Congenital muscular dystrophy type 1A (CMD1A) is a severe genetic neuromuscular disorder caused by mutations in the LAMA2 gene, which encodes the laminin-alpha 2 subunit, an essential structural protein for maintaining muscle integrity during contraction. Affected children experience progressive muscle damage, hypotonia, delayed motor development, and respiratory tract insufficiency. CMD1A muscles undergo repeated cycles of degeneration and regeneration accompanied by chronic inflammation. Beyond its established role in bone remodeling, the receptor activator of nuclear factor-kappa B/receptor activator of nuclear factor-kappa B ligand (RANKL)/osteoprotegerin signaling axis has also been implicated in muscle pathophysiology. A 10-day treatment with full-length osteoprotegerin fused to an Fc fragment was previously shown to restore muscle function in a Duchenne muscular dystrophy mouse model. In this study, anti-RANKL therapy was evaluated in a more severe mouse model, specifically 4week-old male dy2J/dy2J mice, which recapitulate key CMD1A features. A 1-month anti-RANKL treatment significantly improved specific muscle strength, increased myofiber cross-sectional area, and reduced edema and immune cell infiltration. It also enhanced bone strength and microarchitecture. However, absolute muscle force and global motor performance remained unchanged. Overall, anti-RANKL treatment improved muscle intrinsic properties and bone parameters in dy2J/dy2J dystrophic mice, but these improvements were insufficient to enhance absolute muscle force or global j.ajpath.2026.04.011)
Organ and tissue functions emerge from the coordinated activity of cell networks. Therapeutics that act on pathogenic cell networks, modulating their cellular interplay, follow naturally. Over several decades, our laboratory has developed a series of approaches for rewiring cell networks, culminating in a class of cell surface-directed signal converter proteins (SCPs) that do so by modulating juxtacrine and autocrine signaling in and among their nodal cells. A first such SCP has now produced encouraging clinical data for cancer immunotherapy. Yet, these early network-directed fusion proteins rest on a deliberately simplified picture: discrete end-cell types plugged into graphically tractable networks. That picture is increasingly at odds with what computational cell typing and spatiotemporal analytics, along with epigenetics, now reveal & horbar;a hyperdiverse, plastic, experience-shaped cellular landscape embedded in dynamic, multiway networks. Setting the stage for a next generation of network modulators, an extended cell differentiation synthesis is proposed, which formalizes paracell ultra-differentiation and aging-associated differentiation phases. According to this model, cells are ever evolving, and no two cells are alike. A richer cellular ontology forces a more elaborate network ontology, with paralogous networks and their shifting subnetworks opening a concrete design space for next-generation network-directed SCP therapeutics. This exploration calls for a willingness to embrace complexity more fully and borrow freely from conceptual fields close and afar.
