Associations of osteoclastogenesis and nerve growth in subchondral bone marrow lesions with clinical symptoms in knee osteoarthritis

Abstract

Background/objective: Subchondral bone marrow lesions (BMLs) are common magnetic resonance imaging (MRI) features in joints affected by osteoarthritis (OA), however, their clinical impacts and mechanisms remain controversial. Thus, we aimed to investigate subchondral BMLs in knee OA patients who underwent total knee arthroplasty (TKA), then evaluate the associations of osteoclastogenesis and nerve growth in subchondral BMLs with clinical symptoms.

Methods: Total 70 patients with primary symptomatic knee OA were involved, then separated into three groups based on MRI (without BMLs group, n ​= ​14; BMLs without cyst group, n ​= ​37; BMLs with cyst group, n ​= ​19). Volume of BMLs and cyst-like lesions was calculated via the OsiriX system. The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) questionnaire was used to assess clinical symptoms. Histology and immunohistochemistry were deployed to assess subchondral osteoclastogenesis and nerve distribution. Pearson's correlation coefficient was used to evaluate the associations between volume of BMLs and joint symptoms, and to assess the associations of osteoclastogenesis and nerve growth in subchondral BMLs with joint symptoms.

Results: In BMLs combined with cyst group, patients exhibited increased osteoclastogenesis and nerve distribution in subchondral bone, as shown by increased expression of tartrate resistant acid phosphatase (TRAP) and protein gene product 9.5 (PGP9.5). Volume of subchondral cyst-like component was associated with joint pain (p ​< ​0.05). Subchondral osteoclastogenesis and nerve distribution were positively associated with joint pain in BMLs with cyst group (p ​< ​0.05).

Conclusion: The subchondral cyst-like lesion was an independent factor for inducing pain in OA patients; osteoclastogenesis and nerve growth in subchondral cyst-like lesions could account for this joint pain.

The translational potential of this article: Our results indicated that the increased osteoclastogenesis and nerve growth in subchondral cyst-like lesions could account for the pain of OA joints. These findings may provide valuable basis for the treatment of OA.

Keywords: Bone marrow lesions; Cyst-like lesions; Knee osteoarthritis; Nerve growth; Osteoclastogenesis.

Figure 1

MRI images of various types of BMLs. (a) OA patient without BMLs. (b) Subchondral BMLs without cyst-like component (white arrows) in the tibia. (c) BMLs combined with cyst-like component (white arrows) in the tibia. (d) 3D image of subchondral BMLs combined with cyst (e, f) 3D models of the knee joint were reconstructed based on the MRI images.

Figure 2

Histological observation of subchondral bone and articular cartilage. (a) H&E staining showed the structure of subchondral bone. (b) S&F indicated the cartilage damage among the three groups of patients. (c) OARSI score of the cartilage in the tibia, compared by K–W test. “∗” indicated p ​< ​0.05, “∗∗” indicated p ​< ​0.01, “CC” indicated cystic cavity, “SB” indicated subchondral bone.

Figure 3

Osteoclast density and nerve growth in subchondral bone. (a) TRAP/PGP9.5 double immunofluorescence staining. (b) Quantitative analysis of TRAP among the three groups, compared by K–W test. (c) Quantitative analysis of PGP9.5 among the three groups, compared by Student's t test. “∗” indicated p ​< ​0.05, “∗∗” indicated p ​< ​0.01, “CC” indicated cystic cavity, “SB” indicated subchondral bone.

Figure 4

Expression of MMP-13 in subchondral bone. (a) MMP-13 immunofluorescence staining in subchondral bone. (b) Quantitative analysis of MMP-13 among the three groups, compared by K–W test. “∗” indicated p ​< ​0.05, “∗∗” indicated p ​< ​0.01, “CC” indicated cystic cavity, “SB” indicated subchondral bone.