Osteophyte formation after ACL rupture in mice is associated with joint restabilization and loss of range of motion

Abstract

Osteophytes are a typical radiographic finding during osteoarthritis (OA). Osteophytes are thought to form in response to joint instability, however the time course of osteophyte formation and joint stabilization following joint injury is not well understood. In this study, we investigated the time course of osteophyte formation and joint function following non-invasive knee injury in mice. We hypothesized that initial joint instability following knee injury would initiate osteophyte formation, which would in turn restabilize the joint and reduce range of motion (ROM). Mice were subjected to non-invasive anterior cruciate ligament (ACL) rupture. Anterior-posterior (AP) joint laxity, ROM, and chondro/osteophyte formation were measured immediately after injury, and 2, 4, 6, and 8 weeks post-injury. Chondrophyte areas at each time point were measured with histology, while mineralized osteophyte volume was determined using micro-computed tomography. Immediately after ACL rupture, AP joint laxity was increased 2-fold, while ROM was increased 11.7%. Chondrophytes appeared by 2 weeks post-injury, corresponding with a decrease in AP joint laxity and ROM. By 8 weeks post-injury, considerable osteophyte formation was observed around the joint, AP joint laxity returned to control levels, and joint ROM decreased to 61% of control values. These data support a role for chondro/osteophytes in joint restabilization after injury, and provide crucial insight into the time course and pathology of joint degeneration during OA development in the mouse.

Size of Medial Knee Osteophytes Correlates With Knee Alignment But Not With Coronal Laxity in Patients With Medial Knee Osteoarthritis

“…Increases in mechanical loading may thus promote osteophyte formation, and the current study demonstrated that osteophyte size increased as the alignment deteriorated. These results were supported by previous animal and clinical studies involving knees with a damaged or deficient anterior cruciate ligament, in which the loads to the knee joint were mainly increased in the AP direction.…”

Osteophytes and fracture calluses share developmental milestones and are diminished by unloading

“…The formation of fracture calluses and osteophytes is generally similar, and recapitulate the differentiation pattern in the growth plate during development . Both begin as cartilaginous soft tissue that gradually ossifies to become bone, both are highly modulated by the TGF‐β superfamily, and both are thought to act as mechanical stabilizers . We previously showed that chondro/osteophyte formation after injury correlates with increasing joint stability after ACL rupture in mice, with a full return to control levels after 8 weeks .…”

“…Whole knee joints and femora were scanned using μCT (SCANCO μCT 35, Brüttisellen, Switzerland) to determine total mineralized osteophyte and fracture callus volumes at 14, 21, and 28 days post‐injury. Earlier time points were not evaluated using μCT because we previously found that mineralized osteophytes were not detectable by μCT until at least 2 weeks following non‐invasive knee injury . Scans were performed according to rodent bone structure analysis guidelines (X‐ray tube potential = 55 kVp, intensity = 114 μA, 10 μm isotropic nominal voxel size, integration time = 900 ms) .…”

“…The global threshold for “bone” was set equivalent to 567 mg HA/cm 3 . Total mineralized osteophyte volume was determined using previously defined methods . Briefly, contours were drawn around all heterotopic mineralized tissue attached to the distal femur and proximal tibia, as well as the entire patella, fabellae, and menisci.…”

Attenuation of Post‐Traumatic Osteoarthritis After Anterior Cruciate Ligament Injury Via Inhibition of Hedgehog Signaling

“…The sections were stained with Safranin‐O–fast‐green to assess osteophyte formation and articular cartilage degeneration. The osteophyte (including chondrophyte) areas were quantified using freehand traces in ImageJ (National Institutes of Health, Bethesda, MD) . Histologic grading of articular cartilage damage severity was performed using the scoring system reported by Kamekura et al, which consisted of a 0‐4 scale for cartilage degeneration (0: No apparent changes; 1: Loss of superficial zone in articular cartilage; 2: Defects limited above tidemark; 3: Defects extending to calcified cartilage; 4: Exposure of subchondral bone) and a 0‐3 scale for osteophyte formation (0: None; 1: Formation of cartilage‐like tissues; 2: Increase in cartilaginous matrix; 3: Endochondral ossification).…”