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.

Current understanding of osteoarthritis pathogenesis and relevant new approaches

“… 19 Due to the lack of satisfactory management for OA-associated pain, the mechanisms of OA-associated pain and related signaling pathways remain unclear. 20 – 22 Recent findings have provided new insights into the roles of new forms of regulated cell death and the synovial lymphatic system in the pathogenesis of OA. 23 – 26 To better understand the molecular mechanisms and identify key target(s) for drug discovery and OA treatment, we need to use novel approaches to comprehensively investigate OA mechanisms using newly developed techniques and methodologies.…”

Maintaining hypoxia environment of subchondral bone alleviates osteoarthritis progression

“…Over-activated osteoclasts in subchondral bone are closely associated with OA progression ( 9 ). Physiologically the bone remodeling activity and number of osteoclasts are strictly controlled in the subchondral bone and the number of osteoclasts dramatically increases at the early stage of OA mice model ( 10, 11 ).…”

Babam2 negatively regulates osteoclastogenesis by interacting with Hey1 to inhibit Nfatc1 transcription

“…Osteoclasts are multinucleated cells differentiated from the bone marrow monocyte-macrophage lineage by the stimulation of macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor-κB ligand (RANKL) [11][12][13]. After binding to the cell surface receptors of osteoclast precursors, M-CSF and RANKL stimulate downstream signaling pathways and activate the Ivyspring International Publisher transcription of transcription factors essential for osteoclast differentiation and bone resorption activities [14][15][16]. Of these transcription factors, the nuclear factor of activated T cells, cytoplasmic 1 (Nfatc1) is the master regulator for osteoclast formation, which regulates the transcription of various osteoclast marker genes including Ctsk, Trap, Dcstamp, and Mmp9 [17][18][19].…”