ARTHRITIS & RHEUMATISM Vol. 64, No. 4, April 2012, pp 1193–1203 DOI 10.1002/art.33445 © 2012, American College of Rheumatology Regulation of Subchondral Bone Osteoblast Metabolism by Cyclic Compression Christelle Sanchez, 1 Laurence Pesesse, 1 Odile Gabay, 2 Jean-Pierre Delcour, 3 Philippe Msika, 4 Caroline Baudouin, 4 and Yves E. Henrotin 1 Objective. Recent data have shown that abnormal subchondral bone remodeling plays an important role in osteoarthritis (OA) onset and progression, and it was suggested that abnormal mechanical pressure applied to the articulation was responsible for these metabolic changes. This study was undertaken to evaluate the effects of cyclic compression on osteoblasts from OA subchondral bone. Methods. Osteoblasts were isolated from sclerotic and nonsclerotic areas of human OA subchondral bone. After 28 days, the osteoblasts were surrounded by an abundant extracellular matrix and formed a resistant membrane, which was submitted to cyclic compression (1 MPa at 1 Hz) for 4 hours. Gene expression was evaluated by reverse transcription–polymerase chain reaction. Protein production in culture supernatants was quantified by enzyme-linked immunosorbent assay or visualized by immunohistochemistry. Results. Compression increased the expression of genes coding for interleukin-6 (IL-6), cyclooxygenase 2, RANKL, fibroblast growth factor 2, IL-8, matrix metal- loproteinase 3 (MMP-3), MMP-9, and MMP-13 but reduced the expression of osteoprotegerin in osteoblasts in both sclerotic and nonsclerotic areas. Col1(I) and MMP-2 were not significantly affected by mechanical stimuli. Nonsclerotic osteoblasts were significantly more sensitive to compression than sclerotic ones, but after compression, differences in messenger RNA levels between nonsclerotic and sclerotic osteoblasts were largely reduced or even abolished. Under basal condi- tions, sclerotic osteoblasts expressed similar levels of 5, v, 1, and 3 integrins and CD44 as nonsclerotic osteoblasts but 30% less connexin 43, an important mechanoreceptor. Conclusion. Genes involved in subchondral bone sclerosis are mechanosensitive. After compression, non- sclerotic and sclerotic osteoblasts expressed a similar phenotype, suggesting that compression could be re- sponsible for the phenotype changes in OA subchondral osteoblasts. Osteoarthritis (OA) is a common cause of dis- ability in the elderly, and is characterized by cartilage degradation, synovium and tendon inflammation, mus- cle weakness, osteophyte formation, and subchondral bone plate thickening (1). Although it is not yet clear if it precedes (2–4) or occurs subsequent to (5–7) cartilage damage, subchondral bone sclerosis is an important feature in OA pathophysiology, with local bone resorp- tion and accumulation of weakly mineralized osteoid substance (8). Subchondral bone sclerosis is suspected to be linked to cartilage degradation, not only by modifying the mechanical properties of subchondral bone (9), but also by releasing biochemical factors that affect cartilage metabolism (10–12). Thus, understanding of the mech- anisms leading to bone sclerosis would be an important factor in efforts to improve the treatment of OA. Previous studies have demonstrated that osteoblasts from sclerotic OA subchondral bone are phenotypically different from nonsclerotic osteoblasts (13–16). We have shown that osteoblasts from the thickened (sclerotic) subchondral bone located just below the main cartilage lesion had increased alkaline phosphatase activity and Supported in part by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal Diseases, NIH. Dr. Sanchez is a postdoctoral researcher at the FNRS; her work was supported by a postdoctoral research grant from the FNRS. 1 Christelle Sanchez, PhD, Laurence Pesesse, Bsc, Yves E. Henrotin, PhD: University of Lie `ge, Lie `ge, Belgium; 2 Odile Gabay, PhD: National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, Maryland; 3 Jean-Pierre Delcour, MD: Cen- tre Hospitalier du Bois de l’Abbaye, Seraing, Belgium; 4 Philippe Msika, PhD, Caroline Baudouin, PhD: Laboratoires Expanscience, Epernon, France. Address correspondence to Yves E. Henrotin, PhD, Bone and Cartilage Research Unit, Institute of Pathology, CHU Bat B23, B-4000 Lie `ge, Belgium. E-mail: yhenrotin@ulg.ac.be. Submitted for publication December 17, 2010; accepted in revised form October 20, 2011. 1193