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J Biol Chem, Vol. 275, Issue 5, 3335-3342, February 4, 2000

Parathyroid Hormone-activated Volume-sensitive Calcium Influx Pathways in Mechanically Loaded Osteocytes^*

From the ^a National Sanatorium Hyogo Chuo Hospital, Sanda, Hyogo 669-1515, ^d Pharmaceutical Research Division, Takeda Chemical Industries Limited, Yodogawa-ku, Osaka 532-8686, ^e Department of Oral Biochemistry, Kanagawa Dental College, Yokosuka 238-8580, ^f Department of Orthodontics, Tokushima University Dental School, Tokushima 770-0042, ^g Department of Orthodontics, Okayama University Dental School, Shikatacho, Okayama 700-8525, ^h First Department of Oral Anatomy, Meikai University School of Dentistry, Sakado, Saitama 350-0248, ^b Third Division, Department of Medicine, Kobe University School of Medicine, Kobe 650-0017, and ⁱ Calcium Research Institute, Kishiwada 596-0842, Japan

This paper documents for the first time a volume-sensitive Ca²⁺ influx pathway in osteocytes, which transmits loading-induced signals into bone formation. Stretch loading by swelling rat and chicken osteocytes in hypo-osmotic solution induced a rapid and progressive increase of cytosolic calcium concentration, [Ca²⁺]_i. The influx of extracellular Ca²⁺ explains the increased [Ca²⁺]_i that paralleled the increase in the mean cell volume. Gadolinium chloride (Gd³⁺), an inhibitor of stretch- activated cation channels, blocked the [Ca²⁺]_i increase caused by hypotonic solutions. Also, the expression of 1C subunit of voltage-operated L-type Ca²⁺ channels (1C) is required for the hypotonicity-induced [Ca²⁺]_i increase judging from the effect of 1C antisense oligodeoxynucleotides. Parathyroid hormone (PTH) specifically potentiated the hypotonicity-induced [Ca²⁺]_i increase in a dose-dependent manner through the activation of adenyl cyclase. The increases induced by both PTH and hypotonicity were observed primarily in the processes of the osteocytes. In cyclically stretched osteocytes on flexible-bottomed plates, PTH also synergistically elevated the insulin-like growth factor-1 mRNA level. Furthermore, Gd³⁺ and 1C antisense significantly inhibited the stretch-induced insulin-like growth factor-1 mRNA elevation. The volume-sensitive calcium influx pathways of osteocytes represent a mechanism by which PTH potentiates mechanical responsiveness, an important aspect of bone formation.

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