Macrophage Plasticity in OPLL: From Inflammation to Pathological Ossification

OPLL was already multifactorial; the new review adds an immune cell layer

Earlier work established OPLL as a multifactorial degenerative disorder with strong genetic and metabolic contributions. Prevalence ranges from 1.9% to 4.3% in Japan, 1.1% to 1.7% in China, and 0.9% to 3.6% in Korea, compared with approximately 1.3% in Western populations, and GWAS have identified susceptibility loci including RSPO2, SNX17, and SUPT3H [1]. Clinical studies link OPLL to diabetes, obesity, visceral adiposity, dyslipidemia, and hepatic steatosis, all characterized by chronic low-grade inflammation [1]. A separate case report and review on asymptomatic ossification of the anterior longitudinal ligament reinforces that ligament ossification can be clinically silent and underdiagnosed, with a postmortem study finding hypertrophic osteophytes in 21 of 75 asymptomatic patients (28%) [2]. What the 2026 review adds is a mechanistic immune layer: polygenic risk is enriched in active enhancer regions of immune and hematopoietic cell populations, and single-cell transcriptomic analyses in a heterotopic ossification model show OPLL susceptibility genes expressed within myeloid-lineage clusters [1]. This shifts the question from which genes and metabolites predispose to OPLL toward which immune cells translate that risk into ossification.

Macrophage plasticity cuts both ways in the ligament niche

The review's central claim is that macrophages are not a single inflammatory force but a spectrum of functional states shaped by cytokines, metabolites, extracellular matrix, and mechanical forces [1]. Pro-inflammatory macrophages secrete TNF-α, IL-1β, IL-6, IL-12, and IL-23, release reactive oxygen species and matrix metalloproteinases, and sustain chronic inflammation through NF-κB and MAPK signaling [1]. Anti-inflammatory macrophages, traditionally viewed as reparative, are implicated in disease progression through TGF-β1 and PDGF secretion, myofibroblast trans-differentiation, and angiogenesis via VEGF, which together create a hypoxic niche that amplifies BMP signaling and endochondral ossification [1]. This dual role is consistent with broader macrophage polarization literature showing that M1 and M2 macrophages exist in dynamic balance and that imbalance worsens inflammatory disease [4]. The review also notes that the traditional M1/M2 binary is an oversimplification; single-cell RNA sequencing and high-dimensional proteomics show tissue macrophages co-express genes associated with both classical and alternative activation [1]. For OPLL researchers, this means macrophage phenotyping must move beyond surface markers toward functional and metabolic states.

Heterotopic ossification provides the mechanistic precedent, but OPLL is not HO

Much of the mechanistic evidence for macrophage-driven ossification comes from heterotopic ossification models. In a traumatic HO mouse model, matrine downregulated TGF-β and VEGF expression in anti-inflammatory macrophages and reduced ectopic bone volume and maturity [1]. Macrophage depletion significantly reduced local BMP-7 levels and bone formation, positioning macrophages upstream of BMP signaling [7]. More recently, a muscle-repairing macrophage subset (Ly6ChiCX3CR1loPDPN+CD9+) was shown to secrete activin A via TLR4/TRIF/TBK1/IRF3/7 signaling, promoting muscle regeneration physiologically but inducing HO in a genetically induced model; TLR4 inhibition suppressed HO [3]. Metformin has also been shown to prevent trauma-induced HO by inhibiting macrophage-mediated inflammation through SIRT1-dependent NF-κB suppression [8] and by blocking NF-κB crosstalk between macrophages and preosteoblasts, reducing BMP signaling and osteogenic differentiation [9]. TGF-β1 signaling in macrophages, not mesenchymal progenitors, is critical for HO formation after trauma, and a TGF-βRII-Fc ligand trap decreased HO and delayed macrophage infiltration [10]. Macrophage-derived extracellular DNA from M2 macrophages initiates pathological calcification in HO, and deoxyribonuclease reversed calcification in a rat tendon model [11]. A 2025 review on macrophage polarization in HO further catalogs M1 and M2 contributions and therapeutic agents including IL-1 inhibitors, parovastatin, metformin, TGF-βRII-Fc, galunisertib, and ruxolitinib [12]. The 2026 OPLL review explicitly cautions that these studies were conducted in acute traumatic HO or fibrodysplasia ossificans progressiva (FOP) models, whereas OPLL is a chronic, age-related degenerative process unfolding over years in the distinct biochemical and biomechanical niche of the posterior longitudinal ligament [1]. Mechanistic inferences from HO and FOP should therefore be regarded as hypothesis-generating rather than directly validated in OPLL.

