Tyrosine at the Crossroads: Hepatic Osteodystrophy as a State of Metabolic Tyrosine Kinase Inhibition
Chi-Ming Chiang
Chi-Ming Chiang
1) Center for General Education, Chung Yuan Christian University, Taiwan, China.
2) Department of Orthopedics, Chon-Inn Hospital, Chon-Inn Medical Corporation, Taiwan, China.
Hepatic osteodystrophy (HOD) is a prevalent and clinically consequential complication of chronic liver
disease, classically attributed to multifactorial deficits in insulin-like growth factor-1 (IGF-1), vitamin
D, sex hormones, and nutrition, together with inflammatory and metabolic perturbations of the liver–
bone axis. While this multifactorial framing is descriptively correct, it often remains mechanistically
diffuse and therapeutically additive. Here, we propose a unifying systems-biology framework—
Metabolic Tyrosine Kinase Inhibition (MTKI)—that reframes HOD as an endogenous, pharmacologylike
syndrome in which anabolic signaling is not only under-supplied but is also functionally suppressed
at the receptor level. We posit that in advanced liver dysfunction, the aromatic amino acid pool (tyrosine
and its tightly coupled phenylalanine pool) is rerouted away from canonical anabolic usage and toward
decarboxylation-dependent accumulation of trace amines and false neurotransmitters, including
β-phenethylamine (PEA), tyramine, octopamine, and phenylethanolamine, which have been measured
in hepatic encephalopathy and severe hepatic dysfunction. We hypothesize that these metabolites
function as “false hepatokines” within the skeletal niche by engaging trace amine–associated receptor
1 (TAAR1), a Gαs-coupled G protein–coupled receptor that elevates intracellular cAMP and activates
protein kinase A (PKA) signaling . Drawing on established models of insulin resistance—where increased
cAMP/PKA tone and inhibitory serine phosphorylation can silence insulin/IGF-family receptor
signaling—we propose that sustained TAAR1-driven kinase tone imposes heterologous inhibitory serine
phosphorylation on the IGF-1 receptor (IGF-1R) and/or its proximal adaptor IRS-1, thereby “locking”
the IGF-1R tyrosine kinase domain in a low-output state despite ligand availability. At the tissue level,
this mechanism would bias bone remodeling toward a deterministic low-gain “fragility attractor,”
conceptually isomorphic to skeletal remodeling disturbances observed with pharmaceutical tyrosine
kinase inhibitors (TKIs). We discuss testable predictions and therapeutic strategies that move beyond
replacement toward disinhibition and re-sensitization, including upstream reduction of trace-amine
load and downstream restoration of IGF-1R signaling competence.
