Induction of osteoclast formation by parathyroid hormone depends on an action on stromal cells

Abstract

It is believed that parathyroid hormone (PTH) increases the resorptive activity of pre-existing osteoclasts through a primary interaction with cells of the osteoblastic lineage. Much less is known, however, of the mechanisms by which PTH induces osteoclast formation. It is known that osteoclast formation occurs through a contact-dependent interaction between stromal cells and haemopoietic precursors, but it is not known whether PTH acts on stromal cells or precursors to induce osteoclast formation. To address this issue, we compared the ability of haemopoietic cultures to generate osteoclasts, identified as calcitonin receptor positive (CTRP) cells, and to resorb bone in response to PTH and 1,25(OH) 2 vitamin D 3 (1,25(OH) 2 D 3 ). We found that when murine haemopoietic tissues were incubated at densities sufficiently high to support haemopoiesis, both PTH and 1,25(OH) 2 D 3 induced bone resorption in bone marrow cells, but in cultures of haemopoietic spleen only 1,25(OH) 2 D 3 induced CTRP cells, and neither hormone induced bone resorption. To determine whether these differences were attributable to differences in stromal cells or haemopoietic precursors, lower densities of haemopoietic spleen cells were incubated on osteoblastic (UMR 106), splenic or bone marrow stromal cells. We found that the behaviour of the cocultures reflected the characteristics and origin of the stromal cells. Thus, the ability of both osteoblastic and splenic stromal cells to induce CTRP cells with 1,25(OH) 2 D 3 , while only osteoblastic cells induced osteoclasts with PTH, from the same precursors, suggests that the ability of PTH to induce osteoclastic differentiation cannot be attributed to a hormonal action on osteoclast precursors, but depends on a response in stromal cells.

The Role of Parathyroid Hormone‐Related Protein in the Regulation of Osteoclastogenesis by Cementoblasts

“…Additional soluble RANKL in this system was also enough to promote TRAP-positive cells to a similar extent as that induced by PTHrP. In contrast to our results, Fuller et al reported no additive effect with the combination of PTHrP and RANKL on osteoblasts, 34 but in the present study with cementoblasts, this combination significantly increased the number of TRAPpositive multinucleated osteoclasts in co-culture.…”

Parathyroid hormone regulates the distribution and osteoclastogenic potential of hematopoietic progenitors in the bone marrow

“…In contrast, most of the literature agrees that osteoclasts and their precursor cells lack high-affinity PTH receptors. (3,(6)(7)(8) Therefore, it has been proposed that the effects of PTH on osteoclasts are indirect. (9) The PTH receptor on target cells is activated by the binding of PTH or PTHrP.…”

The Multifaceted Actions of PTHrP in Skeletal Metastasis

“…In bone, the PPR is primarily expressed in osteoblasts, osteocytes and bone marrow stromal cells such as osteoblast precursor cells. Osteoclasts do not express the PPR, as demonstrated by the lack of response to PTH [22]. The actions of PTH and PTHrP in osteoclasts are mediated by osteoblasts and osteocytes responsible for secretion of factors that activate osteoclasts.…”