Several studies [
3‐
5] demonstrated that treatment
in vivo with parathyroid gland extract (PTE) resulted in increased bone synthesis of hexosamine-containing compound(s). Based on such findings, Severson et al. [
6] used organ cultures of neonatal mouse calvaria, treated with PTE and then labeled with
3H-glucosamine (glcN), to demonstrate that PTE caused a 4-fold increase in papain-resistant macromolecular material that was identified as hyaluronic acid, now called hyaluronan (HA). Luben and coworkers provided data that clearly linked parathyroid hormone (PTH)-induced synthesis of HA to bone resorption. Using organ cultures of bones pre-labeled
in vivo with
45Ca
++, they demonstrated that
in vitro treatment with PTH followed by radiolabeling with
3H-glcN resulted in a 3–4-fold increase in HA synthesis [
7]. This increase was detectable by 4 h and was maximal at 24 h. Changes in
45Ca
++ release followed a parallel course but with a delayed onset (24 h) and peak (48 h). Addition of HA, hyaluronidase or glucosamine to the culture medium in the absence or presence of PTH had no significant effect on
45Ca
++ release. Using a similar system to assay calcium release and HA synthesis, Luben and Cohn [
8] also found that addition of calcitonin to PTH-stimulated cultures caused HA synthesis and, subsequently, calcium release to return to control levels. After 24 h in the presence of both hormones, an "escape" phenomenon [
9] was observed, i.e., the rate of HA synthesis and calcium release again increased, with the former preceding the latter. These data strongly linked induction of HA synthesis to osteoclastic resorption, prompting the authors to suggest "that a change in hyaluronate synthesis is a metabolic prerequisite for demineralization". Luben et al., [
7] speculated that the role for HA in bone resorption could be to act as a calcium binding agent, to act as a barrier to the diffusion of enzymes away from the resorption site or to regulate the mobility of osteoclasts or osteoclast precursor cells. To our knowledge, none of these possibilities has been proven nor excluded and all deserve additional exploration.
Thus, though HA's role was not known, sufficient evidence existed linking HA to bone resorption that Wong and coworkers [
10,
11] utilized PTH stimulation of HA synthesis as a specific marker during the purification of osteoclastic cells. The studies cited above and others prompted Stern and Raisz [
12] to comment in a discussion of markers of bone resorption that "hyaluronic acid seems to be the most appropriate for study because, unlike the other biochemical changes, it has been clearly linked to bone resorption."