gms | German Medical Science

Objectives: Alterations in innervation pattern of sensory nerves might contribute to the ongoing degenerative processes in subchondral bone in osteoarthritis (OA). Sensory neuropeptides like substance P (SP) and alpha calcitonin-gene-related peptide ( α CGRP) are trophic factors in bone cell metabolism. SP effects on bone are ambivalent and can be either catabolic or anabolic whereas α CGRP effects are primarily anabolic. How sensory neuropeptides are involved in OA subchondral bone pathology is not well understood. Here, we aim to analyze the influence of an altered sensory neuropeptide microenvironment on subchondral bone changes in a murine OA model.

Methods: OA was induced in wildtype (WT), SP-knockout (Tachykinin1 (Tac)1^-/-) and αCGRP-knockout mice by surgical destabilization of the medial meniscus (DMM). Subchondral bone alterations were assessed by µCT and measurement of serum concentration of bone turnover marker CTX-I. Bone microstructure of selected samples was analyzed using ultrahigh-resolution nano-CT technique.

Results and conclusion: Osteophytes were observed in all DMM groups 2 weeks after surgery. In contrast to WT Sham mice, Tac1^-/- and αCGRP^-/- had not developed osteophytes 12 weeks after Sham surgery. Bone volume density (BV/TV), specific bone surface (BS/BV), trabecular thickness (Tb.Th.) and number (Tb.N.) of subchondral bone from Tac1^-/- DMM mice was significantly altered compared to Sham controls 2 weeks after surgery. In addition, Tac1^-/- mice had higher BS/BV and Tb.N. as well as lower Tb.Th. in relation to WT mice, 2 weeks after Sham surgery. In late OA, 12 weeks after DMM surgery, WT mice had lower BV/TV and Tb.Th. and higher BS/BV and Tb.N. compared to αCGRP^-/- DMM mice. The same effects were observed comparing bone parameters of WT with αCGRP^-/- and Tac1^-/- mice, 12 weeks after sham surgery. NanoCT analysis of subchondral bone from WT DMM and WT Sham mice 8 weeks after surgery demonstrated a thicker layer of calcified cartilage in the medial tibia of DMM mice. Furthermore, DMM mice had a significantly longer medial condyle compared to Sham mice. Serum concentration of bone turnover marker CTX-I was significantly higher in α CGRP^-/- sham mice compared to α CGRP DMM and Tac1^-/- Sham mice, 8 weeks after the respective surgery. Serum CTX-I of Tac1^-/- Sham mice was reduced compared to WT Sham mice, 12 weeks after surgery.

Absence of SP contributes to early subchondral bone structural changes in murine OA whereas the bone of Sham mice without SP and αCGRP exhibits differences compared to WT mice relatable to advanced aging and not to OA. Subchondral bone changes of WT mice are subtle and require more refined analysis. Serum CTX-I analysis did not reflect changes observed by µCT/nanoCT and hence might not be an adequate marker for bone alterations observed during murine OA progression.