Metabolic dysregulation and immunometabolism converge on macrophage phenotype

The review integrates metabolic and immune mechanisms by showing how lipid and glucose metabolism shape macrophage phenotype in OPLL. Lipid droplets are dynamic regulators of inflammatory signaling; arachidonic acid liberation fuels pro-inflammatory eicosanoids, and loss of diacylglycerol O-acyltransferase 1 exacerbates inflammatory activation while adipose triglyceride lipase deficiency suppresses inflammation and tilts toward anti-inflammatory polarization [1]. In chronic metabolic-inflammatory diseases such as atherosclerosis, pro-inflammatory macrophages upregulate scavenger receptors CD36 and scavenger receptor class A, take up oxidized LDL, form foam cells, and activate NLRP3 and AIM2 inflammasomes, driving IL-1β production [1]. Sterol regulatory element-binding protein-2 directly engages NLRP3, and 25-hydroxycholesterol promotes mitochondrial DNA leakage and AIM2 inflammasome activation under cholesterol overload [1]. These pathways matter for OPLL because macrophage-driven inflammation stimulates TGF-β1 secretion, which promotes BMP expression in mesenchymal stem cells and osteogenic differentiation [1]. A separate systematic review on human immunometabolism confirms that effector T cells and M1 macrophages favor glycolysis for rapid ATP and pro-inflammatory signaling, whereas memory T cells and M2 macrophages rely on oxidative phosphorylation and fatty-acid oxidation, with mTORC1/AMPK, glutaminolysis, and the kynurenine pathway integrating metabolic and immune cues [6]. That review also notes that metabolic dysregulation in obesity or tumor microenvironments skews these pathways toward chronic inflammation or immune escape [6]. The OPLL review's contribution is to connect this immunometabolic framework to a specific degenerative spinal disease and to propose that targeting macrophage metabolism could disrupt the fibro-osteogenic cascade [1].

Therapeutic targeting of macrophages is promising but unproven in OPLL

The review surveys therapeutic strategies targeting macrophage polarization, recruitment, and secretome, including metformin, rapamycin, dexamethasone, garetosmab (activin A-neutralizing antibody), JNJ-40346527 (CSF-1R inhibitor), sorafenib, verteporfin, and aspirin/sodium salicylate [1]. Many of these agents have shown efficacy in HO or FOP models but not in OPLL. For example, activin A-neutralizing antibodies or BMP ligand traps suppressed spontaneous and trauma-induced HO in FOP mice, reduced osteogenic marker expression, and decreased bone formation area [1]. Garetosmab, an activin A-neutralizing antibody, has been tested in a phase 2 trial in FOP [1]. Metformin prevented trauma-induced HO in mice through SIRT1-dependent NF-κB inhibition [8] and through AMPK-mediated suppression of monocyte-to-macrophage transition and BMP signaling in preosteoblasts [9]. However, the OPLL review explicitly states that macrophage-targeted therapy for OPLL has not been validated in clinical trials and that the molecular mechanisms governing macrophage function in OPLL remain incomplete [1]. A competing perspective from diabetic wound healing shows that macrophage polarization is context-dependent: diabetic wounds show dysregulated and persistent M1 polarization, whereas normal wounds transition to M2 around day three, and treatment likely requires a multimodal approach including glycemic control and infection prevention [13]. This reinforces that simply shifting M1 to M2 may not be therapeutic in OPLL, where anti-inflammatory macrophages themselves drive fibrosis and angiogenesis [1]. Validation evidence from macrophage depletion in a SARM1-dependent neuropathy model shows that macrophage depletion blocked and reversed neuropathic phenotypes, demonstrating that macrophage-targeted therapy can work in principle in a chronic degenerative disease [5]. But that model is mechanistically distinct from OPLL, and the OPLL review's boundary remains: the efficacy of macrophage-targeted therapy in OPLL is an open question requiring OPLL-specific specimens and models [1].

About These Sources

This research page is built on 13 peer-reviewed studies — published from 2021 to 2026, 6 from 2024 or later, 8 in Q1 journals, collectively cited 1,083 times — selected as the most relevant from 13 studies that passed quality screening, drawn from 153 papers retrieved from a database of over 500 million.

Sources used in this answer