ALPHA-CTX is associated with subchondral bone turnover and predicts progression of joint space narrowing and osteophytes in osteoarthritis

Osteoarthritis (OA) is the most common form of arthritis and involves multiple components of the joint including synovium, articular cartilage, and bone. The relationship between bone and cartilage in OA has been a source of controversy for a long time. Turnover of subchondral bone in OA has been shown to be as much as 20-fold higher than that of normal bone (1). Moreover, bone marrow lesions, considered areas of high turnover detected in the subchondral bone by magnetic resonance imaging (MRI), have been shown to be highly associated with OA and a strong risk factor for OA progression (2). In preclinical settings, studies using anterior cruciate ligament transection (ACLT) in dogs, as well as ACLT and meniscectomy (MNX) in rats, have been instrumental in characterizing the role of subchondral bone changes in OA (3–5). In clinical settings, however, there is a lack of sensitive and non-invasive measures of subchondral bone turnover. The qualification of biomarkers or methods to quantify subchondral bone remodeling may differentiate OA patient phenotypes and provide a means of defining subpopulations that may benefit from interventions focused on the bone-cartilage interface (6). Such investigations would have the added benefit of improving our understanding of OA disease pathogenesis and progression. Molecules in body fluids (serum, plasma, synovial fluid, and/or urine), which can potentially serve as biochemical markers of joint pathophysiology, include proteins involved in the enzymatic degradation of joint tissues, molecules reflecting the inflammatory component of joint disease, or molecules reflecting proteolysis, synthesis, or turnover of joint tissues (7). Examples include markers of cleavage products by proteases (MMPs, ADAMTS, Cathepsin K), markers of synovial inflammation (PIIINP, HA), differentiation and matrix production (PINP, PIINP, Osteocalcin, TRACP), signaling (RANKL, OPG, Dkk1), and matrix destruction (COMP, CTX, CTXII, Col2-1, etc) (8). In addition, imaging modalities, such as radiography and scintigraphy, can be used as surrogate markers of disease progression, although the rate at which these changes occur can be quite slow. However, combining the use of biological markers with imaging markers of disease has been demonstrated to provide independent and thus additive information (9). Mature collagen types I and II are cross-linked triple helical structures that critically contribute to the tensile properties of both bone and articular cartilage, respectively. Collagen type I is the most abundant form of collagen in the human body and the major protein in bone, comprising approximately 90–96% of the entire collagen content of bone. Metabolites of type I collagen (CTXI and N-terminal type I collagen [NTx]) have been positively associated with knee OA progression (10). The CTX epitope, 1207EKAHGDDR1214, is located in the C-telopeptide α1 chain of collagen type I (11) and exists in two forms--an isomerized and a non-isomerized form. Isomerization of the CTX epitope to the beta form occurs in situ with aging (12, 13). The non-isomerized ALPHA CTX is mostly found in newly formed bone. In addition to being an indicator of newly formed bone, urinary ALPHA CTX has been shown to be a sensitive marker for detection and monitoring of skeletal metastases corresponding to sites of high bone turnover (13–15). Type II collagen is the most abundant collagen in articular cartilage representing 10–20% of the wet weight of cartilage (16). The CTXII epitope, 1230EKGPDP1235, is located on the C-telopeptide fragment of type II collagen. Urinary CTXII has been associated with both OA severity and progression (17–19). In addition to biochemical markers of disease, there is great interest in the utility of imaging markers as indicators of disease. Dieppe, et. al. were the first to report the association of increased subchondral bone turnover, detected by bone scintigraphy, with progression of knee OA (20, 21). More recently, bone scintigraphy has been identified as a sensitive indicator of severity of radiographic features and symptoms of knee OA (22). Radiographic features have recently been used to identify distinct phenotypes of osteoarthritis progression including a bone-specific phenotype (23). These studies and others (24) support a role for bone in the pathophysiology of progressive cartilage degradation and OA symptoms. The goal of this study was to evaluate the association of two markers of matrix destruction, uALPHA CTX, a marker of high turnover and new bone resorption, and uCTXII, a marker of type II collagen degradation, with OA severity and progression in a cohort of subjects with baseline bone scintigraphy and longitudinal radiographic knee evaluation over 3 years.