Pain Neuropeptides CGRP and Substance P Increase in Ankle Osteoarthritis Bone as Cartilage Degenerates | Research

The takeaway

CGRP and substance P neuropeptides were significantly upregulated in sclerotic subchondral bone of ankle OA patients, correlating strongly with bone density changes, cartilage degeneration severity, and osteoclast activity.

CGRP appears before SP
In ankle OA progression, CGRP expression in subchondral bone was detectable at moderate degeneration stages before substance P appeared, suggesting it may serve as an earlier marker of disease-related neuropeptide activation.

What the researchers found

In 17 ankle joints from OA patients, CGRP and substance P expression were significantly upregulated in sclerotic subchondral bone. Both neuropeptides showed strong positive correlations with:

- Hounsfield unit (HU) values (bone density on CT)

- Subchondral bone plate thickness

- Modified Mankin scores (cartilage degeneration severity)

CGRP expression appeared earlier than substance P, detectable at moderate degeneration stages. TRAP-positive osteoclast numbers also increased with disease progression and followed a distribution pattern matching CGRP and SP expression, suggesting a functional relationship between neuropeptide signaling and bone remodeling.

Why it matters

This is the first study to systematically map neuropeptide expression in subchondral bone specifically in ankle OA, revealing that the bone itself — not just the joint lining or cartilage — is a source of pain-related neuropeptides. The finding that CGRP appears before substance P suggests it may serve as an earlier biomarker or therapeutic target. The link between neuropeptides and osteoclast activity opens the possibility that pain signaling and bone destruction are mechanistically connected, not just coincidental.

How the study worked

Seventeen ankles from 16 patients who underwent total ankle arthroplasty for OA were analyzed. Researchers conducted radiographic evaluation, CT imaging with Hounsfield unit measurements, and histologic analysis including subchondral bone plate thickness and trabecular bone area measurements. Cartilage degeneration was scored using modified Mankin criteria. Immunohistochemistry was performed for CGRP, substance P, collagen types I, II, and X, and TRAP staining identified osteoclasts. Correlations between neuropeptide expression and structural/degenerative parameters were analyzed.

What this study cannot tell us

This is a cross-sectional study, meaning it captures one timepoint and cannot establish whether neuropeptide upregulation causes or results from bone changes and cartilage degeneration. The sample size is small (17 ankles from 16 patients). All specimens came from end-stage OA requiring arthroplasty, so findings may not represent earlier disease stages. The study is specific to ankle OA and may not generalize to hip or knee OA. Quantitative neuropeptide measurements were not performed — only immunohistochemical staining patterns.

How to read the evidence

This is a cross-sectional histologic study of human surgical specimens with systematic immunohistochemical analysis. While it provides direct evidence from human tissue, the small sample size and inability to establish causation (due to the cross-sectional design) place it at a moderate evidence level.

When this study was published

Published in 2025, this is a very current study contributing to the active research area of neuropeptide involvement in OA pathogenesis and the role of subchondral bone in joint disease.

The bigger picture

This study adds important evidence to the emerging understanding that OA is not just a cartilage disease — the subchondral bone plays an active role in both structural damage and pain generation. The neuropeptides CGRP and substance P, already targets of breakthrough therapies for migraine, may represent treatable pathways in OA as well. The connection between neuropeptide expression and osteoclast activity suggests that pain and bone destruction may share common signaling mechanisms, potentially allowing single therapies to address both.

Questions still open

Could CGRP-targeted therapies (already available for migraine) be repurposed to treat osteoarthritis pain and potentially slow bone remodeling?
Does the earlier appearance of CGRP compared to substance P make it a useful biomarker for detecting OA progression before severe cartilage damage occurs?
Is the connection between neuropeptide expression and osteoclast activity causal — do CGRP and SP directly stimulate bone resorption?

Common questions

Can the bone underneath cartilage actually cause osteoarthritis pain?

Yes — this study shows that subchondral bone (the bone just beneath joint cartilage) contains increasing amounts of pain-signaling neuropeptides CGRP and substance P as OA progresses. Since cartilage itself has no nerves, the underlying bone is likely a major source of OA pain, especially as it becomes thicker and denser during the disease.

Could migraine drugs that block CGRP also help osteoarthritis?

It's a promising idea but unproven. CGRP-blocking drugs are highly effective for migraine, and this study shows CGRP is significantly elevated in OA bone tissue. However, joint tissues are very different from the nervous system, and clinical trials would be needed to determine whether CGRP-targeted therapies can reduce OA pain or slow joint damage.

Read the original research

Neuropeptide-Mediated Crosstalk between Subchondral Bone and Articular Cartilage in Ankle Osteoarthritis: A Cross-Sectional Histologic Study of 17 Ankles.

Foot & ankle international, 46(11), 1311-1321

View on PubMed ↗Publisher’s paper ↗

Citation

Ishibashi, Saori; Nakasa, Tomoyuki; Ikuta, Yasunari; Sakurai, Satoru; Moriwaki, Dan; Chujo, Taro; Adachi, Nobuo. (2025). Neuropeptide-Mediated Crosstalk between Subchondral Bone and Articular Cartilage in Ankle Osteoarthritis: A Cross-Sectional Histologic Study of 17 Ankles.. Foot & ankle international, 46(11), 1311-1321. https://doi.org/10.1177/10711007251372141