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Evidence that the Cells Responsible for Marrow Fibrosis in a Rat Model for Hyperparathyroidism Are Preosteoblasts

Department of Nutrition and Exercise Science (S.L., R.T.T.), Oregon State University, Corvallis, Oregon 97331; and Life Sciences Division (J.D.S.), Universities Space Research Association, Houston, Texas 77058

Address all correspondence and requests for reprints to: Russell T. Turner, Department of Nutrition and Exercise Science, 108 Milam Hall, Oregon State University, Corvallis, Oregon 97331. E-mail: russell.turner{at}oregonstate.edu.

We examined proliferation of cells associated with PTH-induced peritrabecular bone marrow fibrosis in rats as well as the fate of those cells after withdrawal of PTH. Time-course studies established that severe fibrosis was present 7 d after initiation of a continuous sc PTH infusion (40 µg/kg·d). To ascertain cell proliferation, rats were coinfused for 1 wk with PTH (treated) or vehicle (control) and [³H]thymidine (1.5 mCi/rat). Groups of control and treated rats were killed immediately (d 0) and 1 wk (d 7) later. Few osteoblasts (Obs) and osteocytes in treated and control groups were radiolabeled on d 0. Peritrabecular cells expressing a fibroblastic (Fb) phenotype and surrounded by an extracellular matrix were not present in controls on either d 0 or d 7. Multiple cell layers of Fbs lined most (70%) of the bone surface on d 0 in treated rats and nearly all (85%) of the Fbs were radiolabeled. Fbs had entirely disappeared from bone surfaces on d 7. Eighty-five percent of the Obs on and 73% of the osteocytes within the active remodeling sites were radiolabeled. Immunohistochemistry revealed that Fbs induced by PTH treatment produced osteocalcin, osteonectin, and core binding factor-1. These data provide compelling evidence that Fbs recruited to bone surfaces in response to a continuous PTH infusion undergo extensive proliferation, express osteoblast-specific proteins, and produce an extracellular matrix that is similar to osteoid. After restoration of normal PTH levels, Fbs differentiated to Obs, providing further evidence that Fbs are preosteoblasts.

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