fixation hardware create a high-risk environment for debilitating contractures and nerve compression, and recurrence rates after surgical excision remain alarmingly high. These lesions develop under low O2 tension and involve a complex metabolic environment in which canonical TGFβ triggers an IL11 autocrine loop that drives a persistent fibrotic phenotype, further intensified by the NKA-Src (Tyr419) signaling hub and the PI3K-mTORC-HIF1α pathway, thereby sustaining Erk/MAPK activation and promoting scarring myofibroblast differentiation. A key element of this process is the HIF1α→HOXC6 axis, which is specifically upregulated in keloid myofibroblasts (KMFs) under hypoxia, amplifying abnormal proliferation and aberrant extracellular matrix deposition by converging with other effectors on Erk/MAPK myofibroblast activation. We have shown that NM1157 (Novomedix), a first-in-class small-molecule inhibitor of IL11, reduces the scarring phenotype in synoviocytes from patients with arthrofibrosis and in commercial KMFs under normoxia by blocking the IL11 autocrine loop. We predict that NM1157 will reduce excessive collagen type I (COL1) production by KMFs under hypoxia, thereby alleviating pathological cellular stress and impairing the HIF1α→HOXC6 signaling axis, which otherwise amplifies the fibrotic phenotype.
Methods: To simulate the high-stress, low-O2 conditions of keloiding orthopedic scars, human KMFs (ATCC) and healthy dermal fibroblasts (DFs; Cell Applications) were subjected to a 48-hour hypoxic challenge (1% O2) or normoxia (21% O2). Hypoxia was confirmed using the Image-iT Green fluorogenic probe. At the two oxygen tensions, experimental cell replicates were treated with 10 μM NM1157 or vehicle. At the endpoint, protein was extracted and quantified using a bicinchoninic acid assay. The Jess Simple Western (JSW) platform provided automated, total-protein-normalized quantification of the key mechanistic proteins HIF1α (~120 kDa) and HOXC6 (~27 kDa). Functional COL1 output was measured by sandwich ELISA (Abcam). Statistical significance was assessed using two-way ANOVA with Tukey’s post hoc tests at α = 0.05.
Results: The hypoxia probe confirmed the end-point status of KMFs under low O2. JSW analysis demonstrated that while hypoxia stabilized HIF1α in both cell types (p < 0.0001), significant induction of the oncogenic driver HOXC6 occurred exclusively in hypoxic KMFs (p = 0.0004), identifying a keloid-specific molecular vulnerability. NM1157 treatment significantly reduced the levels of both hypoxia-stabilized proteins. Furthermore, KMFs exhibited significantly higher basal COL1 levels than DFs (p = 0.0471), and these levels were further augmented by environmental hypoxia. NM1157 successfully mitigated COL1 output in all groups.
Discussion: This study identifies the HIF1α→HOXC6 axis as a keloid-specific "pathogenic switch" activated by the low-O2 environment of orthopedic wounds. While HIF1α stabilization is a universal response to hypoxia, its induction of HOXC6 —and resulting enhancement of Erk/MAPK signaling— is specific to KMFs. NM1157 has been shown to disrupt the decoupling of the NKA-Src hub, which can help lower hypoxia-stabilized protein levels and reduce excessive COL1 production. By potentially re-engaging the AMPK metabolic "brake," NM1157 shuts down the hyperactive mTORC pathway, restoring metabolic health, as evidenced by an 110% increase in metabolic activity in NM1157+ fibrotic synoviocytes. The new findings presented here, along with those previously reported by others in our lab, demonstrate that NM1157 successfully reverses hyperactive KMFs to a state resembling DFs.
Significance/Clinical relevance: NM1157 has the potential to be a transformative, first-in-class topical pharmacotherapy that disrupts the keloid-specific HIF1α→HOXC6 "pathogenic switch" and the IL11 autocrine loop, thereby reversing the hyperactive fibrotic phenotype of KMFs and helping mitigate the high recurrence rates of hypertrophic and keloiding scars that can impair functional recovery and success of high-tension site surgery.