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Accelerated Cartilage Resorption by Chondroclasts during Bone Fracture Healing in Osteoprotegerin-Deficient Mice

Departments of Orthopaedic Surgery (N.O., H.T., N.K., J.T., M.Y., T.T., K.C., H.I., Y.T.), Pathology (T.K., Y.O.), and Spine and Spinal Cord Disease (M.M.), School of Medicine, Keio University, Tokyo 160-8582, Japan; Nagahama Institute for Biochemical Science (H.Y.), Oriental Yeast Co., Ltd., Shiga 526-0804, Japan; and Sensory and Motor system Medicine (H.K.), Faculty of Medicine, University of Tokyo, Tokyo 113-8655, Japan

Address all correspondence and requests for reprints to: Dr. Hironari Takaishi, Department of Orthopaedic Surgery, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. E-mail: hironari{at}sc.itc.keio.ac.jp.

Receptor activator of nuclear factor-B ligand (RANKL) and osteoprotegerin (OPG), a decoy receptor of RANKL, maintain bone mass by regulating the differentiation of osteoclasts, which are bone-resorbing cells. Endochondral bone ossification and bone fracture healing involve cartilage resorption, a less well-understood process that is needed for replacement of cartilage by bone. Here we describe the role of OPG produced by chondrocytes in chondroclastogenesis. Fracture healing in OPG^–/– mice showed faster union of the fractured bone, faster resorption of the cartilaginous callus, and an increased number of chondroclasts at the chondroosseous junctions compared with that in wild-type littermates. When a cultured pellet of OPG^–/– chondrocytes was transplanted beneath the kidney capsule, the pellet recruited many chondroclasts. The pellet showed the ability to induce tartrate-resistant acid phosphatase-positive multinucleated cells from RAW 264.7 cells in vitro. Finally, OPG^–/– chondrocytes (but not wild-type chondrocytes) cultured with spleen cells induced many tartrate-resistant acid phosphatase-positive multinucleated cells. The expression of RANKL and OPG in chondrocytes was regulated by several osteotropic factors including 1,25-dihydroxyvitamin D₃, PTHrP, IL-1, and TNF-. Thus, local OPG produced by chondrocytes probably controls cartilage resorption as a negative regulator for chondrocyte-dependent chondroclastogenesis.