Different Presentation of Bone Mass in Mice and Humans with Congenital Leptin Deficiency

Metin Ozata

Department of Endocrinology and Metabolism, Gülhane School of Medicine, TR-06018 Etlik/Ankara, Turkey

Address requests for reprints to: Metin Ozata, M.D., Associate Professor of Medicine, Department of Endocrinology and Metabolism, Gülhane School of Medicine, TR-06018 Etlik/Ankara, Turkey. or metinozata{at}hotmail.com

To the editor:

I read with great interest the editorial by Karsenty (1) on the importance of leptin in the control of bone mass and usefulness of the dialogue between clinical medicine and animal experimentation. In this regard, as a clinician, I would like to mention about the different presentation of bone mass in mice and humans with congenital leptin deficiency.

The obese are usually protected against osteoporosis and have increased bone mineral density (BMD) and plasma leptin levels (2, 3). The mechanism by which obesity protects people from osteoporosis is still a mystery (4). This has been previously attributed to the mechanical effects of their excessive weight on bone tissue. A recent in vitro study demonstrated that leptin enhances osteoblast differentiation but suppresses adipocyte differentiation in bone marrow, suggesting a role for leptin in bone metabolism (5). Ducy et al. (6) recently demonstrated that ob/ob and db/db mice have higher bone mass than normal mice despite hypogonadism and hypercortisolism. It is well known that hypogonadism causes bone resorption and hypercortisolism suppresses bone formation. Ducy et al. (6) demonstrated that high bone mass in these mice is due to an increase in bone formation, which per se is a result of an absent leptin signaling pathway. However, they have suggested that effects of leptin on bone were indirect because intracerebroventricular administration of leptin in normal and ob/ob mice caused low bone mass and they were not able to identify leptin receptor on osteoblasts. However, this central control by leptin on bone is not mediated via Neuropeptide Y. Ducy et al. (6) have also suggested that leptin may use two different pathways to regulate the control of body weight and bone mass, and their findings indicate neuroendocrine control mechanism. In contrast, Steppan et al. (7) have recently demonstrated that primary adult osteoblasts and chondrocytes have long leptin receptor and leptin signaling and that the effect of leptin on bone was more likely to be direct. Thus, additional studies are needed to clarify this issue.

We have previously demonstrated a missense mutation in the gene encoding leptin in four morbidly obese individuals consisting of three adults and one child, from a highly consanguineous Turkish family. This mutation is shown to occur at the same location as that found in the ob/ob mice, but this was a missense instead of nonsense mutation (8, 9). Consistent with the rodent model of leptin deficiency, congenital leptin deficiency in humans was also associated with hypogonadotropic hypogonadism and morbid obesity. We found alterations in PTH-calcium and BMD in leptin-deficient patients (9). Male homozygous patient had PTH levels in the normal range; however, BMD of the spine showed osteopenia [BMD of L2–L4, 0.924 g/cm2; bone mineral content (BMC), 52.60 g; t-score, -1.96; z-score, -2.36]. In contrast, a female adult homozygous patient has elevated PTH levels on repeated measurements, several days apart, and low total calcium and ionized calcium levels. She had normal BMD (L2–L4, 1.042 g/cm2; BMC, 46.049; t-score, 0.0; z-score, -0.17). Another female adult homozygous patient had PTH levels in the upper normal range, normal calcium level, and normal BMD (L2–L4, 1.185 g/cm2; BMC, 54.47 g; t-score, 1.23; z-score, 1.06). The homozygous female child had high PTH levels but her plasma ionized calcium level was normal. We did not find any abnormalities in PTH-calcium in any heterozygous or wild-type members of the family. BMD in two heterozygous males are normal (BMD of L2–L4, 0.981 g/cm2; BMC, 69.14 g; t-score, -1.00; z-score, -1.00; and BMD of L2–L4, 1.082 g/cm2; BMC, 65.60 g; t-score, -0.08; z-score, -0.08, respectively). Although the plasma osteocalcin level in the homozygous male subject was slightly higher (20.1 ng/ml, normal, 3.1–13.7 ng/ml), urinary hydroxypiroline was in the normal range (15.3 mg/24 h, normal, 2–17 mg/24 h) which shows that osteopenia in this homozygous patient may possibly result from decreased bone formation but not bone resorption. Although osteocalcin levels are in the normal range in two male heterozygous subjects (13.5 and 13.8 ng/ml; normal, 3.1–13.7 ng/ml), urinary hydroxyproline levels are slightly higher in heterozygous male subjects (26.8 and 22.4 mg/24 h; normal, 2–17 mg/24 h).

Contrary to high bone mass observed in ob/ob mice, one male carrying two copies of the defective leptin gene has osteopenia and two additional adult females have normal bone mass. Differences in hormonal environment seem to be the reason for distinct characteristics of bone metabolism in leptin-deficient humans and its respective mouse model. ob/ob mice have hypercortisolism, but humans do not. Furthermore, heterozygous ob/ob mice have also high bone mass. But in humans, heterozygous males have normal bone mass. An unknown sex-dependent factor may influence or modify the effects of leptin on bone, because males lacking leptin have osteopenia whereas females have normal bone mass. Alternatively, T deficiency may exert relatively more detrimental effects on bone or override defective leptin signaling in bone tissue. Thus, observations on leptin deficiency in mice may not be largely applicable for humans as also indicated by Himms-Hagen (10).

Taken together, data from leptin-deficient humans and mice suggest a role for leptin on bone, although mechanisms underlying different presentations in both mammals are yet to be defined.

Received July 6, 2001.

References

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