Soluble Biomarkers of Osteoporosis and Osteoarthritis, from Pathway Mapping to Clinical Trials: An Update

Abstract

Serum biomarkers of osteoarticular diseases have been in the limelight of current clinical research trends. Laboratory validation of defined and candidate biomarkers for both osteoarthritis and osteoporosis is of key importance for future decisional algorithms in the diagnosis, monitoring, and prognosis of these diseases. The current guidelines recommend the use of collagen degradation remnants, eg, CTX-I and CTX-II, in the complementary diagnosis of both osteoporosis and osteoarthritis. Besides the collagen degradation markers, enzymes that regulate bone and articular metabolism are useful in the clinical evaluation of osteoarticular pathologies. Along these, several other recommended and new nominee molecules have been recently studied. Wnts and Wnt-related molecules have a cardinal role in the bone-joint homeostasis, making them a promising target not only for pharmaceutical modulation, but also to be considered as soluble biomarkers. Sclerostin and dickkopf, two inhibitor molecules of the Wnt/β-catenin signaling, might have a dual role in the assessment of the clinical manifestations of the osteoarticular unit. In osteoarthritis, besides fragments of collagen type II many pathway-related molecules have been studied and proposed for biomarker validation. The most serious limitation is that a significant proportion of studies lack statistical power due to the reduced number of cases enrolled. Serum biomarkers of bone and joint turnover markers represent an encouraging possibility for the diagnosis and prognosis of osteoarticular diseases, although further studies and laboratory validations should be carried out as to solely rely on them.

Keywords: biomarkers; osteoarthritis; osteoporosis.

Figure 1

Metabolic imbalance is the source of biomarkers in osteoporosis In osteoporosis, a balanced activity between osteoblasts and osteoclasts is of utmost importance. An imbalance between the bone-forming and disturbing activities on the hand of the latter results in altered bone formation and eventually osteoporosis. Bone turnover biomarkers are promising candidates to monitor these molecular changes in this microcosm. Collagen type I produced by osteoblasts is of key importance in bone integrity and homeostasis. Under proteolytic activity promoted by osteoclast derived CTSK, collagen type I is degraded into several remnants, like CTX-I, NTX, PYD, and DPD. These collagen degradation products are candidate molecules for laboratory diagnosis of osteoporosis from biological fluids (patients’ sera and urine), CTX-I being currently the most widely accepted BTM for this clinical purposes. On the other hand, procollagens and osteocalcin are key participants in bone metabolism. According to the current guidelines PINP is considered the clinical counterpart of CTX-I, as a BTM of osteoporosis. Wnt signal molecules have a cardinal role in the interplay of cellular participants in bone tissues. Osteocyte derived sclerostin and DKKs secreted by BMSCs and osteoblasts, as inhibitors of the Wnt pathways and subsequently bone formation are two nominee molecules for future perspectives. Arrows in green represent activation or secretory mechanisms. Arrows in red indicate inhibition or degradation mechanisms. Abbreviations: DPD, deoxypyridinoline; PYD, pyridinoline; NTX, amino-terminal cross-linking telopeptide of type I collagen; CTSK, cathepsin K; CTX, carboxy-terminal cross-linking telopeptide of type I collagen; TRACP, tartrate-resistant acid phosphatase; OC, osteocalcin ; PICP, procollagen type I C propeptide; PINP, procollagen type I N propeptide ; ALP, alkaline phosphatase; BALP, bone-specific alkaline phosphatase.

Figure 2

The basic structures of the cartilage, molecular sources and main groups of osteoarthritis biomarkers. Superficial and deep cartilage, synovial membrane and the subchondral bone marrow are all affected in osteoarthritis. Inflammatory cells invade the synovial membrane, the subchondral bone suffers intense remodeling, and the metabolic turnover of the extracellular matrix components is high. Collagen type II fragments: CTX-II, Coll2-1, Helix II, C2M are cleaved and released in the synovial fluid and the blood. Collagen I, III, vitronectin and proteoglycans are also excessively degraded, which results in the loss of matrix. The main groups of osteoarthritis biomarkers: cartilage turnover/anabolic markers, proinflammatory cytokines/chemokines, collagen II fragments, matrix metalloproteinases, and various homeostatic molecules are shown in boxes. Abbreviations: CTX-II, carboxy-terminal cross-linking telopeptide of type II collagen; Coll2-1, collagen type II degradation nonapeptide; C2M, collagen type II degradation hexapeptide.