Innervation of the knee and TMJ

The over-arching goal for the RE-JOIN Consortium is to define how the neurons that mediate
chronic joint pain innervate different articular and peri-articular tissues, with a focus on the knee
and temporomandibular joint (TMJ). With an improved understanding of how different neural
subtypes distribute through the joint and how these subtypes change with age and disease, new
therapies can be developed to reduce the heavy burden of chronic joint pain. To achieve this goal,
our team will focus on advancing our understanding of pathology-pain relationships in the knee
and TMJ by combining expertise in neural tracing, 3-dimensional imaging, and evaluations of
chronic joint pain and disability. Our proposal brings together a highly collaborative team that
spans basic science and clinical research with extensive experience in both the knee and TMJ,
allowing us to evaluate shared vs. joint-specific shifts in innervation networks and the
development of chronic joint pain. Specifically, our team will first use neural tracing dyes to identify
the cell bodies in the dorsal root ganglia and trigeminal ganglia that project to the muscle, bone,
or intra-articular joint tissues. These neurons will then be evaluated for their function using
electrophysiologic tests and their transcriptome using single cell RNA-Seq. By overlapping neural
function with gene expression, we will identify promoter targets and design adeno-associated
virus (AAV) vectors to produce fluorescent labels alongside the expression of these targets.
Importantly, this approach will allow us to develop AAV-based tracers for specific functional neural
subtypes, as well as combine traditional markers of functional subtypes with any newly identified
markers that describe how the neuron changes with age, sex, and osteoarthritis (OA) severity.
Using these tracers, we will then evaluate the distribution of functional neural subtypes throughout
the joint (including bone, cartilage, synovium, joint capsule, ligament, tendon, fascia, and muscle)
and how these innervation networks change with age, sex, and OA severity. Moreover, these
tracers will be used to evaluate how joint innervation adapts following the application of two neural
ablation techniques for pain relief in the knee and TMJ. To evaluate the clinical significance of our
preclinical studies, innervation changes will be assessed in tissues collected from patients
undergoing total joint replacement of the knee or TMJ. In all of our studies, joint innervation will
be paired with detailed analyses of joint pain and disability. In rodents, these analyses will include
detailed behavioral characterizations; in patients, these analyses will include quantitative sensory
tests and other assessments of joint function. Combined, this approach will allow us to evaluate
pathology-pain relationships related to joint innervation from the preclinical model to the clinic.

Grant Number: 4UC2AR082196-02
NIH Institute/Center: NIH
Principal Investigator: Kyle Allen