ates the T3 stimulated expression dose dependently in mouse osteoblasts [7] but shows a synergistic effect on the T3 regulation in rat osteosarcoma cells [9]. In human osteoblasts, T3 attenuates the 1,25D3-induced transcription of OCN [10,11]. Clinically, OCN, a marker protein of the mature osteoblasts, is routinely used as a serum marker for bone formation [12], as well as for bone turnover [13] and gains an increasing importance as a marker for malignancies such as prostate carcinoma [14,15] and leukemia [16].Recently, it was clearly demonstrated that the uncarboxylated form of OCN functions as a hormone regulating glucose metabolism and fat mass in mice [1]. It affects pancreatic ß-cell proliferation by regulating Cyclin D1 and Cdk4 expression. Moreover, OCN increases the expression of insulin as well as genes regulating adipocyte development and differentiation [17].Like OCN, MMP-13 (collagenase-3) has a double Abstract. Osteocalcin (OCN), the most abundant non-collagenous protein of the bone matrix, whose function is not fully understood, was recently suggested to act as endocrine factor regulating energy metabolism. Besides OCN, osteoblasts also express MMP-13, a matrix metallo-proteinase important for bone development and remodeling. Although differentially, both genes are regulated by 1,25-dihydroxy vitamin D3 (1,25D3) and T3, important hormones for bone metabolism. In mouse osteoblasts with a distinct differentiation status, T3 increases the expression of both proteins. By contrast, 1,25D3 stimulates the expression of MMP-13 but inhibits the expression of OCN in these cells. In humans, however, 1,25D3 upregulates both genes while T3 inhibits the OCN expression. using northern blot hybridization we studied gene expression in the mouse osteoblastic cell line MC3T3-e1. We show that MMP-13 expression was strongly increased by T3 when the stimulation of OCN was low and, inversely, that the MMP-13 increase was low when T3 strongly stimulated the OCN expression. These findings suggest an interrelationship between OCN and MMP-13 expression. In fact, we observed that externally added OCN attenuated the T3 induced MMP-13 expression dose dependently and, furthermore, increased the 1,25D3 stimulated MMP-13 expression. using a protein kinase A inhibitor we were able to show that this inhibitor mimics the effect of OCN suggesting a PKA dependent pathway to be involved in this regulatory process. We therefore hypothesize that OCN is a modulator of the hormonally regulated MMP-13 expression. [6,7]. By contrast, T3 -induced OCN-expression is specific for murine osteoblasts [7,8]. 1,25D3, however, attenu-